Compositions and inhibitors of polrmt

Abstract

The present invention provides novel oxadiazole compounds and compounds that are inhibitors of mitochondrial RNA polymerase.

Description

COMPOSITIONS AND INHIBITORS OF POLRMT CROSS-REFERENCE TO APPLICATIONS

[0001] The present application claims priority to US provisional application number 63 / 546,388 filed on October 30, 2023, the entirety of which is incorporated herein. FIELD OF THE INVENTION

[0002] The present disclosure relates to POLRMT modulators, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The present disclosure also relates to novel oxadiazole compositions, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The present disclosure also relates to methods of making the modulator compounds and / or oxadiazole compositions. The present disclosure further relates to methods of using such compounds and compositions, including to inhibit or promote POLRMT. BACKGROUND OF THE INVENTION

[0003] Human mitochondrial RNA polymerase, POLRMT (also referred to as h- mtRNAP), is a nuclear-encoded single-subunit DNA-dependent RNA polymerase. POLRMT is 1230 amino acids in length and consists of three distinct regions: (1) a C- terminal polymerase domain (CTD) (residues 648–1230); (2) an N-terminal domain (NTD) (residues 369–647); and (3) an N- terminal extension (NTE) (residues 1–368). See, e.g., Arnold, J.J., et al., “Human mitochondrial RNA polymerase: Structure-function, mechanism and inhibition,” Biochim. Biophys. Acta, 1819, 948-960 (2012). It is structurally related to the single-subunit RNA polymerase encoded by bacteriophage T7. The CTD is also known as the catalytic domain due to its function of catalyzing nucleotide incorporation into a growing RNA molecule during transcription. This domain is highly conserved across species, whereas by contrast the NTE demonstrates significant sequence variability, suggesting organism-specific roles for this domain of POLRMT.

[0004] POLRMT is of fundamental importance for both expression and replication of the human mitochondrial genome. While aspects of POLRMT biochemistry are known, its full physiological role in mitochondrial gene expression and homeostasis, as well as its underlying impact in the etiology of various disease states, remains unclear. Its dysfunction and / or deregulation impacts mitochondrial metabolism, sometimes through the OXPHOS system, which ultimately contributes to many metabolic, degenerative and age-related diseases such as cancer, diabetes, obesity, and Alzheimer's disease. Pharmacological inhibition of POLRMT is one means by which to gain a further understanding of the role of this polymerase in cell physiologyand the development of disease. Regulation of metabolic mechanisms, including oxidative phosphorylation, with POLRMT modulators affords an opportunity for intervention in complex disorders. In view of the numerous and varied roles of POLRMT, the need exists for potent and specific modulators of POLRMT. SUMMARY OF THE INVENTION

[0005] Briefly, therefore, the present disclosure is directed to compounds, pharmaceutically acceptable salts of the compounds, and methods of using the compounds, salts of the compounds to treat various neurodegenerative and metabolic disorders, cancer, and also disorders related to aging and mitochondrial diseases.

[0006] In a first aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by Formula (I),

[0007] In some embodiments, X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, - C(O)NHY1, -C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2.

[0008] In some embodiments, Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0009] In some embodiments, X6-X8 are each independently a C, N, S, or O.

[0010] In some embodiments, R3is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0011] In some embodiments, R4is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0012] In some embodiments, if R3and R4are optionally interconnected they form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5- membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0013] In some embodiments, A1 and A2 are each independently a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6 heterocyclyl, substituted C3-C6heterocyclyl, or absent.

[0014] In some embodiments, A1 and A2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a -CY1S(O)2Y3.

[0015] In some embodiments, Y3is independently hydrogen or C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, C1-C4haloalkoxyl, and C1-C4alkoxyl.

[0016] Some aspects of the present disclosure include compounds described above, wherein the compound has a POLRMT IC50of 200 nM or less.

[0017] Some aspects of the present disclosure include a pharmaceutical composition comprising a compound according to any of the previous claims.

[0018] Some aspects of the present disclosure are directed towards a method of inhibiting the activity of POLRMT comprising administering a compound of any of the previous claims to a subject in need thereof.

[0019] Other aspects and iterations of the present disclosure are detailed below. DETAILED DESCRIPTION OF THE INVENTION

[0020] Modulators of POLRMT are useful in compositions and methods suitable for treating many disorders, such as cancer, neurodegenerative disorders, metabolic disorders, as well as diseases related to aging and mitochondrial diseases. Provided herein are novel compositions, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Provided herein are compounds of Formulae (I), (IIa), (IIa-2), (IIb-1), (IIb-2)a, (IIc), (IIc-1), (IIc-2a), (IIc-2b), (IId), (IIe), (IIf), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (Va), (Va-1), (Vb), and (Vb-1) pharmaceutically acceptable salts thereof, prodrugs thereof, and pharmaceutical compositions comprising such compounds, their salts, or their prodrugs that are useful as inhibitors of POLRMT.(I) Definitions

[0021] The term “alkyl” as used herein refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range. For example, the term “C1-C6alkyl” means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, or 6 carbon atoms. Furthermore, alkyl groups allow for substituents to be located on any of the carbon atoms. For example, a substituted C3alkyl group allows for the substituent to be located on any of the three carbon atoms.

[0022] The term “alkoxy” or “alkoxyl” as used herein refers to an -O-alkyl group. For example, the term “ C1-C4alkoxyl” means -O- C1-C4alkyl. Examples of alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.

[0023] The term “haloalkoxy” or “haloalkoxyl” as used herein refers to an -O-alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced with a halogen atom. Examples of haloalkoxyl include trifluoromethoxyl, 2,2,2-trifluoroethoxyl, and the like.0027 The term “alkanoyl” or “acyl” as used herein refers to an -C(O)-alkyl group. For example, the term “C1-C6alkanoyl” means -C(O)-C1-C6alkyl. Examples of alkanoyl include acetyl, propionyl, butyryl, and the like.

[0024] The term “bicyclic” as used herein refers to a saturated or unsaturated 6- to 12- membered ring consisting of two joined cyclic substructures, and includes fused, bridged, and spiro bicyclic rings.

[0025] The term “heterobicyclic” as used herein refers to a bicyclic ring that contains 1 or more heteroatom(s) in one or more rings that are optionally substituted or oxidized, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. Examples of heterobicyclic rings include, but are not limited to, 8-azabicyclo[3.2.1]octan-8- yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, and 5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl.

[0026] The term “cycloalkyl” as used herein refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specified range. Thus, for example, “ C3-C6cycloalkyl” encompasses each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] The term “aryl” as used herein refers to a monocyclic or fused bicyclic ring system having the characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system. Typically, aryl groups contain 6 to 14 carbon atoms (“C6- C14aryl”) or preferably, 6 to 12 carbon atoms (“C6-C12aryl”). Fused aryl groups may include anaryl ring (e.g., a phenyl ring) fused to another aryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such fused aryl ring systems may be a C atom of the aromatic portion or a C or N atom of the non-aromatic portion of the ring system. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, indanyl, indenyl, and tetrahydronaphthyl.

[0028] The term “cycloaryl” herein refers to a polycyclic group wherein an aryl group is fused to a 5- or 6-membered aliphatic or heterocyclic ring. For example, “C6-C12cycloaryl” means a C6- C12aryl fused to a 5- or 6-membered aliphatic or heterocyclic ring. One example of C6cycloaryl is 2,3-dihydrobenzo[b][1,4]dioxine.

[0029] The term “heteroaryl” as used herein refers to (i) a 5- or 6-membered ring having the characteristics of aromaticity containing at least one heteroatom selected from N, O and S, wherein each N is optionally in the form of an oxide, and (ii) a 9- or 10- membered bicyclic fused ring system, wherein the fused ring system of (ii) contains at least one heteroatom independently selected from N, O and S, wherein each ring in the fused ring system contains zero, one or more than one heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)2. Typically, heteroaryl groups contain 5 to 14 ring atoms (“5-14 membered heteroaryl”), and preferably 5 to 12 ring atoms (“5-12 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, 3-fluroropyridyl, 4-fluoropyridyl, 3- methoxypyridyl, 4-methoxypyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or 1,2,4- triazolyl), tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl (i.e., the 1,2,3-, 1,2,4-, 1,2,5- (furazanyl), or 1,3,4- isomer), oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, chromenyl, quinolinyl, isoquinolinyl, benzopiperidinyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, indazolyl, indolinyl, and isoindolinyl.

[0030] The term “heteroaryloxy” or “heteroaryloxyl” as used herein refers to an -O- heteroaryl group.0035 The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein represents a stable 3- to 10-membered monocyclic, non-aromatic ring that is either saturated or unsaturated, and that consists of carbon atoms and from one to two heteroatoms selected from the group consisting of N, O, and S. Examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, and oxazepanyl.

[0031] The term “oxo” as used herein refers to a group which consists of oxygen which is double bonded to carbon or any other element.

[0032] The term “imine” as used herein refers to a group containing a carbon-nitrogen double bond.

[0033] The term “carboxyl” as used herein refers to a combination of two functional groups attached to a single carbon atom, namely, hydroxyl (OH) and carbonyl (O).

[0034] The term “optionally substituted” or “optional substituents” as used herein means that the groups are either unsubstituted or substituted with one or more of the substituents specified. When the groups are substituted with more than one substituent, the substituents may be the same or different. Furthermore, when using the terms “independently,” “independently are,” and “independently selected from” mean that the groups may be the same or different.

[0035] The term “deuterium” as used herein refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium herein is represented by the symbol “D”.

[0036] The term “deuterated” by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon. For example, the term “deuterated compound” refers to a compound which contains one or more carbon-bound deuterium(s). In a deuterated compound of the present invention, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015 %.

[0037] The term “undeuterated” or “non-deuterated” as used herein refers to the ratio of deuterium atoms of which is not more than the natural isotopic deuterium content, which is about 0.015 %; in other words, all hydrogen are present at their natural isotopic percentages. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.

[0038] The term “isotopic enrichment factor” as used herein refers to the ratio between the isotope abundance and the natural abundance of a specified isotope.

[0039] The term “isotopologue” as used herein refers to a species in which the chemical structure differs from a specific compound of the invention only in the isotopic composition thereof.

[0040] The term “substantially free of other stereoisomers” as used herein means less than 10 % of other stereoisomers, preferably less than 5 % of other stereoisomers, more preferably less than 2 % of other stereoisomers and most preferably less than 1 % of other stereoisomers are present.

[0041] The term “pharmaceutically acceptable salt” as used herein refers to a salt that is not biologically or otherwise undesirable (e.g., not toxic or otherwise harmful). A salt of a compound of the invention is formed between an acid and a basic group of the compound, or a base and an acidic group of the compound. For example, when the compounds of the invention contain at least one basic group (i.e., groups that may be protonated), the invention includes the compounds in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid. When compounds of the invention contain one or more acidic groups (e.g., a carboxylic acid), the invention includes the pharmaceutically acceptable salts of the compounds formed with but not limited to alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Additional examples of such salts may be found in Stahl, P. H. et al. Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, Wiley, 2011.

[0042] The term “prodrug” as used herein refers to derivatives of compounds of the invention which may have reduced pharmacological activity, but can, when administered to a patient, be converted into the inventive compounds. Design and use of prodrugs may be found in “Pro- drugs as Novel Delivery Systems,” Vol.14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. The terms “treatment”, “treating” and “treat” as used herein, include their generally accepted meanings, i.e., the management and care of a patient for the purpose of preventing, reducing the risk in incurring or developing a given condition or disease, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, delaying, or reversing the progression or severity, and holding in check existing characteristics of a disease, disorder, or pathological condition, including the alleviation or relief of symptoms or complications, or the cure or elimination of the disease, disorder, or condition.

[0043] The term “therapeutically effective amount” as used herein refers to that amount of compound of the invention that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other. As will be recognized by a person of ordinary skill in the art, a therapeutically effective amount of the compounds of the invention will vary and will depend on the diseases treated, the severity of the disease, the route of administration, and the gender, age, and general health condition of the subject to whom the compound is being administered. The therapeutically effective amount may be administered as a single dose once a day, or as split doses administered multiple (e.g., two, three or four) times a day. The therapeutically effective amount may also be administered through continuous dosing, such as through infusion or with an implant. (II) Compounds A. General Structures

[0044] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (I):wherein X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2;Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy; X6-X8are each independently a C, N, S, or O; R3is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl; R4is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen; if R3and R4are optionally interconnected they form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring; A1and A2are each independently a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6heterocyclyl, substituted C3-C6heterocyclyl, or absent; wherein A1and A2may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a -CY1S(O)2Y3; Y3is independently a hydrogen or a C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl; with the proviso that formula (I) excludes the following compounds: 5-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-3-[1-(5-fluoro-2- methylphenyl)cyclopropyl]-1,2,4-oxadiazole; 3-[1-(3-methylphenyl)cyclopropyl]-5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazole; 3-[1-(3-Methoxyphenyl)cyclopropyl]-5-[5-(1-methylethyl)-1H-pyrazol-3-yl]-1,2,4- oxadiazole; 3-[1-(5-fluoro-2-methylphenyl)cyclopropyl]-5-(5-methoxy-1-methyl-1H-pyrazol-3-yl)- 1,2,4-oxadiazole; 5-(1-methyl-1H-pyrazol-3-yl)-3-(1-phenylcyclopropyl)-1,2,4-oxadiazole; 3-[1-(3,5-Dimethylphenyl)cyclopropyl]-5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazole; 1-methyl-5-(3-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2,3-dihydro- 1H-pyrazol-3-ol, 1,2-Dihydro-1-methyl-5-[3-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]-1,2,4- oxadiazol-5-yl]-3H-pyrazol-3-one;5-(1-Methyl-1H-pyrazol-5-yl)-3-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]-1,2,4- oxadiazole; 3-[1-(3-Methoxyphenyl)cyclopropyl]-5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazole; 3-[1-(3-Bromophenyl)cyclopropyl]-5-(1-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazole; and 5-(3-Ethyl-1-methyl-1H-pyrazol-5-yl)-3-[1-(3-methylphenyl)cyclopropyl]-1,2,4- oxadiazole.

[0045] In some aspects, X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2, wherein Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0046] In some aspects, X6-X8may each independently be a C, N, S, or O.

[0047] In some aspects, R3may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0048] In some aspects, R4may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0049] In other aspects, R3 and R4 may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0050] In some aspects, A1 and A2 may each independently be a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6heterocyclyl, substituted C3-C6heterocyclyl, or absent.

[0051] In some aspects, A1 and A2 are each independently be one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a - CY1S(O)2Y3, wherein Y3may be independently a hydrogen or a C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl.

[0052] In some aspects, A1and A2may each independently be -C(O)NY3Y4, -CY1(O)NY3Y4, or - NY3Y4. In some aspects, Y3is independently a hydrogen or a C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl. In some asptects, Y4is independently Y3, cyano, C3-C6cycloheteroalkyl, C1-C6amide, C1-C6amine, C1-C6carboxyl, aryl, C1-C6alkyl optionallysubstituted with one or more halogen groups, 5- or 6-membered heterocyclyl, or C3-C6cycloalkyl, C1-C6alkoxy, C1-C6hydroxy, or -C(O)C1-C4alkyl optionally substituted with one or more halogen groups. In yet other aspects, Y3and Y4are attached to the same nitrogen atom, Y3and Y4together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing one or more heteroatoms that is N, O, S, S(O), SO2, or S(O)NY3, and such heterocyclic ring is optionally substituted with one or more groups, each group independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxyl, C1-C4haloalkoxyl, carboxyl, oxo, and C1-C4^alkylcarboxylate. B. Compounds with Formulae (IIa-1) and (IIa-2)

[0053] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IIa-1):

[0054] In some aspects, X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2, wherein Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0055] In some aspects, R3may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0056] In some aspects, R4 may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0057] In other aspects, R3and R4may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-memberedheterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0058] In some aspects, R10-R15may each independently be a hydrogen, an alkoxy, a halogen, a C1-C6alkyl, or a carboxylic acid.

[0059] In some examples, X1may be a C1-C6alkyl or a halogen.

[0060] In some examples, X2may be a hydrogen or a halogen.

[0061] In some examples, X3may be a hydrogen, a halogen, or a C1-C6alkyl.

[0062] In some examples, X4may be hydrogen.

[0063] In some examples, X5may be a hydrogen or a C1-C6alkyl.

[0064] In some examples, at least two of X2- X5are hydrogen.

[0065] In some examples, at least three of X2- X5are hydrogen.

[0066] In some examples, X2- X5may be hydrogen.

[0067] In some examples, X1may be methyl or Cl.

[0068] In some examples, X2may be Cl or hydrogen and X3may be methyl, F, Cl, or hydrogen.

[0069] In some examples, R3may be a hydrogen, a methyl or -CHF2.

[0070] In some examples, R4may be hydrogen.

[0071] In some examples, R10-R15may each independently be a hydrogen, a methyl, a methoxy, a halogen, a carboxylic acid, or an amide.

[0072] In some examples, R3may be -CHF2, methyl, or hydrogen, and R4is hydrogen.

[0073] In some examples, the X1may be halogen or methyl and R3may be methyl, -CHF2, or - CF3.

[0074] In some examples, the X2may be hydrogen or halogen and R3may be methyl, -CHF2, or -CF3.

[0075] In some examples, the X3may be hydrogen or halogen and R3may be methyl, -CHF2, or -CF3.

[0076] In some examples, X1-X3may each be independently hydrogen, halogen, or methyl, and R3may be methyl, -CHF2, or -CF3.

[0077] In some examples, X1-X3may each be independently hydrogen, halogen, or methyl, and R3-R4are independently hydrogen, methyl, -CHF2, or -CF3.

[0078] In some examples, at least one of R10-R15is carboxylic acid.

[0079] In some examples, at least one of R10-R11is carboxylic acid

[0080] In some examples, at least one of R12-R13is carboxylic acid

[0081] In some examples, at least one of R14-R15is carboxylic acid.

[0082] In some examples, R12-R13may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.

[0083] In some examples, R10-R11and R14-R15may be hydrogen and the compound may be represented by Formula (IIa-2):

[0084] In some embodiments of Formula (IIa-2), X1-X5may each independently be hydrogen, halogen, or C1-C6alkyl.

[0085] In some embodiments of Formula (IIa-2), R3may be halogen, hydrogen, C1-C6alkyl, substituted C1-C6alkyl, or C3-C6cycloalkyl.

[0086] In some embodiments of Formula (IIa-2), R4 may be hydrogen, C1-C6alkyl, or substituted C1-C6alkyl.

[0087] In some embodiments of Formula (IIa-2), R12and R13are each independently a C1-C6alkyl, a hydrogen, a halogen, a carboxylic acid, an alkoxy, or an amide.

[0088] In some embodiments of Formula (IIa-2), X1may be methyl.

[0089] In some embodiments of Formula (IIa-2), X3may be a halogen or a hydrogen.

[0090] In some embodiments of Formula (IIa-2), X2, X4, and X5may be hydrogen.

[0091] In some embodiments of Formula (IIa-2), R3may be hydrogen, C1-C6alkyl, or substituted C1-C6alkyl.

[0092] In some embodiments of Formula (IIa-2), R4may be hydrogen.

[0093] In some embodiments of Formula (IIa-2), R12and R13may each independently be hydrogen, carboxylic acid, alkoxy, or amide.

[0094] In some embodiments of Formula (IIa-2), X1may be methyl, X2, X4, and X5are hydrogen, X3may be a halogen or a hydrogen, R3may be hydrogen, C1-C6alkyl, or substituted C1-C6alkyl, R4may be hydrogen, and R12and R13may each independently be hydrogen, carboxylic acid, alkoxy, or amide.

[0095] In some embodiments of Formula (IIa-2), R3 may be difluoromethyl.

[0096] In some embodiments of Formula (IIa-2), R10may be carboxylic acid and R11may be hydrogen.

[0097] In some embodiments of Formula (IIa-2), R10may be amide and R11may be hydrogen.

[0098] In some embodiments of Formula (IIa-2), X1may be a halogen.

[0099] In some embodiments of Formula (IIa-2), X2may be hydrogen or halogen.

[0100] In some embodiments of Formula (IIa-2), X3may be methyl, halogen, or hydrogen.

[0101] In some embodiments of Formula (IIa-2), X4and X5may be hydrogen

[0102] In some embodiments of Formula (IIa-2), X1may be a halogen, X2is hydrogen or halogen, X3is methyl, halogen, or hydrogen, and X4and X5are hydrogen.

[0103] In some embodiments of Formula (IIa-2), R3may be difluoromethyl and R4may be hydrogen

[0104] In some embodiments of Formula (IIa-2), R12and R13are each independently hydrogen or carboxylic acid.

[0105] In some embodiments of Formula (IIa-2), R10may be carboxylic acid and R11may be methoxy.

[0106] In some embodiments of Formula (IIa-2), R10may be carboxylic acid and R11may be methyl. C. Compounds with Formulae (IIb-1) & (IIb-2)

[0107] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formulae (IIb-1) & (IIb-2):Formula (IIb-1); or

[0108] In some aspects, X1-X5may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2, wherein Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0109] In some aspects, R3may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0110] In some aspects, R4 may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0111] In other aspects, R3 and R4 may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0112] In some aspects, R20-R29may each independently be a hydrogen, a C1-C6alkyl, a carboxylic acid, an amide, a substituted amide, an alkoxy, or a halogen.

[0113] In some examples, X1may be a C1-C6alkyl.

[0114] In some examples, X1may be a methyl.

[0115] In some examples, X2and X4may be hydrogen.

[0116] In some examples, X3may be a hydrogen or halogen.

[0117] In some examples, X5may be a hydrogen or a C1-C6alkyl.

[0118] In some examples, at least two of X2- X5may be hydrogen.

[0119] In some examples, at least three of X2- X5may be hydrogen.

[0120] In some examples, X2-X5may be hydrogen.

[0121] In some examples, R3may be a hydrogen, a methyl, or -CHF2.

[0122] In some examples, R4may be hydrogen.

[0123] In some examples, R20-R29are each independently a hydrogen, a C1-C6alkyl, an alkoxy, a halogen, a carboxylic acid, amide, or a substituted amide.

[0124] In some examples, the substituted amide may be substituted with one or more C1-C6alkyl.

[0125] In some examples, at least one of R20-R29 may be carboxylic acid, amide, or substituted amide.

[0126] In some examples, at least one of R20-R21 may be carboxylic acid, amide, or substituted amide.

[0127] In some examples, at least one of R22-R23 may be carboxylic acid, amide, or substituted amide.

[0128] In some examples, at least one of R24-R25 may be carboxylic acid, amide, or substituted amide.

[0129] In some examples, at least one of R26-R27 may be carboxylic acid, amide, or substituted amide.

[0130] In some examples, at least one of R28-R29 may be carboxylic acid, amide, or substituted amide.

[0131] In some examples, X1 may be halogen or methyl and R3 may be hydrogen, methyl, CHF2, or CF3.

[0132] In some examples, X2 may be hydrogen or halogen and R3 may be hydrogen, methyl, CHF2, or CF3.

[0133] In some examples, X3 may be hydrogen or halogen and R3 may be hydrogen, methyl, CHF2, or CF3.

[0134] In some examples, X1-X3 may each independently be hydrogen, halogen, or methyl, and R3is H, methyl, CHF2, or CF3.

[0135] In some examples, X1-X3may each independently be hydrogen, halogen, or methyl, X4- X5may each independently be hydrogen or halogen, and R3-R4may independently be hydrogen, methyl, CHF2, or CF3.

[0136] In some examples, X1-X3may each independently be hydrogen, fluorine, chlorine, bromine, or methyl, X4-X5are each independently hydrogen or halogen, and R3-R4are independently hydrogen, methyl, CHF2, or CF3.

[0137] In some examples, at least one of R20-R29may be carboxylic acid.

[0138] In some examples, at least one of R20-R23may be carboxylic acid.

[0139] In some examples, at least one of R24-R25may be carboxylic acid.

[0140] In some examples, at least one of R26-R29may be carboxylic acid.

[0141] In some examples, R24-R25may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.

[0142] In some examples, R24-R25may each independently be hydrogen or carboxylic acid.

[0143] In some examples, wherein R3and R4may be interconnected to form a 5-membered cyclic ring.

[0144] In some examples, R3and R4may be interconnected to form a phenyl ring. D. Compounds with Formulas (IIc), (IIc-1), (IIc-2a), and (IIc-2b)

[0145] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IIc):

[0146] In some aspects, X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2. Y1and Y2may each be independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0147] In some aspects, R3may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0148] In some aspects, R4 may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0149] In other aspects, R3and R4may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0150] In other aspects, A3is a hydrogen, a C1-C6alkyl, a C2-C6branched alkyl, a C1-C6alkyl substituted with heterocyclyl, a C1-C6alkyl substituted with a substituted heterocyclyl, or a C1-C6alkyl substituted C1-C6alkoxy.

[0151] In other aspects, B is -C(O)OH, -C(O)NH2, C(O)NHY3, C(O)NY3Y4, -CS(O)2Y3, - Y3CS(O)2Y3, or absent. Y3and Y4may each independently be a C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl.

[0152] In some examples, X1 is a hydrogen, a halogen, a cyano, a C1-C6alkyl, a substituted C1- C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, a C1-C6cycloalkoxy, - COOH, -C(O)NH2, -C(O)NHY1, or -C(O)NY1Y2and Y1and Y2are methyl.

[0153] In some examples, X1 is a C1-C6alkyl. For examples, the C1-C6alkyl may be methyl or ethyl.

[0154] In some examples, X1 is halogen. For example, the halogen may be fluorine, chlorine, or bromine.

[0155] In some examples, the C3-C6cycloalkyl may be cyclopropyl

[0156] In some examples, X1 may be -CH2OCH3, -CH2OH, or -CF3.

[0157] In some examples, X1 may be -C(O)NH2, -C(O)NHCH3, or -C(O)NCH3CH3.

[0158] In some examples, X2 and X3 may be a hydrogen, a halogen, or a C1-C6alkyl.

[0159] In some examples, X4 may be a hydrogen, a halogen, a hydroxy, a methoxy, a C1-C6alkyl, or a substituted C1-C6alkyl. For example, the substituted C1-C6alkyl may be -CH2OH.

[0160] In some examples, X5 may be a hydrogen, halogen, hydroxy, methoxy, a C1-C6alkyl, or a substituted C1-C6alkyl.

[0161] In some examples, A3may be a C1-C6alkyl or substituted C1-C6alkyl and B is carboxylic acid. For example, A3may be methyl, ethyl, 1-methyl-methyl, dimethyl-methyl, methyl ethyl, dimethyl ethyl, or methyl-cyclopropyl. Furthermore, the methyl may be connected to a thiazole via a carbon-carbon bond. The methyl may also be connected to a phenyl or a cyclopropyl.

[0162] In some aspects, the substituted C1-C6alkyl may be substituted methyl, substituted ethyl, or substituted propyl. For example, the substituted methyl may be -C(H)(CH3).Alternatively, the substituted ethyl may be -CH2CH(OCH3), -CH2CH(OH), - CH2C(CH3)H, or CH2C(CH3)2.

[0163] In some examples, X1may be C1-C6alkyl or halogen.

[0164] In some examples, X2may be hydrogen or halogen.

[0165] In some examples, X3may be hydrogen, C1-C6alkyl, or halogen.

[0166] In some examples, X4may be hydrogen.

[0167] In some examples, X1may be C1-C6alkyl or hydrogen.

[0168] In some examples, R3may be C1-C6alkyl substituted with one or more halogen. For example, R3 may be -CHF2or -CF3.

[0169] In some examples, R4 may be hydrogen.

[0170] In some examples, X1-X5 may each independently be hydrogen, a halogen, or a C1-C6alkyl.

[0171] In some examples, X3-X4 may each independently be hydrogen, methyl, cyclopropyl, - CHF2, or -CF3.

[0172] In some examples, A3 may be substituted with at least one halogen, ester, ether, or carboxylic acid.

[0173] In some examples, A3 may be substituted with at least one -C(O)NH2, -CS(O)2Y3, or - CY1S(O)2Y3.

[0174] In some examples, B may be carboxylic acid, amide, methanesulfonamide, methoxy, substituted amide, amine, substituted amine, or substituted sulfoxide.

[0175] In some examples, B may be amine or substituted amine with Formula (IIc-1):

[0176] In some embodiments of Formula (IIc-1), X1 may be a C1-C6alkyl.

[0177] In some embodiments of Formula (IIc-1), X2-X5 may be hydrogen.

[0178] In some embodiments of Formula (IIc-1), R3may be -CHF2.

[0179] In some embodiments of Formula (IIc-1), R4may be hydrogen.

[0180] In some embodiments of Formula (IIc-1), A3may be a C1-C6alkyl.

[0181] In some embodiments of Formula (IIc-1), B3and B4may each independently be hydrogen or a C1-C6alkyl.

[0182] In some embodiments of Formula (IIc-1), X1is a C1-C6alkyl, X2-X5are hydrogen, R3is - CHF2, R4is hydrogen, A3 is a C1-C6alkyl; and B3and B4are each independently hydrogen or a C1-C6alkyl.

[0183] In some examples, B may be amide or substituted amide with Formula (IIc-2a) or Formula (IIc-2b):Formula (IIc-2a); or

[0184] In some embodiments of Formulae (IIc-2a) and (IIc-2b), X1may be C1-C6alkyl or halogen.

[0185] In some embodiments of Formulae (IIc-2a) and (IIc-2b), X2-X4may be hydrogen or halogen.

[0186] In some embodiments of Formulae (IIc-2a) and (IIc-2b), X5may be hydrogen, halogen, or C1-C6alkyl.

[0187] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R3may be -CHF2, -CF3or a C3- C6cycloalkyl.

[0188] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R4 may be hydrogen.

[0189] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be a C1-C6alkyl or branched C1-C6alkyl.

[0190] In some embodiments of Formulae (IIc-2a) and (IIc-2b), B3 and B4 may be each independently hydrogen, a C1-C6alkyl, a substituted a C1-C6alkyl, a C3-C6cycloalkyl, a substituted a C3-C6cycloalkyl, a C3-C6heterocyclyl, a substituted a C3-C6heterocyclyl, phenyl, substituted phenyl.

[0191] In some embodiments of Formulae (IIc-2a) and (IIc-2b), if B3and B4are optionally interconnected they form a 4-membered, 5- membered, 6- membered cycloalkyl ring, substituted cycloalkyl ring, heterocyclyl ring, or substituted heterocyclyl ring.

[0192] In some embodiments of Formulae (IIc-2a) and (IIc-2b), B5 and B6 may each independently be hydrogen or C1-C6alkyl.

[0193] In some embodiments of Formulae (IIc-2a) and (IIc-2b), the C1-C6alkyl may be methyl of ethyl.

[0194] In some embodiments of Formulae (IIc-2a) and (IIc-2b), the branched C1-C6alkyl may be -CH2(CH3)-.

[0195] In some embodiments of Formulae (IIc-2a) and (IIc-2b), the substituted C1-C6alkyl may be - CH2CH2OCH3, -CH2C(CH3)2OH, -CH2CH2OH, -CH2COOH, -CH(CH3)COOH, - C(CH3)2COOH, methyl-pyridyl, methyl-methyl substituted-pyridyl, methyl cyclopropyl, methyl cyclobutyl, -CH2CONH2,CH2CONHCH3, -CH2CH2N(CH3)2, -CH(CH3)CONH2, or -CH2CF3.

[0196] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be ethyl and B may be methanesulfonamide

[0197] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be ethyl and B may be methoxy.

[0198] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be ethyl and B may be substituted sulfoxide.

[0199] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R3 may be -CHF2, halogen, cyclopropyl, or methyl.

[0200] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R4 may be hydrogen or methyl.

[0201] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R3 and R4 may be connected to form a 5-membered cycloalkyl ring. E. Compounds with Formula (IId)

[0202] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IId):

[0203] In some aspects, X1-X5may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2. Y1and Y2may each be independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0204] In some aspects, R3 may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0205] In some aspects, R4 may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0206] In other aspects, R3 and R4 may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0207] In some aspects, R30-R34 may each independently be a hydrogen, a carboxylic acid, an ester, a halogen, an amide, a substituted amide, a cyano, an ether, or a C1-C6alkyl.

[0208] In some examples, X1 may be a C1-C6alkyl or a halogen. The C1-C6alkyl may be methyl. The halogen may be chlorine.

[0209] In some examples, X2 and X4 may each independently be a hydrogen or a halogen.

[0210] In some examples, X3 may be a hydrogen, a C1-C6alkyl or a halogen. The C1-C6alkyl may be methyl. The halogen may be chlorine or fluorine

[0211] In some examples, X5may be a C1-C6alkyl or a hydrogen.

[0212] In some examples, at least two of X2-X5may be hydrogen.

[0213] In some examples, at least three of X2-X5may be hydrogen.

[0214] In some examples, X2-X5may be hydrogen.

[0215] In some examples, R3may be C1-C6alkyl or C1-C6alkyl substituted with one or more halogen. The C1-C6alkyl substituted with one or more halogen may be -CHF2. The C1-C6alkyl may be methyl.

[0216] In some examples, R4 may be hydrogen.

[0217] In some examples, R30-R34 may be hydrogen.

[0218] In some examples, R30 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

[0219] In some examples, R31 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

[0220] In some examples, R32 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

[0221] In some examples, R33 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

[0222] In some examples, R34 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

[0223] In some examples, at least two of R30-R34 may be hydrogen, -OCH3, -COOH, -C(O)NH2, -C(O)NHCH3, cyano, methyl, - C(O)OCH3, or fluorine.

[0224] In some examples, X1-X5 may each independently be hydrogen, halogen, Cl, F, or methyl, and R3-R4are independently H, methyl, CHF2, or CF3.

[0225] In some examples, at least one of R30-R34 may be carboxylic acid.

[0226] In some examples, at least one of R30-R34 may be amide.

[0227] In some examples, at least one of R30-R34may be ester.

[0228] In some examples, at least one of R30-R34may be ether.

[0229] In some examples, at least one of R30-R34may be cyano.

[0230] In some examples, at least one of R30-R34may be methyl.

[0231] In some examples, at least two of R30-R34may be carboxylic acid, amide, ester, ether, cyano, or methyl.F. Compounds with Formula (IIe)

[0232] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IIe):wherein X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2; Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy; R3 is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C10cycloalkyl; R4 is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen; if R3 and R4 are optionally interconnected they form a C3-C10cycloalkyl, a substituted C3-C10cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring; and R40-R43 are independently hydrogen, a C1-C6alkyl, or a substituted C1-C6alkyl.

[0233] In some embodiments, X1may be a C1-C6alkyl or a halogen. In some examples, X1may be methyl. In some examples, X1may be chlorine.

[0234] In some embodiments, X2, X4, and X5may be hydrogen.

[0235] In some embodiments, X3may be a hydrogen or halogen.

[0236] In some embodiments, at least two of X2-X5may be hydrogen.

[0237] In some embodiments, at least three of X2-X5may be hydrogen.

[0238] In some embodiments, X2-X5 may be hydrogen.

[0239] In some embodiments, R3 may be straight or branched C1-C6alkyl optionally substituted with one or more halogen. For example, the straight or branched C1-C6alkyl may be substituted with one or more fluorine.

[0240] In some embodiments, R3 may be -CHF2or -CF3.

[0241] In some embodiments, R4 may be hydrogen.

[0242] In some embodiments, X1-X3 may each independently be hydrogen, fluorine, chlorine, bromine, or methyl, X4-X5 may each independently be hydrogen or halogen, and R3-R4 may each independently be hydrogen, methyl, -CHF2, or -CF3. G. Compounds with Formula (IIf)

[0243] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IIf):wherein X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2; Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy; Y is carbon or nitrogen; R30-R34are each independently a hydrogen, a carboxylic acid, a halogen, an amide, a substituted amide, a cyano, a C1-C6alkyl, or absent; R3 is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl; R4 is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen; if R3 and R4 are optionally interconnected they form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring; and R30-R34 are each independently be a hydrogen, a carboxylic acid, an ester, a halogen, an amide, a substituted amide, a cyano, an ether, a C1-C6alkyl, or absent.

[0244] In some embodiments, X1 and X2 may be halogen. The halogen may be fluorine or chlorine.

[0245] In some embodiments, X2, X3, and X5 may be hydrogen.

[0246] In some embodiments, at least two of X2-X5 may be hydrogen.

[0247] In some embodiments, at least three of X2-X5 may be hydrogen.

[0248] In some embodiments, at least one Y may be nitrogen.

[0249] In some embodiments, R30-R34 may each independently be a hydrogen or absent.

[0250] In some embodiments, R3 may be -CH(CH3)2. H. Compounds with Formulae (III), (IIIa), (IIIb), (IV), (IVa), and (IVb)

[0251] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (III) or Formula (IV):

[0252] In some aspects, X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2. Y1and Y2may each be independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy.

[0253] In some aspects, R3may be a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl.

[0254] In some aspects, R4may be a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen.

[0255] In other aspects, R3and R4may optionally be interconnected to form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0256] In some aspects, A1and A2may each independently be a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6heterocyclyl, substituted C3-C6heterocyclyl, or absent. A1and A2may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a -CY1S(O)2Y3. Y3may independently be a hydrogen or a C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl.

[0257] In some aspects, the present disclosure is directed to a compound with any one or Formulae (IIIa), (IIIb), (IVa), and (IVb):

[0258] In some embodiments, X1may be C1-C6alkyl.

[0259] In some embodiments, X2, X3, and X5may be hydrogen.

[0260] In some embodiments, X4may be hydrogen or fluorine.

[0261] In some embodiments, A1and A2may each be independently a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6heterocyclyl, or substituted C3-C6heterocyclyl. A1and A2may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a -CY1S(O)2Y3.

[0262] In some embodiments, R3 may be C1-C6alkyl substituted with one or more halogen.

[0263] In some embodiments, R4 may be a hydrogen.

[0264] In some embodiments, X1 may be methyl.

[0265] In some embodiments, X4 may behydrogen or fluorine.

[0266] In some embodiments, at least two of X2-X5 may be hydrogen.

[0267] In some embodiments, at least three of X2-X5are hydrogen.

[0268] In some embodiments, A1and A2may be substituted C1-C6alkyl. A1and A2may be substituted ethyl. The ethyl may be substituted with carboxylic acid or amide.

[0269] In some embodiments, A1and A2may be -CH(CH3)COOH.

[0270] In some embodiments, A1and A2may be -CH2CH3COOH.

[0271] In some embodiments, A1and A2may be -CH2CH3CONH2.

[0272] In some embodiments, A1 and A2 may be substituted C3-C6cycloalkyl.

[0273] In some embodiments, the substituted C3-C6cycloalkyl may be a cyclobutyl or cyclohexyl substituted with one or more carboxylic acid.

[0274] In some embodiments, A1 and A2 may be substituted phenyl. The phenyl may be substituted with one or more carboxylic acid.

[0275] In some embodiments, R3 may be -CHF2or -CF3.

[0276] In some embodiments, X1-X5 may each independently be hydrogen, halogen, or methyl. I. Compounds with Formulae (Va), (Va-1), (Vb), or (Vb-1)

[0277] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (III) or Formula (IV):Formula (Vb); wherein X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2; Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy; A1 and A2 are each independently a hydrogen, a C1-C6alkyl, a substituted C1-C6alkyl, an aryl, substituted aryl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C3-C6heterocyclyl, substituted C3-C6heterocyclyl, or absent; wherein A1 and A2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH2, -CS(O)2Y3, a -CY1S(O)2Y3; Y3is independently a hydrogen or a C1-C4alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4haloalkoxyl, and a C1-C4alkoxyl; R3 is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C6cycloalkyl; and R4 is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen; if R3 and R4 are optionally interconnected they form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.

[0278] In some embodiments, A1-A2are independently hydrogen or methyl.

[0279] In some embodiments, X1-X5may be independently hydrogen, halogen, or methyl.

[0280] In some embodiments, R3-R4 may be independently hydrogen, -CHF2or -CF3.

[0281] In some aspects, A1 may be absent and the compound is with Formula (Va-1) or Formula (Vb-1):wherein: X1is C1-C6alkyl; X2, X3, and X5are hydrogen; X4is hydrogen or halogen; A2 is C1-C6alkyl; R3 is hydrogen or C1-C6alkyl substituted with one or more halogen; and R4 is hydrogen.

[0282] In some embodiments, at least two of X2-X5 may be hydrogen.

[0283] In some embodiments, at least three of X2-X5 may be hydrogen.

[0284] In some embodiments, X2-X5 may be hydrogen.

[0285] In some embodiments, the C1-C6alkyl may be methyl.

[0286] In some embodiments, the C1-C6alkyl substituted with one or more halogen may be - CHF2or -CF3.J. Compounds

[0287] The disclosure is intended to encompass the compounds listed below and the non- stereochemistry and the alternative stereochemistry of the compounds listed below.

[0288] In certain embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof:

[0289] In certain embodiments, the compound is Compound 2, or a pharmaceutically acceptable salt thereof:

[0290] In certain embodiments, the compound is Compound 3, or a pharmaceutically acceptable salt thereof:

[0291] In certain embodiments, the compound is Compound 4, or a pharmaceutically acceptable salt thereof:

[0292] In certain embodiments, the compound is Compound 5, or a pharmaceutically acceptable salt thereof:

[0293] In certain embodiments, the compound is Compound 6, or a pharmaceutically acceptable salt thereof:

[0294] In certain embodiments, the compound is Compound 7, or a pharmaceutically acceptable salt thereof:

[0295] In certain embodiments, the compound is Compound 8, or a pharmaceutically acceptable salt thereof:

[0296] In certain embodiments, the compound is Compound 9, or a pharmaceutically acceptable salt thereof:

[0297] In certain embodiments, the compound is Compound 10, or a pharmaceutically acceptable salt thereof:

[0298] In certain embodiments, the compound is Compound 11, or a pharmaceutically acceptable salt thereof:

[0299] In certain embodiments, the compound is Compound 12, or a pharmaceutically acceptable salt thereof:

[0300] In certain embodiments, the compound is Compound 13, or a pharmaceutically acceptable salt thereof:

[0301] In certain embodiments, the compound is Compound 14, or a pharmaceutically acceptable salt thereof:

[0302] In certain embodiments, the compound is Compound 15, or a pharmaceutically acceptable salt thereof:

[0303] In certain embodiments, the compound is Compound 16, or a pharmaceutically acceptable salt thereof:

[0304] In certain embodiments, the compound is Compound 17, or a pharmaceutically acceptable salt thereof:

[0305] In certain embodiments, the compound is Compound 18, or a pharmaceutically acceptable salt thereof:

[0306] In certain embodiments, the compound is Compound 19, or a pharmaceutically acceptable salt thereof:

[0307] In certain embodiments, the compound is Compound 20, or a pharmaceutically acceptable salt thereof:

[0308] In certain embodiments, the compound is Compound 21, or a pharmaceutically acceptable salt thereof:

[0309] In certain embodiments, the compound is Compound 22, or a pharmaceutically acceptable salt thereof:

[0310] In certain embodiments, the compound is Compound 23 or a pharmaceutically acceptable salt thereof:

[0311] In certain embodiments, the compound is Compound 24, or a pharmaceutically acceptable salt thereof:

[0312] In certain embodiments, the compound is Compound 25, or a pharmaceutically acceptable salt thereof:

[0313] In certain embodiments, the compound is Compound 26, or a pharmaceutically acceptable salt thereof:

[0314] In certain embodiments, the compound is Compound 27, or a pharmaceutically acceptable salt thereof:

[0315] In certain embodiments, the compound is Compound 28, or a pharmaceutically acceptable salt thereof:

[0316] In certain embodiments, the compound is Compound 29, or a pharmaceutically acceptable salt thereof:

[0317] In certain embodiments, the compound is Compound 30, or a pharmaceutically acceptable salt thereof:

[0318] In certain embodiments, the compound is Compound 31, or a pharmaceutically acceptable salt thereof:

[0319] In certain embodiments, the compound is Compound 32, or a pharmaceutically acceptable salt thereof:

[0320] In certain embodiments, the compound is Compound 33, or a pharmaceutically acceptable salt thereof:

[0321] In certain embodiments, the compound is Compound 34, or a pharmaceutically acceptable salt thereof:

[0322] In one embodiment, the compound is Compound 332, or a pharmaceutically acceptable salt thereof:

[0323] In one embodiment, the compound is Compound 333, or a pharmaceutically acceptable salt thereof:

[0324] In one embodiment, the compound is Compound 348, or a pharmaceutically acceptable salt thereof:

[0325] In one embodiment, the compound is Compound 349, or a pharmaceutically acceptable salt thereof:

[0326] In one embodiment, the compound is Compound 358, or a pharmaceutically acceptable salt thereof:

[0327] In one embodiment, the compound is Compound 359, or a pharmaceutically acceptable salt thereof:

[0328] In one embodiment, the compound is Compound 368, or a pharmaceutically acceptable salt thereof:

[0329] In one embodiment, the compound is Compound 369, or a pharmaceutically acceptable salt thereof:

[0330] In certain embodiments, the compound is Compound 35, or a pharmaceutically acceptable salt thereof:

[0331] In certain embodiments, the compound is Compound 36, or a pharmaceutically acceptable salt thereof:.

[0332] In certain embodiments, the compound is Compound 37, or a pharmaceutically acceptable salt thereof:

[0333] In certain embodiments, the compound is Compound 38, or a pharmaceutically acceptable salt thereof:

[0334] In certain embodiments, the compound is Compound 39, or a pharmaceutically acceptable salt thereof:

[0335] In certain embodiments, the compound is Compound 40, or a pharmaceutically acceptable salt thereof:

[0336] In certain embodiments, the compound is Compound 41, or a pharmaceutically acceptable salt thereof:

[0337] In certain embodiments, the compound is Compound 42, or a pharmaceutically acceptable salt thereof:

[0338] In certain embodiments, the compound is Compound 43, or a pharmaceutically acceptable salt thereof:

[0339] In certain embodiments, the compound is Compound 44, or a pharmaceutically acceptable salt thereof:

[0340] In certain embodiments, the compound is Compound 45, or a pharmaceutically acceptable salt thereof:.

[0341] In certain embodiments, the compound is Compound 46, or a pharmaceutically acceptable salt thereof:

[0342] In certain embodiments, the compound is Compound 47, or a pharmaceutically acceptable salt thereof:.

[0343] In certain embodiments, the compound is Compound 48, or a pharmaceutically acceptable salt thereof:

[0344] In certain embodiments, the compound is Compound 49, or a pharmaceutically acceptable salt thereof:

[0345] In certain embodiments, the compound is Compound 50, or a pharmaceutically acceptable salt thereof:

[0346] In certain embodiments, the compound is Compound 51, or a pharmaceutically acceptable salt thereof:

[0347] In certain embodiments, the compound is Compound 52, or a pharmaceutically acceptable salt thereof:

[0348] In one embodiment, the compound is Compound 316, or a pharmaceutically acceptable salt thereof:

[0349] In one embodiment, the compound is Compound 317, or a pharmaceutically acceptable salt thereof:

[0350] In one embodiment, the compound is Compound 335, or a pharmaceutically acceptable salt thereof:

[0351] In one embodiment, the compound is Compound 336, or a pharmaceutically acceptable salt thereof:

[0352] In one embodiment, the compound is Compound 346, or a pharmaceutically acceptable salt thereof:

[0353] In one embodiment, the compound is Compound 347, or a pharmaceutically acceptable salt thereof:

[0354] In one embodiment, the compound is Compound 355, or a pharmaceutically acceptable salt thereof:

[0355] In one embodiment, the compound is Compound 356, or a pharmaceutically acceptable salt thereof:

[0356] In one embodiment, the compound is Compound 366, or a pharmaceutically acceptable salt thereof:

[0357] In one embodiment, the compound is Compound 367, or a pharmaceutically acceptable salt thereof:

[0358] In certain embodiments, the compound is Compound 53, or a pharmaceutically acceptable salt thereof:

[0359] In certain embodiments, the compound is Compound 54, or a pharmaceutically acceptable salt thereof:

[0360] In certain embodiments, the compound is Compound 55, or a pharmaceutically acceptable salt thereof:

[0361] In certain embodiments, the compound is Compound 56, or a pharmaceutically acceptable salt thereof:

[0362] In certain embodiments, the compound is Compound 57, or a pharmaceutically acceptable salt thereof:

[0363] In certain embodiments, the compound is Compound 58, or a pharmaceutically acceptable salt thereof:

[0364] In certain embodiments, the compound is Compound 59, or a pharmaceutically acceptable salt thereof:

[0365] In certain embodiments, the compound is Compound 60, or a pharmaceutically acceptable salt thereof:

[0366] In certain embodiments, the compound is Compound 61, or a pharmaceutically acceptable salt thereof:

[0367] In certain embodiments, the compound is Compound 62, or a pharmaceutically acceptable salt thereof:

[0368] In certain embodiments, the compound is Compound 63, or a pharmaceutically acceptable salt thereof:

[0369] In certain embodiments, the compound is Compound 64, or a pharmaceutically acceptable salt thereof:

[0370] In certain embodiments, the compound is Compound 65, or a pharmaceutically acceptable salt thereof:

[0371] In certain embodiments, the compound is, Compound 66, or a pharmaceutically acceptable salt thereof:

[0372] In certain embodiments, the compound is, Compound 67, or a pharmaceutically acceptable salt thereof:

[0373] In certain embodiments, the compound is Compound 68, or a pharmaceutically acceptable salt thereof:

[0374] In certain embodiments, the compound is Compound 69, or a pharmaceutically acceptable salt thereof:

[0375] In certain embodiments, the compound is Compound 70, or a pharmaceutically acceptable salt thereof:.

[0376] In certain embodiments, the compound is Compound 71, or a pharmaceutically acceptable salt thereof:.

[0377] In certain embodiments, the compound is Compound 72, or a pharmaceutically acceptable salt thereof:

[0378] In certain embodiments, the compound is Compound 73, or a pharmaceutically acceptable salt thereof:

[0379] In certain embodiments, the compound is Compound 74, or a pharmaceutically acceptable salt thereof:

[0380] In certain embodiments, the compound is Compound 75, or a pharmaceutically acceptable salt thereof:

[0381] In one embodiment, the compound is Compound 319, or a pharmaceutically acceptable salt thereof:

[0382] In one embodiment, the compound is Compound 320, or a pharmaceutically acceptable salt thereof:

[0383] In one embodiment, the compound is Compound 324, or a pharmaceutically acceptable salt thereof:

[0384] In one embodiment, the compound is Compound 325, or a pharmaceutically acceptable salt thereof:

[0385] In one embodiment, the compound is Compound 326, or a pharmaceutically acceptable salt thereof:

[0386] In one embodiment, the compound is Compound 327, or a pharmaceutically acceptable salt thereof:

[0387] In one embodiment, the compound is Compound 328, or a pharmaceutically acceptable salt thereof:

[0388] In one embodiment, the compound is Compound 329, or a pharmaceutically acceptable salt thereof:

[0389] In one embodiment, the compound is Compound 330, or a pharmaceutically acceptable salt thereof:

[0390] In one embodiment, the compound is Compound 331, or a pharmaceutically acceptable salt thereof:

[0391] In one embodiment, the compound is Compound 334, or a pharmaceutically acceptable salt thereof:

[0392] In one embodiment, the compound is Compound 337, or a pharmaceutically acceptable salt thereof:

[0393] In one embodiment, the compound is Compound 338, or a pharmaceutically acceptable salt thereof:

[0394] In one embodiment, the compound is Compound 350, or a pharmaceutically acceptable salt thereof:

[0395] In one embodiment, the compound is Compound 351, or a pharmaceutically acceptable salt thereof:

[0396] In one embodiment, the compound is Compound 352, or a pharmaceutically acceptable salt thereof:

[0397] In one embodiment, the compound is Compound 353, or a pharmaceutically acceptable salt thereof:

[0398] In one embodiment, the compound is Compound 354, or a pharmaceutically acceptable salt thereof:

[0399] In one embodiment, the compound is Compound 357, or a pharmaceutically acceptable salt thereof:

[0400] In one embodiment, the compound is Compound 360, or a pharmaceutically acceptable salt thereof:

[0401] In one embodiment, the compound is Compound 361, or a pharmaceutically acceptable salt thereof:

[0402] In one embodiment, the compound is Compound 362, or a pharmaceutically acceptable salt thereof:

[0403] In one embodiment, the compound is Compound 363, or a pharmaceutically acceptable salt thereof:

[0404] In one embodiment, the compound is Compound 364, or a pharmaceutically acceptable salt thereof:

[0405] In one embodiment, the compound is Compound 365, or a pharmaceutically acceptable salt thereof:

[0406] In one embodiment, the compound is Compound 370, or a pharmaceutically acceptable salt thereof:

[0407] In one embodiment, the compound is Compound 371, or a pharmaceutically acceptable salt thereof:

[0408] In certain embodiments, the compound is Compound 76, or a pharmaceutically acceptable salt thereof:

[0409] In certain embodiments, the compound is Compound 77, or a pharmaceutically acceptable salt thereof:

[0410] In certain embodiments, the compound is Compound 78, or a pharmaceutically acceptable salt thereof:

[0411] In certain embodiments, the compound is Compound 79, or a pharmaceutically acceptable salt thereof:

[0412] In certain embodiments, the compound is Compound 80, or a pharmaceutically acceptable salt thereof:

[0413] In certain embodiments, the compound is Compound 81, or a pharmaceutically acceptable salt thereof:

[0414] In certain embodiments, the compound is Compound 82, or a pharmaceutically acceptable salt thereof:

[0415] In certain embodiments, the compound is Compound 83, or a pharmaceutically acceptable salt thereof:

[0416] In certain embodiments, the compound is Compound 84, or a pharmaceutically acceptable salt thereof:

[0417] In certain embodiments, the compound is Compound 85, or a pharmaceutically acceptable salt thereof:

[0418] In certain embodiments, the compound is Compound 86, or a pharmaceutically acceptable salt thereof:

[0419] In certain embodiments, the compound is Compound 87, or a pharmaceutically acceptable salt thereof:

[0420] In certain embodiments, the compound is Compound 88, or a pharmaceutically acceptable salt thereof:

[0421] In certain embodiments, the compound is Compound 89, or a pharmaceutically acceptable salt thereof:

[0422] In certain embodiments, the compound is Compound 90, or a pharmaceutically acceptable salt thereof:

[0423] In certain embodiments, the compound is Compound 91, or a pharmaceutically acceptable salt thereof:

[0424] In certain embodiments, the compound is Compound 92, or a pharmaceutically acceptable salt thereof:

[0425] In certain embodiments, the compound is Compound 93, or a pharmaceutically acceptable salt thereof:

[0426] In certain embodiments, the compound is Compound 94, or a pharmaceutically acceptable salt thereof:

[0427] In certain embodiments, the compound is Compound 95, or a pharmaceutically acceptable salt thereof:

[0428] In certain embodiments, the compound is Compound 96, or a pharmaceutically acceptable salt thereof:

[0429] In certain embodiments, the compound is Compound 97, or a pharmaceutically acceptable salt thereof:

[0430] In certain embodiments, the compound is Compound 98, or a pharmaceutically acceptable salt thereof:

[0431] In certain embodiments, the compound is Compound 99, or a pharmaceutically acceptable salt thereof:

[0432] In certain embodiments, the compound is Compound 100, or a pharmaceutically acceptable salt thereof:

[0433] In certain embodiments, the compound is Compound 101, or a pharmaceutically acceptable salt thereof:

[0434] In certain embodiments, the compound is Compound 102, or a pharmaceutically acceptable salt thereof:

[0435] In certain embodiments, the compound is Compound 103, or a pharmaceutically acceptable salt thereof:

[0436] In certain embodiments, the compound is Compound 104, or a pharmaceutically acceptable salt thereof:

[0437] In certain embodiments, the compound is Compound 105, or a pharmaceutically acceptable salt thereof:

[0438] In certain embodiments, the compound is Compound 106, or a pharmaceutically acceptable salt thereof:

[0439] In certain embodiments, the compound is Compound 107, or a pharmaceutically acceptable salt thereof:

[0440] In certain embodiments, the compound is Compound 108, or a pharmaceutically acceptable salt thereof:

[0441] In certain embodiments, the compound is Compound 109, or a pharmaceutically acceptable salt thereof:

[0442] In certain embodiments, the compound is Compound 110, or a pharmaceutically acceptable salt thereof:

[0443] In certain embodiments, the compound is Compound 111, or a pharmaceutically acceptable salt thereof:

[0444] In certain embodiments, the compound is Compound 112, or a pharmaceutically acceptable salt thereof:

[0445] In certain embodiments, the compound is Compound 113, or a pharmaceutically acceptable salt thereof:

[0446] In certain embodiments, the compound is Compound 114, or a pharmaceutically acceptable salt thereof:

[0447] In certain embodiments, the compound is Compound 115, or a pharmaceutically acceptable salt thereof:.

[0448] In certain embodiments, the compound is Compound 116, or a pharmaceutically acceptable salt thereof:

[0449] In certain embodiments, the compound is Compound 117, or a pharmaceutically acceptable salt thereof:

[0450] In certain embodiments, the compound is Compound 118, or a pharmaceutically acceptable salt thereof:

[0451] In certain embodiments, the compound is Compound 119, or a pharmaceutically acceptable salt thereof:

[0452] In certain embodiments, the compound is Compound 120, or a pharmaceutically acceptable salt thereof:

[0453] In certain embodiments, the compound is Compound 121, or a pharmaceutically acceptable salt thereof:

[0454] In certain embodiments, the compound is Compound 122, or a pharmaceutically acceptable salt thereof:

[0455] In certain embodiments, the compound is Compound 123, or a pharmaceutically acceptable salt thereof:

[0456] In certain embodiments, the compound is Compound 124, or a pharmaceutically acceptable salt thereof:

[0457] In certain embodiments, the compound is Compound 125, or a pharmaceutically acceptable salt thereof:

[0458] In certain embodiments, the compound is Compound 126, or a pharmaceutically acceptable salt thereof:

[0459] In certain embodiments, the compound is Compound 127, or a pharmaceutically acceptable salt thereof:

[0460] In certain embodiments, the compound is Compound 128, or a pharmaceutically acceptable salt thereof:

[0461] In certain embodiments, the compound is Compound 129, or a pharmaceutically acceptable salt thereof:

[0462] In certain embodiments, the compound is Compound 130, or a pharmaceutically acceptable salt thereof:

[0463] In certain embodiments, the compound is Compound 131, or a pharmaceutically acceptable salt thereof:

[0464] In certain embodiments, the compound is Compound 132, or a pharmaceutically acceptable salt thereof:

[0465] In certain embodiments, the compound is Compound 133, or a pharmaceutically acceptable salt thereof:

[0466] In certain embodiments, the compound is Compound 134, or a pharmaceutically acceptable salt thereof:

[0467] In certain embodiments, the compound is Compound 135, or a pharmaceutically acceptable salt thereof:

[0468] In certain embodiments, the compound is Compound 136, or a pharmaceutically acceptable salt thereof:

[0469] In certain embodiments, the compound is Compound 137, or a pharmaceutically acceptable salt thereof:

[0470] In certain embodiments, the compound is Compound 138, or a pharmaceutically acceptable salt thereof:

[0471] In certain embodiments, the compound is Compound 139, or a pharmaceutically acceptable salt thereof:

[0472] In certain embodiments, the compound is Compound 140, or a pharmaceutically acceptable salt thereof:

[0473] In certain embodiments, the compound is Compound 141, or a pharmaceutically acceptable salt thereof:

[0474] In certain embodiments, the compound is Compound 142, or a pharmaceutically acceptable salt thereof:

[0475] In certain embodiments, the compound is Compound 143, or a pharmaceutically acceptable salt thereof:

[0476] In certain embodiments, the compound is Compound 144, or a pharmaceutically acceptable salt thereof:.

[0477] In certain embodiments, the compound is Compound 145, or a pharmaceutically acceptable salt thereof:

[0478] In certain embodiments, the compound is Compound 146, or a pharmaceutically acceptable salt thereof:

[0479] In certain embodiments, the compound is Compound 147, or a pharmaceutically acceptable salt thereof:

[0480] In certain embodiments, the compound is Compound 148, or a pharmaceutically acceptable salt thereof:

[0481] In certain embodiments, the compound is Compound 149, or a pharmaceutically acceptable salt thereof:

[0482] In certain embodiments, the compound is Compound 150, or a pharmaceutically acceptable salt thereof:

[0483] In certain embodiments, the compound is Compound 151, or a pharmaceutically acceptable salt thereof:

[0484] In certain embodiments, the compound is Compound 152, or a pharmaceutically acceptable salt thereof:.

[0485] In certain embodiments, the compound is Compound 153, or a pharmaceutically acceptable salt thereof:

[0486] In certain embodiments, the compound is Compound 154, or a pharmaceutically acceptable salt thereof:

[0487] In certain embodiments, the compound is Compound 155, or a pharmaceutically acceptable salt thereof:

[0488] In certain embodiments, the compound is Compound 156, or a pharmaceutically acceptable salt thereof:

[0489] In certain embodiments, the compound is Compound 157, or a pharmaceutically acceptable salt thereof:

[0490] In certain embodiments, the compound is Compound 158, or a pharmaceutically acceptable salt thereof:

[0491] In certain embodiments, the compound is Compound 159, or a pharmaceutically acceptable salt thereof:

[0492] In certain embodiments, the compound is Compound 160, or a pharmaceutically acceptable salt thereof:

[0493] In certain embodiments, the compound is Compound 161, or a pharmaceutically acceptable salt thereof:

[0494] In one embodiment, the compound is Compound 162, or a pharmaceutically acceptable salt thereof:

[0495] In one embodiment, the compound is Compound 163, or a pharmaceutically acceptable salt thereof:

[0496] In one embodiment, the compound is Compound 164, or a pharmaceutically acceptable salt thereof:

[0497] In one embodiment, the compound is Compound 165, or a pharmaceutically acceptable salt thereof:

[0498] In one embodiment, the compound is Compound 166, or a pharmaceutically acceptable salt thereof:

[0499] In one embodiment, the compound is Compound 167, or a pharmaceutically acceptable salt thereof:

[0500] In one embodiment, the compound is Compound 168, or a pharmaceutically acceptable salt thereof:

[0501] In one embodiment, the compound is Compound 169, or a pharmaceutically acceptable salt thereof:

[0502] In one embodiment, the compound is Compound 170, or a pharmaceutically acceptable salt thereof.

[0503] In one embodiment, the compound is Compound 171, or a pharmaceutically acceptable salt thereof:

[0504] In one embodiment, the compound is Compound 172, or a pharmaceutically acceptable salt thereof:

[0505] In one embodiment, the compound is Compound 173, or a pharmaceutically acceptable salt thereof:

[0506] In one embodiment, the compound is Compound 174, or a pharmaceutically acceptable salt thereof:

[0507] In one embodiment, the compound is Compound 175, or a pharmaceutically acceptable salt thereof:

[0508] In one embodiment, the compound is Compound 176, or a pharmaceutically acceptable salt thereof:

[0509] In one embodiment, the compound is Compound 177, or a pharmaceutically acceptable salt thereof:

[0510] In one embodiment, the compound is Compound 178, or a pharmaceutically acceptable salt thereof:

[0511] In one embodiment, the compound is Compound 179, or a pharmaceutically acceptable salt thereof:

[0512] In one embodiment, the compound is Compound 180, or a pharmaceutically acceptable salt thereof:

[0513] In one embodiment, the compound is Compound 181, or a pharmaceutically acceptable salt thereof:

[0514] In one embodiment, the compound is Compound 182, or a pharmaceutically acceptable salt thereof:

[0515] In one embodiment, the compound is Compound 183, or a pharmaceutically acceptable salt thereof:

[0516] In one embodiment, the compound is Compound 184, or a pharmaceutically acceptable salt thereof:

[0517] In one embodiment, the compound is Compound 185, or a pharmaceutically acceptable salt thereof:

[0518] In one embodiment, the compound is Compound 186, or a pharmaceutically acceptable salt thereof:

[0519] In one embodiment, the compound is Compound 187, or a pharmaceutically acceptable salt thereof:

[0520] In one embodiment, the compound is Compound 188, or a pharmaceutically acceptable salt thereof:

[0521] In one embodiment, the compound is Compound 189, or a pharmaceutically acceptable salt thereof:

[0522] In one embodiment, the compound is Compound 190, or a pharmaceutically acceptable salt thereof:

[0523] In one embodiment, the compound is Compound 191, or a pharmaceutically acceptable salt thereof:

[0524] In one embodiment, the compound is Compound 192, or a pharmaceutically acceptable salt thereof:

[0525] In one embodiment, the compound is Compound 193, or a pharmaceutically acceptable salt thereof:

[0526] In one embodiment, the compound is Compound 194, or a pharmaceutically acceptable salt thereof:

[0527] In one embodiment, the compound is Compound 195, or a pharmaceutically acceptable salt thereof:

[0528] In one embodiment, the compound is Compound 196, or a pharmaceutically acceptable salt thereof:

[0529] In one embodiment, the compound is Compound 197, or a pharmaceutically acceptable salt thereof:

[0530] In one embodiment, the compound is Compound 198, or a pharmaceutically acceptable salt thereof:

[0531] In one embodiment, the compound is Compound 199, or a pharmaceutically acceptable salt thereof:

[0532] In one embodiment, the compound is Compound 200, or a pharmaceutically acceptable salt thereof:

[0533] In one embodiment, the compound is Compound 201, or a pharmaceutically acceptable salt thereof:

[0534] In one embodiment, the compound is Compound 202, or a pharmaceutically acceptable salt thereof:

[0535] In one embodiment, the compound is Compound 203, or a pharmaceutically acceptable salt thereof:

[0536] In one embodiment, the compound is Compound 204, or a pharmaceutically acceptable salt thereof:

[0537] In one embodiment, the compound is Compound 205, or a pharmaceutically acceptable salt thereof:

[0538] In one embodiment, the compound is Compound 206, or a pharmaceutically acceptable salt thereof:

[0539] In one embodiment, the compound is Compound 207, or a pharmaceutically acceptable salt thereof:

[0540] In one embodiment, the compound is Compound 208, or a pharmaceutically acceptable salt thereof:

[0541] In one embodiment, the compound is Compound 209, or a pharmaceutically acceptable salt thereof:

[0542] In one embodiment, the compound is Compound 210, or a pharmaceutically acceptable salt thereof:

[0543] In one embodiment, the compound is Compound 211, or a pharmaceutically acceptable salt thereof:

[0544] In one embodiment, the compound is Compound 212, or a pharmaceutically acceptable salt thereof:

[0545] In one embodiment, the compound is Compound 213, or a pharmaceutically acceptable salt thereof:

[0546] In one embodiment, the compound is Compound 214, or a pharmaceutically acceptable salt thereof:

[0547] In one embodiment, the compound is Compound 215, or a pharmaceutically acceptable salt thereof:

[0548] In one embodiment, the compound is Compound 216, or a pharmaceutically acceptable salt thereof:

[0549] In one embodiment, the compound is Compound 217, or a pharmaceutically acceptable salt thereof:

[0550] In one embodiment, the compound is Compound 218, or a pharmaceutically acceptable salt thereof:

[0551] In one embodiment, the compound is Compound 219, or a pharmaceutically acceptable salt thereof:

[0552] In one embodiment, the compound is Compound 220, or a pharmaceutically acceptable salt thereof:

[0553] In one embodiment, the compound is Compound 221, or a pharmaceutically acceptable salt thereof:

[0554] In one embodiment, the compound is Compound 222, or a pharmaceutically acceptable salt thereof:

[0555] In one embodiment, the compound is Compound 223, or a pharmaceutically acceptable salt thereof:

[0556] In one embodiment, the compound is Compound 224, or a pharmaceutically acceptable salt thereof:

[0557] In one embodiment, the compound is Compound 225, or a pharmaceutically acceptable salt thereof:

[0558] In one embodiment, the compound is Compound 226, or a pharmaceutically acceptable salt thereof:

[0559] In one embodiment, the compound is Compound 227, or a pharmaceutically acceptable salt thereof:

[0560] In one embodiment, the compound is Compound 228, or a pharmaceutically acceptable salt thereof:

[0561] In one embodiment, the compound is Compound 229, or a pharmaceutically acceptable salt thereof:

[0562] In one embodiment, the compound is Compound 230, or a pharmaceutically acceptable salt thereof:

[0563] In one embodiment, the compound is Compound 231, or a pharmaceutically acceptable salt thereof:

[0564] In one embodiment, the compound is Compound 232, or a pharmaceutically acceptable salt thereof:

[0565] In one embodiment, the compound is Compound 233, or a pharmaceutically acceptable salt thereof:

[0566] In one embodiment, the compound is Compound 234, or a pharmaceutically acceptable salt thereof:

[0567] In one embodiment, the compound is Compound 235, or a pharmaceutically acceptable salt thereof:

[0568] In one embodiment, the compound is Compound 236, or a pharmaceutically acceptable salt thereof:

[0569] In one embodiment, the compound is Compound 237, or a pharmaceutically acceptable salt thereof:

[0570] In one embodiment, the compound is Compound 238, or a pharmaceutically acceptable salt thereof:

[0571] In one embodiment, the compound is Compound 239, or a pharmaceutically acceptable salt thereof:

[0572] In one embodiment, the compound is Compound 240, or a pharmaceutically acceptable salt thereof:

[0573] In one embodiment, the compound is Compound 241, or a pharmaceutically acceptable salt thereof:

[0574] In one embodiment, the compound is Compound 242, or a pharmaceutically acceptable salt thereof:

[0575] In one embodiment, the compound is Compound 243, or a pharmaceutically acceptable salt thereof:

[0576] In one embodiment, the compound is Compound 244, or a pharmaceutically acceptable salt thereof:

[0577] In one embodiment, the compound is Compound 245, or a pharmaceutically acceptable salt thereof:

[0578] In one embodiment, the compound is Compound 246, or a pharmaceutically acceptable salt thereof:

[0579] In one embodiment, the compound is Compound 247, or a pharmaceutically acceptable salt thereof:

[0580] In one embodiment, the compound is Compound 248, or a pharmaceutically acceptable salt thereof:

[0581] In one embodiment, the compound is Compound 249, or a pharmaceutically acceptable salt thereof:

[0582] In one embodiment, the compound is Compound 250, or a pharmaceutically acceptable salt thereof:

[0583] In one embodiment, the compound is Compound 251, or a pharmaceutically acceptable salt thereof:

[0584] In one embodiment, the compound is Compound 252, or a pharmaceutically acceptable salt thereof:

[0585] In one embodiment, the compound is Compound 253, or a pharmaceutically acceptable salt thereof:

[0586] In one embodiment, the compound is Compound 254, or a pharmaceutically acceptable salt thereof:

[0587] In one embodiment, the compound is Compound 255, or a pharmaceutically acceptable salt thereof:

[0588] In one embodiment, the compound is Compound 256, or a pharmaceutically acceptable salt thereof:

[0589] In one embodiment, the compound is Compound 257, or a pharmaceutically acceptable salt thereof:

[0590] In one embodiment, the compound is Compound 258, or a pharmaceutically acceptable salt thereof:

[0591] In one embodiment, the compound is Compound 259, or a pharmaceutically acceptable salt thereof:

[0592] In one embodiment, the compound is Compound 260, or a pharmaceutically acceptable salt thereof:

[0593] In one embodiment, the compound is Compound 261, or a pharmaceutically acceptable salt thereof:

[0594] In one embodiment, the compound is Compound 262, or a pharmaceutically acceptable salt thereof:

[0595] In one embodiment, the compound is Compound 263, or a pharmaceutically acceptable salt thereof:

[0596] In one embodiment, the compound is Compound 264, or a pharmaceutically acceptable salt thereof:

[0597] In one embodiment, the compound is Compound 265, or a pharmaceutically acceptable salt thereof:

[0598] In one embodiment, the compound is Compound 266, or a pharmaceutically acceptable salt thereof:

[0599] In one embodiment, the compound is Compound 267, or a pharmaceutically acceptable salt thereof:

[0600] In one embodiment, the compound is Compound 268, or a pharmaceutically acceptable salt thereof:

[0601] In one embodiment, the compound is Compound 269, or a pharmaceutically acceptable salt thereof:

[0602] In one embodiment, the compound is Compound 270, or a pharmaceutically acceptable salt thereof:

[0603] In one embodiment, the compound is Compound 271, or a pharmaceutically acceptable salt thereof:

[0604] In one embodiment, the compound is Compound 272, or a pharmaceutically acceptable salt thereof:

[0605] In one embodiment, the compound is Compound 273, or a pharmaceutically acceptable salt thereof:

[0606] In one embodiment, the compound is Compound 274, or a pharmaceutically acceptable salt thereof:

[0607] In one embodiment, the compound is Compound 275, or a pharmaceutically acceptable salt thereof:

[0608] In one embodiment, the compound is Compound 276, or a pharmaceutically acceptable salt thereof:

[0609] In one embodiment, the compound is Compound 277, or a pharmaceutically acceptable salt thereof:

[0610] In one embodiment, the compound is Compound 278, or a pharmaceutically acceptable salt thereof:

[0611] In one embodiment, the compound is Compound 279, or a pharmaceutically acceptable salt thereof:

[0612] In one embodiment, the compound is Compound 280, or a pharmaceutically acceptable salt thereof:

[0613] In one embodiment, the compound is Compound 281, or a pharmaceutically acceptable salt thereof:

[0614] In one embodiment, the compound is Compound 282, or a pharmaceutically acceptable salt thereof:

[0615] In one embodiment, the compound is Compound 283, or a pharmaceutically acceptable salt thereof:

[0616] In one embodiment, the compound is Compound 284, or a pharmaceutically acceptable salt thereof:

[0617] In one embodiment, the compound is Compound 285, or a pharmaceutically acceptable salt thereof:

[0618] In one embodiment, the compound is Compound 286, or a pharmaceutically acceptable salt thereof:

[0619] In one embodiment, the compound is Compound 287, or a pharmaceutically acceptable salt thereof:

[0620] In one embodiment, the compound is Compound 288, or a pharmaceutically acceptable salt thereof:

[0621] In one embodiment, the compound is Compound 289, or a pharmaceutically acceptable salt thereof:

[0622] In one embodiment, the compound is Compound 290, or a pharmaceutically acceptable salt thereof:

[0623] In one embodiment, the compound is Compound 291, or a pharmaceutically acceptable salt thereof:

[0624] In one embodiment, the compound is Compound 292, or a pharmaceutically acceptable salt thereof:

[0625] In one embodiment, the compound is Compound 293, or a pharmaceutically acceptable salt thereof:

[0626] In one embodiment, the compound is Compound 294, or a pharmaceutically acceptable salt thereof:

[0627] In one embodiment, the compound is Compound 295, or a pharmaceutically acceptable salt thereof:

[0628] In one embodiment, the compound is Compound 296, or a pharmaceutically acceptable salt thereof:

[0629] In one embodiment, the compound is Compound 297, or a pharmaceutically acceptable salt thereof:

[0630] In one embodiment, the compound is Compound 298, or a pharmaceutically acceptable salt thereof:

[0631] In one embodiment, the compound is Compound 299, or a pharmaceutically acceptable salt thereof:

[0632] In one embodiment, the compound is Compound 300, or a pharmaceutically acceptable salt thereof:

[0633] In one embodiment, the compound is Compound 301, or a pharmaceutically acceptable salt thereof:

[0634] In one embodiment, the compound is Compound 302, or a pharmaceutically acceptable salt thereof:

[0635] In one embodiment, the compound is Compound 303, or a pharmaceutically acceptable salt thereof:

[0636] In one embodiment, the compound is Compound 304, or a pharmaceutically acceptable salt thereof:

[0637] In one embodiment, the compound is Compound 305, or a pharmaceutically acceptable salt thereof:

[0638] In one embodiment, the compound is Compound 306, or a pharmaceutically acceptable salt thereof:

[0639] In one embodiment, the compound is Compound 307, or a pharmaceutically acceptable salt thereof:

[0640] In one embodiment, the compound is Compound 308, or a pharmaceutically acceptable salt thereof:

[0641] In one embodiment, the compound is Compound 309, or a pharmaceutically acceptable salt thereof:

[0642] In one embodiment, the compound is Compound 310, or a pharmaceutically acceptable salt thereof:

[0643] In one embodiment, the compound is Compound 311, or a pharmaceutically acceptable salt thereof:

[0644] In one embodiment, the compound is Compound 312, or a pharmaceutically acceptable salt thereof:

[0645] In one embodiment, the compound is Compound 313, or a pharmaceutically acceptable salt thereof:

[0646] In one embodiment, the compound is Compound 314, or a pharmaceutically acceptable salt thereof:

[0647] In one embodiment, the compound is Compound 315, or a pharmaceutically acceptable salt thereof:

[0648] In one embodiment, the compound is Compound 318, or a pharmaceutically acceptable salt thereof:

[0649] In one embodiment, the compound is Compound 321, or a pharmaceutically acceptable salt thereof:

[0650] In one embodiment, the compound is Compound 322, or a pharmaceutically acceptable salt thereof:

[0651] In one embodiment, the compound is Compound 323, or a pharmaceutically acceptable salt thereof:

[0652] In one embodiment, the compound is Compound 339, or a pharmaceutically acceptable salt thereof:

[0653] In one embodiment, the compound is Compound 340, or a pharmaceutically acceptable salt thereof:

[0654] In one embodiment, the compound is Compound 341, or a pharmaceutically acceptable salt thereof:

[0655] In one embodiment, the compound is Compound 342, or a pharmaceutically acceptable salt thereof:

[0656] In one embodiment, the compound is Compound 343, or a pharmaceutically acceptable salt thereof:

[0657] In one embodiment, the compound is Compound 344, or a pharmaceutically acceptable salt thereof:

[0658] In one embodiment, the compound is Compound 345, or a pharmaceutically acceptable salt thereof:

[0659] In one embodiment, the compound is Compound 372, or a pharmaceutically acceptable salt thereof:

[0660] In one embodiment, the compound is Compound 373, or a pharmaceutically acceptable salt thereof:

[0661] In one embodiment, the compound is Compound 374, or a pharmaceutically acceptable salt thereof:

[0662] In one embodiment, the compound is Compound 375, or a pharmaceutically acceptable salt thereof:

[0663] In certain embodiments, the compounds inhibits POLRMT.

[0664] In certain embodiments, the compounds promote POLRMT.

[0665] The compounds of the present invention may contain asymmetric carbon atoms (sometimes as the result of a deuterium atom) and thereby may exist as either individual stereoisomers or mixtures of the enantiomers or mixtures of diastereomers. Accordingly, a compound of the present invention may exist as either a racemic mixture, a mixture of diastereomers, or as individual stereoisomers that are substantially free of other stereoisomers. Synthetic, separation, or purification methods to be used to obtain an enantiomer of a given compound are known in the art and are applicable for obtaining the compounds identified herein.

[0666] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Carbon atoms labelled with * or ** refer to a compound that is chiral but the absolute stereochemistry has not been determined.

[0667] The compounds of the present invention may contain double bonds that may exist in more than one geometric isomer. Examples of such double bonds are carbon- carbon double bonds which form alkenes. In the case of carbon-carbon double bonds, the geometric isomers may be E or Z isomers.

[0668] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the geometric isomerism and has one or more possible geometric isomers, it is understood to represent all possible geometric isomers of the compound.

[0669] Certain compounds of the present invention may be able to exist as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of the present invention. For example, in instances where an —OH substituent ispermitted on a heteroaromatic ring and ketoenol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the oxo (═O) form.

[0670] Compounds of the present invention may exist in amorphous form and / or one or more crystalline forms. As such all amorphous and crystalline forms and mixtures thereof of the compounds of the invention are intended to be included within the scope of the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the compounds of this invention are likewise encompassed within the scope of the compounds of the invention and the pharmaceutically acceptable salts thereof, along with un-solvated and anhydrous forms of such compounds.

[0671] In one embodiment, deuterium isotope content at the deuterium substituted position is greater than the natural isotopic deuterium content (0.015%), more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 75%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%. It will be understood that some variation of natural isotopic abundance may occur in any compound depending upon the source of the reagents used in the synthesis. Thus, a preparation of undeuterated compounds may inherently contain small amounts of deuterated isotopologues, such amounts being insignificant as compared to the degree of stable isotopic substitution of the deuterated compounds of the invention. See, e.g., Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 119, 725 (1998). Replacement of hydrogen with deuterium may affect the activity, toxicity, and pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion (“ADME”)) of some drugs. For instance, such replacement may alter the chemical stability and biochemical reactivity of a compound through kinetic isotope effects. Because of the increased mass of deuterium relative to hydrogen, epimerization at stereogenic carbons may be slowed down when hydrogen is replaced with deuterium. See Pirali et al, J. Med. Chem.62, 5276-97 (2019). Additionally, the presence of deuterium may affect how a molecule interacts with enzymes, thereby impacting enzyme kinetics. While in certain cases the increased mass of deuterium as compared to hydrogen may stabilize a compound and thereby improve activity, toxicity, or half-life, such impact is not predictable. In other instances deuteration may have little to no impact on these properties, or may affect them in an undesirable manner. Whether and / or how such replacement will impact drug properties may only be determined if the drug is synthesized, evaluated, and compared toits non-deuterated counterpart. Because some drugs have multiple sites of metabolism or more than one active sites for binding to a target, it is unpredictable as to which sites may benefit by deuterium replacement or to what extent isotope enrichment is necessary to produce a beneficial effect. (III) Methods of making of compounds

[0672] The starting materials and reagents used in each step in the preparation are known and may be readily prepared or purchased from commercial sources.

[0673] The compound obtained in each step may also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof. Alternatively, the compound obtained in each step may be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like according to a conventional method.

[0674] In each reaction step, while the reaction time varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally 1 min. to 48 h., preferably 10 min. to 8 h. In the reaction of each step, while the reaction temperature varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally -78 °C to 300 °C, preferably -78 °C to 150 °C. In the reaction of each step, unless otherwise specified, a reagent is used in 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent is also a reaction solvent, the reagent is used in a solvent amount.

[0675] In the reaction of each step, unless otherwise specified, it is performed without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2- methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2- dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the like; amides: N,N- dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; nitriles: acetonitrile and the like; sulfoxides: dimethyl sulfoxide and the like; aromatic organic bases: pyridine and the like; acid anhydrides: acetic anhydride and the like; organic acids: formic acid, acetic acid, trifluoroacetic acid and the like; inorganic acids: hydrochloric acid, sulfuric acid and the like; esters: ethyl acetate and the like; ketones: acetone, methyl ethyl ketone and the like; and water.

[0676] Two or more kinds of the above-mentioned solvents may be used by mixing at an appropriate ratio.

[0677] Unless otherwise specified, the reaction of each step is performed according to a known method, for example, the methods described in “Reactions and Syntheses: In the Organic Chemistry Laboratory 2nd Edition” (Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen, Andreas Speicher, Nina Schützenmeister) Wiley, 2015; “Organic Syntheses Collective Volumes 1 – 12” (John Wiley & Sons Inc); “Comprehensive Organic Transformations, Third Edition” (Richard C. Larock) Wiley, 2018 and the like.

[0678] In each step, protection or deprotection of a functional group is performed by a known method, for example, the methods described in “Protective Groups in Organic Synthesis, 4thEd.” (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like.

[0679] Deuterated POLRMT modulators of the present invention may be prepared using chemical reactions known to a person of ordinary skill in the art using deuterated starting materials or reagents. Deuterium-containing reagents are well known in the art and may be prepared using known procedures or purchased from commercial sources. The deuterated compounds obtained may be characterized by analytical techniques known to persons of ordinary skill in the art. For example, nuclear magnetic resonance (“NMR”) may be used to determine a compound’s structure while mass spectroscopy (“MS”) may be used to determine the amount of deuterium atom in the compound by comparison to its non-deuterated form. (IV) Compositions

[0680] The present invention further includes pharmaceutical compositions of the compounds or a pharmaceutically acceptable salt of said compounds. In addition to the compound of the invention or a salt thereof, the pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients, such excipients being compatible with other ingredients in the composition and also being not toxic or otherwise harmful. Examples of excipients include carriers, lubricants, binders, disintegrants, solvents, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, preservatives, antioxidants, colorants, taste-modifying agents, absorbents, and / or wetting agents.

[0681] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Such compositions may be prepared by anymethods well known in the art of pharmaceutical formulations and pharmacy. See, e.g., Remington: The Science and Practice of Pharmacy, Elsevier Science, 23rd ed. (2020).

[0682] Formulations for parenteral administration include sterile aqueous or non- aqueous solutions, suspensions, or emulsions. A variety of aqueous carriers may be used, e.g., water, buffered water, saline, and the like. Examples of other suitable vehicles include polypropylene glycol, polyethylene glycol, vegetable oils, hydrogels, gelatin, hydrogenated naphthalenes, and injectable organic esters, such as ethyl oleate. Such formulations may also contain auxiliary substances, such as preserving, wetting, buffering, emulsifying, and / or dispersing agents. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers may be used to control the release of the active ingredients. Alternatively, the compositions may be administered by oral ingestion. Compositions intended for oral use may be prepared in solid or liquid forms, according to any method known to a person of ordinary skill in the art for the manufacture of pharmaceutical compositions. Solid dosage forms for oral administration include capsules (both soft and hard gelatin capsules), tablets, powders, and granules. Generally, these pharmaceutical preparations contain active ingredients admixed with pharmaceutically acceptable excipients. These excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, sucrose, glucose, mannitol, cellulose, starch, calcium phosphate, sodium phosphate, kaolin and the like; binding agents, buffering agents, and / or lubricating agents (e.g., magnesium stearate) may also be used. Tablets and capsules may additionally be prepared with release-controlling coatings such as enteric coatings. The compositions may optionally contain sweetening, flavoring, coloring, perfuming, and preserving agents in order to provide a more palatable preparation.

[0683] In another embodiment, a pharmaceutical composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any pharmaceutically active compound; preferably the second therapeutic agent is known to correct mitochondrial dysfunction. Alternatively, the compounds of the invention and second therapeutic agent may be administered together (within less than 24 hours of one another, consecutively or simultaneously) but in separate pharmaceutical compositions. In certain embodiments, the compounds on the invention and second therapeutic agent may be administered separately (e.g., more than 24 hours of one another.) If the second therapeutic agent acts synergistically with the compounds of this invention, the therapeutically effective amount of such compounds and / or the second therapeutic agent may be less that such amount required when either is administered alone.

[0684] For the treatment of cancer, the compounds described herein may be administered in combination with a chemotherapeutic agent. Therapeutically effective amounts of the additional chemotherapeutic agent(s) are well known to those skilled in the art. However, it is well within the attending physician to determine the amount of other chemotherapeutic agent(s) to be delivered. Examples of these chemotherapeutic agents include, but are not limited to, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Actemra (Tocilizumab), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus), Afinitor Disperz (Everolimus), Aldara (Imiquimod), Alimta (PEMET EXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Avelumab, Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Blincyto (Blinatumomab), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Cyramza (Ramucirumab), Dacogen (Decitabine), Darzalex (Daratumumab), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone), Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Durvalumab, Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Empliciti (Elotuzumab), Enhertu (fam- trastuzumab deruxtecan-nxki), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gazyva (Obinutuzumab), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla(Ado-trastuzumab Emtansine), Kyprolis (Carfilzomib), Leflunomide (SU101), Lartruvo (Olaratumab), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Libtayo (Cemiplimab), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Panretin (Alitretinoin), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Portrazza (Necitumumab), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Removab (Catumaxomab), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Sarclisa (Isatuximab-irfc), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Tremelimumab, Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Unituxin (Dinutuximab), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar(Streptozocin), Zelboraf (Vemurafenib), Zevalin (lbritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zytiga (Abiraterone), Nimotuzumab and immune checkpoint inhibitors such as nivolumab, pembrolizumab / MK-3475, pidilizumab and AMP-224 targeting PD-1; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting. EXAMPLES

[0685] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

[0686] The structures of the compounds are confirmed by either mass spectrometry or nuclear magnetic resonance spectroscopy (NMR), where peaks assigned to the characteristic protons in the title compound are presented where appropriate.1H NMR shift (δH) are given in parts per million (ppm) down field from an internal reference standard. Acceptable1H NMR shifts and masses are within 5% of the reported values (i.e., all reported measurement values herein also include ± 5%, ± 4%, ± 3%, ± 2%, and / or ± 1%). All reported LCMS values herein also include ± 5%, ± 4%, ± 3%, ± 2%, and / or ± 1%.

[0687] The abbreviations used herein are known to a person of ordinary skill in the art. A partial list of abbreviations that may be used herein include: acetonitrile (MeCN), ammonium carbonate (NH4)2CO3, ammonium chloride (NH4Cl), aqueous (aq.), 1,1’- bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino)propane (dppp), bis(pinacolato)diboron (B2pin2), N- bromosuccinimide (NBS), bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBroP),boron tribromide (BBr3), butyl lithium (BuLi), calculated (Calcd.), cesium carbonate (Cs2CO3), dichloromethane (DCM, CH2Cl2), N,N-dicyclohexylcarbodiimide (DCC), dichloroethane (DCE), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N- diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), di-tert-butyl decarbonate (Boc2O), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), electrospray ionization (ESI), enantiomeric excess (ee), ethyl acetate (EtOAc), hour (h.), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), high performance liquid chromatography (HPLC), hydroxybenzotriazole (HOBt), isopropyl alcohol (IPA), lithium hydroxide monohydrate (LiOH HHO), methanol (MeOH), methyl iodide (MeI), minutes (min.), potassium carbonate (K2CO3), liquid chromatography-mass spectrometry (LCMS),phenyliodide(III) diacetate (PIDA), propylphosphonic anhydride (T3P), reverse phase (RP), room / ambient temperature (rt, RT), silver oxide (Ag2O), sodium hydride (NaH), sodium sulfate (Na2SO3), supercritical fluid chromatography (SFC), tetrahydrofuran (THF), triethylamine (Et3N), thionyl chloride (SOCl2), triphenylphosphine (PPh3), dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane (XPhos). Table 1 provides a listing of example compounds of the present invention and IC50values for inhibition of POLRMT.

[0688] The following examples illustrate various non-limiting embodiments of the present disclosure.

[0689] Table 1 correlates Example number with Compound number.Example 1: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Compound 301)

[0690] Synthesis of 1-(5-fluoro-2-methylphenyl)cyclopropane-1-carbonitrile, 2 [Step 1]: To a stirred solution of KOH (2.3 g, 40.2 mmol) in water (10 mL), 2-(5-fluoro-2- methylphenyl)acetonitrile (1, 500 mg, 3.4 mmol) and TBAB (216 mg, 0.67 mmol) were added at 0 °C. After 5 min, 1,2-dibromoethane (1.5 mL, 16.8 mmol) was added dropwise and the resulting reaction mixture was heated at 60 °C for 12 h. After completion, the reaction mixture was poured into cold water and extracted with ethyl acetate (thrice). Combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(5- fluoro-2-methylphenyl)cyclopropane-1-carbonitrile (2, 450 mg).1H NMR (400 MHz, DMSO-d6) δ7.33-7.29 (m, 1H), 7.22-7.11 (m, 1H), 7.06-7.02(m, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 1.69 (s, 2H), 1.41 (s, 2H) [Note: HNMR showed extra peaks.]

[0691] Synthesis of (Z)-1-(5-fluoro-2-methylphenyl)-N'-hydroxycyclopropane-1- carboximidamide, 3 [Step 2]: To a stirred solution of 1-(5-fluoro-2-methylphenyl)cyclopropane-1- carbonitrile (2, 450 mg, 2.6 mmol) in ethanol (2 mL), Na2CO3(545 mg, 5.1 mmol) was added followed by NH2OH.HCl (355 g, 5.1 mmol) and the reaction mixture was heated to reflux at 70 °C for 12h. After completion, the volatiles were evaporated under reduced pressure. The reduced mass was diluted with water and extracted with ethyl acetate (thrice). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-1-(5-fluoro-2- methylphenyl)-N'-hydroxycyclopropane-1-carboximidamide (3, 450 mg). LCMS (ESI) Calcd for C11H13FN2O: 208.1, found [M+H]+= 209.1.

[0692] Synthesis of (Z)-1-(5-fluoro-2-methylphenyl)-N'-((1-methyl-5-(trifluoromethyl)-1H- pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide, 4, [Step 3]: To a stirred solution of 1- methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (100 mg, 0.5 mmol) and (Z)-1-(5-fluoro- 2-methylphenyl)-N'-hydroxycyclopropane-1-carboximidamide (3, 160 mg, 0.8 mmol) in dichloromethane (3 mL), N,N-Diisopropylethylamine (0.2 mL, 1.03 mmol), EDCI.HCl (128 mg, 0.7 mmol) and HOAt (15 mg, 0.1 mmol) were added at 0 °C and the reaction mixture was stirred at ambient temperature for 16h. After completion, the reaction mixture was concentrated under reduced pressure, dissolved with ethyl acetate, washed with water (twice) and brine. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-1-(5-fluoro- 2-methylphenyl)-N'-((1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide (4, 150 mg). LCMS (ESI) Calcd for C17H16F4N4O2: 384.1, found [M+H]+= 385.1.

[0693] Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-5-(trifluoromethyl)- 1H-pyrazol-3-yl)-1,2,4-oxadiazole, Example 1 [Step 4]: To a stirred solution of (Z)-1-(5-fluoro-2- methylphenyl)-N'-((1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide (4, 150 mg, 0.4 mmol) in THF (2 mL), tetrabutylammonium hydroxide (25 mg, 0.04 mmol, 1M in methanol) was added and the resulting reaction mixture was stirred at ambient temperature for 60 min. After completion, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (twice), dried over anhydrous Na2SO4, filtered and concentrated again under reduced pressure. The product was purifiedthrough reverse phase prep-HPLC and lyophilized to afford 3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 1, 25 mg). LCMS (ESI) Calcd for C17H14F4N4O: 366.1, found [M+H]+= 367.1.1HNMR (400 MHz, DMSO-d6) δH7.65 (s, 1H), 7.27-7.20 (m, 2H), 7.10-7.06 (m, 1H), 4.10 (s, 3H), 2.22 (s, 3H), 1.67-1.65 (m, 2H), 1.46-1.44 (m, 2H). Example 2: Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 2):

[0694] 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-1,2,4- oxadiazole was synthesized Scheme 1 using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C17H17FN4O: 312.1, found [M+H]+= 313.2.1HNMR (400 MHz, DMSO-d6) δH7.26-7.19 (m, 2H), 7.09-7.04 (m, 1H), 6.71 (s, 1H), 3.84 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 1.65-1.63 (m, 2H), 1.42-1.39 (m, 2H). Example 3: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 3):

[0695] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-methyl-1H-pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C16H15FN4O: 298.1, found [M+H]+= 299.2.1HNMR (400 MHz, DMSO-d6) δH7.96 (s, 1H), 7.27-7.20 (m, 2H), 7.09-7.06 (m, 1H), 6.91 (s, 1H), 3.97 (s, 3H), 2.22 (s, 3H), 1.65 (m, 2H), 1.42 (m, 2H). Example 4: Synthesis of 5-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 4):

[0696] 5-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 1 using 5-cyclopropyl-1-methyl-1H- pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C19H19FN4O: 338.2, found [M+H]+= 339.2.1HNMR (400 MHz, DMSO-d6) δH 7.26-7.19 (m, 2H), 7.09-7.05 (m, 1H), 6.58 (s, 1H), 3.95 (s, 3H), 2.20 (s, 3H), 1.99-1.92 (m, 1H), 1.64-1.61 (m, 2H), 1.42-1.39 (m, 2H), 1.00-0.93 (m, 2H), 0.75-0.72 (m, 2H). Example 5: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 5)

[0697] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1-methyl-1H-pyrazol-3-yl)- 1,2,4-oxadiazole was synthesized following Scheme 1 using 5-isopropyl-1-methyl-1H-pyrazole- 3-carboxylic acid. LCMS (ESI) Calcd for C19H21FN4O: 340.2, found [M+H]+= 341.2.1HNMR(400 MHz, DMSO-d6, at 100 °C) δH7.24-7.17 (m, 2H), 7.05-7.01 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.11-3.08 (m,1H), 2.25 (s, 3H), 1.67 (brs, 2H), 1.40 (brs, 2H), 1.26-1.25 (d, 6H). Example 6: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-phenyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 6)

[0698] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-phenyl-1H-pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C21H17FN4O: 360.3, found [M+H]+= 361.2.1HNMR (400MHz,DMSO-d6):δ 8.78 (d,1H), 7.39 (d, 2H), 7.56 (t, 2H), 7.42 (t,1H), 7.27-7.22 (m,3H), 7.11-7.06 (m,1H), 2.24 (s,3H), 1.68 (s, 2H), 1.46-1.43 (m, 2H). Example 7: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1- (pyridin-2-yl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 7)

[0699] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1-(pyridin-2-yl)-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 5-isopropyl-1-(pyridin-2-yl)-1H- pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C23H22FN5O: 403.2, found [M+H]+= 404.2.1H NMR (400 MHz, DMSO-d6) δH8.59-8.58 (m, 1H), 8.10-8.07 (m, 1H), 7.86-7.84 (m, 1H), 7.55- 7.52 (m, 1H), 7.27-7.21 (m, 2H), 7.10-7.04 (m, 2H), 3.82-3.75 (m, 1H), 2.23 (s, 3H), 1.68 (m, 2H), 1.45 (m, 2H), 1.24-1.22(m, 6H). Example 8: Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-(2- fluorophenyl)-5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 8)

[0700] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-(2-fluorophenyl)-5-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-(2-fluorophenyl)-5-methyl-1H- pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C22H18F2N4O: 392.4, found [M+H]+= 393.2.1H NMR (400 MHz, DMSO-d6) δH 7.67-7.63 (m, 2H), 7.57 (t, 1H), 7.45 (t, 1H), 7.27-7.20 (m, 2H), 7.10-7.05 (m, 1H), 7.00 (s, 1H), 2.23 (s, 6H), 1.67 (t, 2H), 1.45 (t, 2H). Example 9: Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 9)

[0701] Synthesis of 1-(3-fluorophenyl)cyclopropane-1-carbonitrile, 6 [Step 1]: To a stirred solution of KOH (3.7 g, 66.6 mmol) in water(10 mL), 2-(3-fluorophenyl)acetonitrile (5, 750 mg, 5.6 mmol) and TBAB (360 mg, 1.1 mmol) were added at 0 °C. After 5 min, 1,2-dibromoethane (2.4 mL, 27.7 mmol) was added dropwise and the resulting reaction mixture was heated at 60 °C for 12 h. After completion, the reaction mixture was poured into cold water and extracted with ethyl acetate (thrice). Combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(3-fluorophenyl)cyclopropane-1-carbonitrile (6, 710 mg).1H NMR (400 MHz, CDCl3) δH 7.35-7.25 (m, 1H), 7.08 (d, 1H), 6.99-6.95 (m, 2H), 1.59-1.24 (m, 4H). [Note:1HNMR contain extra peak.]

[0702] Synthesis of (Z)-1-(3-fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide, 7 [Step 2]: To a stirred solution of 1-(3-fluorophenyl)cyclopropane-1-carbonitrile (6, 700 mg, 4.3 mmol) in ethanol (10 mL), Na2CO3(920 mg, 8.7 mmol) was added followed by NH2OH.HCl (605 g, 8.7 mmol) and the reaction mixture was heated to reflux at 70 °C for 12 h. After completion, the volatiles were evaporated under reduced pressure, diluted with water and extracted with ethyl acetate (thrice). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-1-(3-fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide (7, 450 mg). LCMS (ESI) Calcd for C10H11FN2O: 194.1, found [M+H]+= 195.0.

[0703] Synthesis of (Z)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(3- fluorophenyl)cyclopropane-1-carboximidamide, 8 [Step 3]: To a stirred solution of 5- (difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (120 mg, 0.7 mmol) and (Z)-1-(3- fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide (7, 200 mg, 1.0 mmol) in dichloromethane (3 mL), N,N-Diisopropylethylamine (0.2 mL, 1.4 mmol), EDCI.HCl (170 mg, 0.9 mmol) and HOAt (20 mg, 0.1 mmol) were added at 0 °C and reaction mixture was stirred at ambient temperature for 16h. After completion, the reaction mixture was concentrated under reduced pressure, dissolved with ethyl acetate, washed with water (twice) and brine. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-N'-((5- (difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(3-fluorophenyl)cyclopropane-1- carboximidamide (8, 180 mg). LCMS (ESI) calculated for C16H15F3N4O2: 352.1, found [M+H]+= 353.3.

[0704] Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole, Example 9 [Step 4]: To a stirred solution of (Z)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(3-fluorophenyl)cyclopropane-1- carboximidamide (8, 180 mg, 0.5 mmol) in THF (2 mL), tetrabutylammonium hydroxide(33 mg, 0.05 mmol, 1M in methanol) was added and resulting reaction mixture was stirred at ambient temperature for 60 min. After completion, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (twice), dried over anhydrous Na2SO4, filtered and concentrated again under reduced pressure. The product was purified through reverse phase prep-HPLC and lyophilized to afford 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3- yl)-3-(1-(3-fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 9, 80 mg). LCMS (ESI) Calcd for C16H13F3N4O: 334.1, found [M+H]+= 335.1.1HNMR (400 MHz, DMSO-d6) δH 7.5-7.24 (t, 1H), 7.43-7.39 (m, 1H), 7.29-7.27 (m, 3H), 7.17-7.11 (m, 1H), 4.05 (s, 3H), 1.60-1.57 (m, 2H), 1.49- 1.46 (m, 2H). Example 10: Synthesis of 3-(1-(3-fluorophenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 10)

[0705] 3-(1-(3-fluorophenyl)cyclopropyl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole was synthesized following Scheme 2 using 1-methyl-5-(trifluoromethyl)-1H- pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C16H12F4N4O: 352.1, found [M+H]+: = 353.2. 1HNMR (400 MHz, DMSO-d6) δH7.66(s, 1H), 7.44-7.38 (m, 1H), 7.29 (d, 2H), 7.17-7.12 (m, 1H), 4.11 (s, 3H), 1.61-1.59 (m, 2H), 1.50-1.48 (m, 2H). Example 11: Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(3- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole

[0706] 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(3-fluorophenyl)cyclopropyl)-1,2,4-oxadiazole was synthesized following Scheme 2 using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid. LCMS (ESI) Calcd for C16H15FN4O: 298.1, found [M+H]+= 299.2.1HNMR (400 MHz, DMSO-d6) δH7.42-7.37 (m, 1H), 7.28 (d, 2H), 7.15-7.11 (t, 1H), 6.72 (s, 1H), 3.84 (s, 3H), 2.31 (s, 3H), 1.58-1.55 (m, 2H), 1.46-1.43 (m, 2H). Example 12: Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole

[0707] Synthesis of 1-(o-tolyl)cyclopropane-1-carbonitrile, 10 [Step 1]: To a stirred solution of NaOH (31.79 g, 457 mmol) in water (50 mL), 2-(o-tolyl)acetonitrile (9, 5 g, 38.1 mmol) and TBAB (2.46 g, 7.62 mmol) were added at 0 °C. After 5 min 1,2-dibromoethane (29 mL, 191 mmol) was added dropwise and the resulting reaction mixture was heated at 600C for 12 hr. After completion, reaction mixture was poured into cold water and extracted with ethyl acetate (thrice). Combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(o-tolyl)cyclopropane-1-carbonitrile (10, 5 g).1H NMR (400 MHz, DMSO-d6) δ 7.35-7.20 (m, 6H), 2.47 (s, 3H), 2.29 (s, 3H), 1.70-1.67 (m, 2H), 1.36-1.33 (m.2H) [Note: HNMR contain extra peak.]

[0708] Synthesis of (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide, 11 [Step 2]: To a stirred solution of 1-(o-tolyl)cyclopropane-1-carbonitrile (10, 2.00 g, 12.7 mmol) in ethanol (10mL), Na2CO3(2.7 g, 25.4 mmol) was added followed by NH2OH.HCl (177 g, 25.4 mmol) and the reaction mixture was refluxed at 70 °C for 12h. After completion, volatiles are evaporated under reduced pressure, diluted with water and extracted with ethyl acetate (thrice). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-N'-hydroxy- 1-(o-tolyl)cyclopropane-1-carboximidamide (11, 900 mg). LCMS (ESI) calculated for C11H14N2O [M]: 190.1, found [M+H]+: 190.7.

[0709] Synthesis of (Z)-N'-((1,5-dimethyl-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane- 1-carboximidamide, 12, [Step 3]: To a stirred solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.4 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 100 mg, 0.5 mmol) in dichloromethane (2 mL), N,N-Diisopropylethylamine (0.1 mL, 0.7 mmol), EDCI.HCl (90 mg, 0.5 mmol) and HOAt (9.7 mg, 0.1 mmol) were added at 0 °C and reaction mixture was stirred at ambient temperature for 16h. After completion the reaction mixture was concentrated under reduced pressure, dissolved with ethyl acetate, washed with water (twice) and brine. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-N'-((1,5-dimethyl-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1- carboximidamide (12, 100 mg). LCMS (ESI) Calcd for C17H20N4O2: 312.2, found [M+H]+= 313.2.

[0710] Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 12 [Step 4]: To a stirred solution of (Z)-N'-((1,5-dimethyl-1H-pyrazole-3-carbonyl)oxy)- 1-(o-tolyl)cyclopropane-1-carboximidamide (12, 100 mg, 0.3 mmol) in THF (2 mL), tetrabutylammonium hydroxide(105 mg, 0.2 mmol, 1M in methanol) was added and resultingreaction mixture was stirred at ambient temperature for 60 min. After completion, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (twice), dried over anhydrous Na2SO4, filtered and concentrated again under reduced pressure. The product was purified through reverse phase prep-HPLC and lyophilized to afford 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 12, 50 mg). LCMS (ESI) Calcd for C17H18N4O: 294.1 , found [M+H]+= 295.2.1HNMR (400 MHz, DMSO-d6) δH 7.37 (d, 1H), 7.23-7.18 (m, 3H), 6.70 (s, 1H), 3.84 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 1.63 (m, 2H), 1.36 (m, 2H). Example 13: Synthesis of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 13)

[0711] 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 3 using 1-methyl-5-(trifluoromethyl)-1H-pyrazole- 3-carboxylic acid.

[0712] LCMS (ESI) Calcd for C17H15F3N4O: 348.1, found [M+H]+= 349.2.1HNMR (400 MHz, DMSO-d6) δH 1H NMR (400 MHz, DMSO-d6) δH 7.63 (s, 1H), 7.38 (d, 1H), 7.24-7.19 (m, 3H), 4.10 (s, 3H), 2.32 (d, 3H), 1.66 (brs, 2H), 1.40 (brs, 2H). Example 14: Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 14)

[0713] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 3 using 5-(difluoromethyl)-1-methyl-1H-pyrazole- 3-carboxylic acid.

[0714] LCMS (ESI) Calcd for C17H16F2N4O: 330.1, found [M+H]+= 331.2.1HNMR (400 MHz, DMSO-d6) δH 7.50-7.19 (m, 6H), 4.04 (s, 3H), 2.26 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H). Example 15: Synthesis of 5-(1-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole (Example 15)

[0715] 5-(1-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole was synthesized following Scheme 3 using 1-methyl-1H-pyrazole-3-carboxylic acid.

[0716] LCMS (ESI) Calcd for C16H16N4O: 280.1, found [M+H]+: = 281.1.1H NMR (400 MHz, DMSO-d6) δH7.95 (s, 1H), 7.37 (d, 1H), 7.26-7.18 (m, 3H), 6.91 (brs, 1H), 3.97 (s, 3H), 2.26 (s, 3H), 1.65 (brs, 2H), 1.37 (brs, 2H). Example 16: Synthesis of 5-(1,4-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole (Example 16)

[0717] 5-(1,4-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole was synthesized following Scheme 3 using 1,4-dimethyl-1H-pyrazole-3-carboxylic acid.

[0718] LCMS (ESI) Calcd. for C17H18N4O: 294.2, found [M+H]+= 295.1.1H NMR (400 MHz, DMSO-d6) δH7.75 (s, 1H), 7.37 (d, 1H), 7.25-7.19 (m, 3H), 3.89 (s, 3H), 2.26 (d, 6H), 1.65 (s, 2H), 1.37 (s, 2H). Example 17: Synthesis of 5-(5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 17)

[0719] Synthesis of ethyl 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate, 15 [Step 1]: To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole-3-carboxylate (13, 2.0 g, 10.5 mmol) in DMF (50 mL) at 0°C, sodium hydride (505 mg, 12.6 mmol) was added at 0oC. The reaction mixture was stirred at ambient temperature for 1 h and 1-bromo-2-methoxy-ethane (1.5 g, 10.5 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 h and quenched with crushed ice. The resulting mixture was extracted ethyl acetate and washed with ice cold water and brine. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford ethyl 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3- carboxylate (15, 400 mg). LCMS (ESI) Calcd. C10H14F2N2O3: 248.1, found [M+H]+= 249.2.1H NMR (400 MHz, DMSO-d6) δH 7.43-7.05 (m, 2H), 4.46 (t, 2H), 4.31-4.26 (m, 2H), 3.70 (t, 2H), 3.21 (s, 3H), 1.29 (t, 3H). Note: Isolated 900 mg other isomer 14 and the structure was confirmed by NOE experiment.

[0720] Ethyl 3-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-5-carboxylate, 14: LCMS (ESI) Calcd. C10H14F2N2O3: 248.1, found [M+H]+= 249.2.1H NMR (400 MHz, DMSO-d6) δH7.19-6.92 (m, 2H), 4.70 (t, 2H), 4.34-4.29 (m, 2H), 3.69 (t, 2H), 3.19 (s, 3H), 1.31 (t, 3H).

[0721] Synthesis of 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid, 16 [Step 2]: To an ice cold solution of ethyl 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3- carboxylate (15, 420 mg, 1.4 mmol) in THF (4 mL) and methanol (1 mL), an aqueous solution of lithium hydroxide (135 mg, 3.2 mmol) in water (2 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 h and volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of dichloromethane and isopropyl alcohol (9:1). Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid (16, 320 mg). LCMS (ESI) Calcd. for C18H10F2N2O2: 220.1, found [M+H]+= 221.2.

[0722] Synthesis of (Z)-N'-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonyl)oxy)- 1-(o-tolyl)cyclopropane-1-carboximidamide, 17 [Step 3]: To a stirred solution of 5- (difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid (16, 320 mg, 1.5 mmol), and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 275 mg, 1.5 mmol) in dichloromethane (15 mL), N,N-diisopropylethylamine (0.6 mL, 4.4 mmol), 1-hydroxy-7- azabenzotriazole (40 mg, 0.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (360 mg, 1.9 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-N'-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3- carbonyl)oxy)-1-(o-tolyl)cyclopropane-1-carboximidamide (17, 540 mg). LCMS (ESI) Calcd. for C19H22F2N4O3: 392.2, found [M+H] = 393.2.

[0723] Synthesis of 5-(5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 17 [Step 4]: To a stirred solution of (Z)-N'-((5- (difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1- carboximidamide (17, 540 mg, 1.4 mmol) in tetrahydrofuran (10 mL), tetra butyl ammonium hydroxide (39.6 mg, 0.2 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The productwas purified by reverse phase prep HPLC to afford 5-(5-(difluoromethyl)-1-(2-methoxyethyl)-1H- pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 17, 287 mg). LCMS (ESI) Calcd. for C19H20F2N4O2: 374.2, found [M+H]+= 375.3.1H NMR (400 MHz, DMSO-d6) δH7.47- 7.24 (m, 3H), 7.23-7.20 (m, 3H), 4.52 (t, 2H), 3.72 (t, 2H), 3.22 (s, 3H), 2.27 (s, 3H), 1.68-1.65 (m, 2H), 1.41-1.38 (m, 2H). Note: Another isomer was formed during alkylation. Example 18: Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propenamide (Example 18)

[0724] Synthesis of ethyl 1-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylate, 18 and ethyl 2-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylate, 18a [Step 1]: To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole-3-carboxylate (13, 500 mg, 2.6 mmol) in dimethylformamide (25 mL), potassium carbonate (1.8 g, 13.1 mmol) was added. After 1 h, 3- bromopropanamide (600 mg, 3.9 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford a mixture of ethyl 1-(3-amino-3-oxo-propyl)-5- (difluoromethyl)pyrazole-3-carboxylate and ethyl 2-(3-amino-3-oxo-propyl)-5- (difluoromethyl)pyrazole-3-carboxylate (18 and 18a, 470 mg). LCMS (ESI) Calcd. for C10H13F2N3O3: 261.1, found [M+H]+= 262.2.

[0725] Synthesis of 1-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylic acid, 19 and 1-(3-amino-3-oxopropyl)-3-(difluoromethyl)-1H-pyrazole-5-carboxylic acid, 19a [Step 2]: To a cold solution mixture of ethyl 1-(3-amino-3-oxopropyl)-5-(difluoromethyl)-1H-pyrazole-3- carboxylate and ethyl 1-(3-amino-3-oxopropyl)-3-(difluoromethyl)-1H-pyrazole-5-carboxylate (18 and 18a, 300 mg, 1.2 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL), a solution of lithium hydroxide (95 mg, 2.3 mmol) in water (2 mL) was added drop-wise. The reaction mixture wasstirred at ambient temperature for 3 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of ethyl acetate and isopropyl alcohol (1:9). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The products were purified by column chromatography to afford a mixture of 1-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylic acid and 1- (3-amino-3-oxopropyl)-3-(difluoromethyl)-1H-pyrazole-5-carboxylic acid (19 and 19a, 240 mg). LCMS (ESI) Calcd. for C8H9F2N3O3: 405.2, found [M+H]+= 406.4.

[0726] Synthesis of (Z)-3-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)propanamide, 20 and (Z)-3-(5-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-3-(difluoromethyl)-1H-pyrazol-1- yl)propanamide, 20a [Step 3]: To a stirred solution mixture of 1-(3-amino-3-oxo-propyl)-5- (difluoromethyl)pyrazole-3-carboxylic acid and 1-(3-amino-3-oxopropyl)-3-(difluoromethyl)-1H- pyrazole-5-carboxylic acid (19 and 19a, 240 mg, 1.0 mmol) in dichloromethane (10 mL), N,N- Diisopropylethylamine (330 mg, 2.6 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.2 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (255 mg, 1.3 mmol) and (Z)-N'- hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 235 mg, 1.2 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The products were purified by combi-flash chromatography to afford the first product as (Z)-3-(5-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)propanamide (20a, 120 mg) and the second product as (Z)-3-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propanamide (20, 90 mg). LCMS (ESI) Calcd. for C19H21F2N5O3: 405.2, found [M+H]+= 406.4. Note: Structure of both the isomers were confirmed based on NOE experiments of the final products.

[0727] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propanamide, Example 171 [Step 4]: To a stirred solution of (Z)-3-(5-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-3-(difluoromethyl)-1H-pyrazol-1- yl)propanamide (20a, 60 mg, 0.2 mmol) in tetrahydrofuran (5 mL), tetra butyl ammonium hydroxide (0.03 mL, 0.03 mmol, 1M in methanol) was added. The resulting reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residuewas diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford 3-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanamide (Example 171, 9 mg). LCMS (ESI) Calcd. for C19H19F2N5O2: 387.2, found [M+H]+= 388.3.1H NMR (400 MHz, DMSO- d6) δH7.56-7.18 (m, 7H), 6.98 (brs, 1H), 4.48 (t, 2H), 2.74 (t, 2H), 2.26 (s, 3H), 1.65 (brs, 2H), 1.39 (brs, 2H).

[0728] Synthesis of 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propanamide, Example 18 [Step 5]: To a stirred solution of (Z)-3-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propanamide (20, 80 mg, 0.2 mmol) in tetrahydrofuran (2 mL), tetra butyl ammonium hydroxide (10 mg, 0.04 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water followed by brine wash. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford 3-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanamide (Example 18, 22 mg). LCMS (ESI) Calcd. for C19H19F2N5O2: 387.2, found [M+H]+= 388.3.1H NMR (400 MHz, DMSO- d6) δH 7.39-6.90 (m, 8H), 4.79 (t, 2H), 2.68 (t, 2H), 2.29 (s, 3H), 1.71 (brs, 2H), 1.42 (brs, 2H). Note: Structure was confirmed based on NOE experiment. Example 19: Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 19)

[0729] Synthesis of 5-(1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, 25 [Step 1]: To a suspension of methyl 1H-pyrazole-3-carboxylate (265 mg, 2.1 mmol) and (Z)-N'-hydroxy-1- (o-tolyl)cyclopropane-1-carboximidamide (11, 400 mg, 2.1 mmol) in toluene (4 mL) was added potassium carbonate (581 mg, 4.2 mmol), and the reaction mixture was heated to reflux. After16 h, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The compound was purified by column chromatography to afford 5- (1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (25, 360 mg). LCMS calcd. for C15H14N4O: 266.12, found [M+H]+= 267.3.1H NMR (400 MHz, DMSO-d6): δH13.75 (brs, 1H), 8.00 (d, 1H), 7.39-7.37 (m, 1H), 7.24-7.20 (m, 3H), 6.92 (d, 1H), 2.27 (s, 3H), 1.66-1.65 (m, 2H), 1.38-1.37 (m, 2H)

[0730] Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazole, Example 19 [Step 2]: To an ice-cold solution of 5-(1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (25, 150 mg, 0.6 mmol) in THF (6 mL) was added NaH (27 mg, 60% in mineral oil, 0.7 mmol). After 15 min, 1-bromo-2-(methylsulfonyl)ethane (126 mg, 0.7 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was quenched with cold water, and extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The compound was purified by column chromatography using 0-50% ethyl acetate in hexanes to afford 5-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole (Example 19, 125 mg). LCMS calcd. for C18H20N4O3S: 372.13, found [M+H]+= 373.1.1H NMR (400 MHz, DMSO-d6): δH 8.09 (d, 1H), 7.38-7.36 (m, 1H), 7.26-7.17 (m, 3H), 6.95 (d, 1H), 4.70 (t, 2H), 3.77 (t, 2H), 2.96 (s, 3H), 2.26 (s, 3H), 1.67-1.64 (m, 2H), 1.39-1.36 (m, 2H). Structure of the compound was supported by NOE data. Example 20: Synthesis of 5-(5-cyclopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3- (1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 20)

[0731] Synthesis of 5-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole, 26 [Step 1]: To a suspension of methyl 5-cyclopropyl-1H-pyrazole-3-carboxylate (349 mg, 2.1 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 400 mg,2.1 mmol) in toluene (4 mL) was added potassium carbonate (581 mg, 4.2 mmol), and the reaction mixture was heated to reflux. After 16 h, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column afforded 5-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (26, 350 mg). LCMS calcd. for C18H18N4O: 306.15, found [M+H]+= 307.3.1H NMR (400 MHz, DMSO-d6): δH13.49 (brs, 1H), 7.38-7.36 (m, 1H), 7.25-7.18 (m, 3H), 6.57-6.56 (m, 1H), 2.26 (s, 3H), 1.99-1.93 (m, 1H), 1.63 (brs, 2H), 1.37-1.36 (m, 2H), 1.00-0.96 (m, 2H), 0.80-0.77 (m, 2H).

[0732] Synthesis of 5-(5-cyclopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 20 [Step 2]: To an ice-cold solution of 5-(5- cyclopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (26, 150 mg, 0.5 mmol) in THF (5 mL) was added NaH (24 mg, 60% in mineral oil, 0.6 mmol). After 15 min, 1-bromo-2- (methylsulfonyl)ethane (110 mg, 0.6 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was quenched with cold water, and extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The compound was purified by column chromatography using 0-50% ethyl acetate in hexanes to afford 5-(5-cyclopropyl-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 20, 110 mg). LCMS calcd. for C21H24N4O3S: 412.16, found [M+H]+= 413.2.1H NMR (400 MHz, DMSO-d6): δH 7.37-7.36 (m, 1H), 7.25-7.17 (m, 3H), 6.63 (s, 1H), 4.70 (t, 2H), 3.77 (t, 2H), 3.00 (s, 3H), 2.25 (s, 3H), 2.07-2.00 (m, 1H), 1.63 (brs, 2H), 1.37 (brs, 2H), 1.03-0.99 (m, 2H), 0.79- 0.78 (m, 2H). Protons of one cyclopropyl ring appeared as two broad singlets. Structure of the compound was supported by NOE data. Example 21: Synthesis of 5-(5-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 21)

[0733] Synthesis of 5-(5-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, 27 [Step 1]: To a suspension of methyl 5-methyl-1H-pyrazole-3-carboxylate ( 295 mg, 2.1 mmol)and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 400 mg, 2.1 mmol) in toluene (4 mL) was added potassium carbonate (581 mg, 4.2 mmol), and the reaction mixture was heated to reflux. After 16 h, the reaction mixture was filtered through a celite pad, and the filtrate concentrated under reduced pressure. The compound was purified by column chromatography to afford 5-(5-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole (27, 450 mg). LCMS calcd. for C16H16N4O: 280.13, found [M+H]+= 281.3.1H NMR (400 MHz, DMSO-d6): δH 13.43 (brs, 1H), 7.38-7.36 (m, 1H), 7.26-7.17 (m, 3H), 6.65 (s, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.65-1.63 (m, 2H), 1.38-1.35 (m, 2H).

[0734] Synthesis of 5-(5-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 21 [Step 2]: To an ice-cold solution of 5-(5-methyl- 1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (27, 100 mg, 0.4 mmol) in THF (4 mL) was added NaH (17 mg, 60% in mineral oil, 0.4 mmol). After 15 min, 1-bromo-2- (methylsulfonyl)ethane (80 mg, 0.4 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was quenched with cold water, and extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The compound was purified by column chromatography using 0-50% ethyl acetate in hexanes to afford 5-(5-methyl-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 21, 68 mg). LCMS calcd. for C19H22N4O3S: 386.14, found [M+H]+= 387.1.1H NMR (400 MHz, DMSO-d6): δH 7.38-7.36 (m, 1H), 7.22-7.19 (m, 3H), 6.74 (s, 1H), 4.56 (t, 2H), 3.74 (t, 2H), 2.96 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.64 (brs, 2H), 1.37 (brs, 2H). Protons of the cyclopropyl ring appeared as two broad singlets. Structure of the compound was supported by NOE experiment. Example 22: Synthesis of 5-(5-isopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 22) Scheme 9

[0735] Synthesis of (Z)-N'-((5-isopropyl-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1- carboximidamide, 28 [Step 1]: To a stirred solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (220 mg, 1.4 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 407 mg, 2.1 mmol) in dichloromethane (5 mL), N,N-diisopropylethylamine (1.2 mL, 7.1 mmol), EDCI.HCl (545 mg, 2.8 mmol) and HOAt (40 mg, 0.3 mmol) were added at 0 °C. The reaction mixture wasstirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (Z)-N'-((5- isopropyl-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1-carboximidamide (28, 500 mg). LCMS (ESI) calcd. for C18H22N4O2: 326.1, [M+H]+= 327.4.

[0736] Synthesis of 5-(5-isopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, 29 [Step 2]: To a stirred solution of (Z)-N'-((5-isopropyl-1H-pyrazole-3-carbonyl)oxy)-1-(o- tolyl)cyclopropane-1-carboximidamide (28, 465 mg, 1.4 mmol) in THF (5 mL), tetrabutylammonium hydroxide (0.1 mL, 0.1 mmol, 1M in methanol) was added at ambient temperature. The reaction was stirred at ambient temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford 5-(5-isopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (29, 156 mg). LCMS (ESI) calcd. for C18H20N4O: 308.1, [M+H]+= 309.4.

[0737] Synthesis of 5-(5-isopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole and 5-(3-isopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-5- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 22 & Example 172 [Step 3]: To a stirred solution of 5-(5-isopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (29, 155 mg, 0.5 mmol) in THF (5 mL), NaH (25 mg, 0.6 mmol, 60% in oil) was added at 0 °C under nitrogen atmosphere and the reaction mixture was stirred for 10 min. Into the reaction mixture, 1-bromo-2-(methylsulfonyl)ethane ( 114 mg, 0.6 mmol) was added and stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford 5-(5-isopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazole (Example 22, 100 mg) as Peak-1 and 5-(3-isopropyl-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 172, 20 mg) as peak-2. NOTE: The exact structure was confirmed by NOE of peak 1 and Peak-2.

[0738] Analytical data of 5-(5-isopropyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 22 (Peak-1): LCMS (ESI) calcd. for C21H26N4O3S: 414.1, [M+H]+= 415.2.1H NMR (400 MHz, DMSO-d6) δH7.38-7.36 (m, 1H), 7.21-7.13 (m, 3H),6.78 (s, 1H), 4.57 (t, 2H), 3.76 (t, 2H), 3.18-3.15 (m, 1H), 2.98 (s, 3H), 2.25 (s, 3H), 1.70-1.64 (m, 2H), 1.45-1.37 (m, 2H), 1.25-1.23 (m, 6H). Example 23: Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid (Example 23)

[0739] Synthesis of methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate, 31 [Step 1]: To a stirred solution of 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (30, 900 mg, 5.0 mmol) in methanol (20 mL) at 0 °C was added thionyl chloride (0.73 mL, 10.0 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature for 14 h and volatiles were evaporated. The residue was diluted with ethyl acetate and washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (31, 550 mg). LCMS (ESI) Calcd. for C6H5F3N2O2: 194.0, found [M-H]- = 193.1.

[0740] Synthesis of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole, 32 [Step 2]: To a stirred solution of (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 600 mg, 3.2 mmol) in toluene (15 mL) was added potassium carbonate (872 mg, 6.3 mmol) and methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (31, 612 mg, 3.2 mmol). Resulting reaction mixture was refluxed for 16 h and filtered through a celite bed. Combined filtrate was concentrated and the product was purified by column chromatography to afford 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 400 mg). LCMS (ESI) Calcd. for C16H13F3N4O: 334.1, found [M+H]+= 335.0.

[0741] Synthesis of tert-butyl 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)propanoate, 33 and tert-butyl 3-(5-(3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate, 33a [Step 3]: To a stirred solution of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 300 mg, 1.0 mmol) in THF (10 mL) was added potassium carbonate (186 mg, 1.4 mmol). After 10 min., tert-butyl 3-bromopropanoate (281 mg, 1.4 mmol) was added. The reaction mixture was refluxed for 14 h, filtered and combined filtrate was concentrated under reduced pressure. The products were purified by reverse phase preparative HPLC to afford the first product as tert- butyl 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1- yl)propanoate, Peak 1 (33, 50 mg) and the second product as tert-butyl 3-(5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate, Peak-2 (33a, 75 mg). The structure of the regiomers were confirmed by 2D NMR analyses.

[0742] tert-butyl 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propanoate, Peak 1 (33): LCMS (ESI) Calcd. for C23H25F3N4O3: 462.19, found [M+H]+= 463.10.

[0743] tert-butyl 3-(5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)propanoate, Peak-2 (33a): LCMS (ESI) Calcd. for C23H25F3N4O3: 462.19, found [M+H]+= 463.10.

[0744] Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propanoic acid, Example 23 [Step 4]: To a stirred solution of tert-butyl 3-(3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate (33, 50 mg, 0.1 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.08 mL, 1.1 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propanoic acid (Example 23, 15 mg). LCMS (ESI) Calcd. for C19H17F3N4O3: 406.13, found [M+H]+= 407.10.1H NMR (400 MHz, DMSO-d6): δH7.63 (s, 1H), 7.38 (d, 1H), 7.24-7.19 (m, 3H), 4.53 (t, 2H), 2.92 (t, 2H), 2.26 (s, 3H), 1.68-1.65 (m, 2H), 1.41-1.39 (m, 2H). One acid proton was exchangeable.

[0745] Synthesis of 3-(5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)propanoic acid, Example 173 [Step 5]: To a stirred solution of tert-butyl 3-(5-(3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate (33a, 75 mg, 0.2 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.12 mL, 1.6mmol). The reaction mixture was allowed to stir at ambient temperature for 16 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford 3-(5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid (Example 173, 30 mg). LCMS (ESI) Calcd. for C19H17F3N4O3: 406.13, found [M+H]+= 407.10.1H NMR (400 MHz, DMSO-d6): δH7.64 (s, 1H), 7.38 (d, 1H), 7.25-7.18 (m, 3H), 4.84 (t, 2H), 2.85 (t, 2H), 2.29 (s, 3H), 1.71-168 (m, 2H), 1.45- 1.42 (m, 2H). One acid proton was exchangeable. Example 24: Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)propanamide (Example 24)

[0746] Synthesis of 1-(o-tolyl)-N'-((5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane- 1-carboximidamide, 35 [Step 1]: To a stirred solution of N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 500 mg, 2.6 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (520 mg, 2.9 mmol) in dichloromethane (8 mL) were added DIPEA (1.4 mL, 7.9 mmol), EDC.HCl (1.0 g, 5.3 mmol) and HOAt (55 mg, 0.5 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. Organic extract was collected, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure to afford 1-(o-tolyl)-N'-((5- (trifluoromethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide (35, 500 mg). LCMS (ESI) Calcd for C16H15F3N4O2: 352.3, found [M+H]+= 353.1.

[0747] Synthesis of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole, 32 [Step 2]: To a stirred solution of 1-(o-tolyl)-N'-((5-(trifluoromethyl)-1H-pyrazole-3- carbonyl)oxy)cyclopropane-1-carboximidamide (35, 500 mg, 1.4 mmol) in THF (4 mL) was added tetrabutylammonium hydroxide (185 mg, 0.3 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic extract was collected, washed with brine, dried over anhydrous Na2SO4and, concentrated under reduced pressure. The product was purified by column chromatography to afford 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 300 mg). LCMS (ESI) Calcd for C16H13F3N4O: 334.3, found [M+H]+= 335.3.

[0748] Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propanamide & 3-(5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)propanamide, Example 24 & Example 174 [Step 3]: To a stirred solution of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 280 mg, 0.8 mmol) in THF (5mL) was added K2CO3(462 mg, 3.4 mmol) at 0 °C. After 15 min 3- bromopropanamide (255 mg, 1.7 mmol) was added to the reaction mixture and stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic extract was collected, washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by column chromatography and isolated compound was lyophilized to afford 3-(3- (3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide (Example 24, 62 mg) and 3-(5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)propanamide (Example 174, 62 mg). Note: Structure was confirmed by HMBC & HSQC.

[0749] Analytical data of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)propanamide, Example 24: LCMS (ESI) Calcd for C19H18F3N5O2: 405.3, found [M+H]+= 406.3.1H NMR (400 MHz, DMSO-d6) δH 7.62 (s, 1H), 7.49 (brs, 1H), 7.38 (d, 1H), 7.24-7.20 (m, 3H), 6.90 (brs, 1H), 4.52 (t, 2H), 2.78 (t, 2H), 2.26 (s, 3H), 1.66 (s, 2H), 1.40 (s, 2H). Example 25: Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propanoic acid (Example 25)

[0750] Synthesis of methyl 5-cyclopropyl-1H-pyrazole-3-carboxylate, 38 [Step 1]: To a stirred solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid (37, 1.5 g, 9.8 mmol) in methanol (30 mL) at 0 °C was added thionyl chloride (1.4 mL, 19.7 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature for 14 h, quenched with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated to afford methyl 5-cyclopropyl-1H- pyrazole-3-carboxylate (38, 720 mg). LCMS (ESI) Calcd. for C8H10N2O2: 166.0, found [M+H]+= 167.2.

[0751] Synthesis of 5-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole, 26 [Step 2]: To a stirred solution of (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 700 mg, 3.7 mmol) in toluene (15 mL) were added potassium carbonate (1.0 g, 7.4 mmol) and methyl 5-cyclopropyl-1H-pyrazole-3-carboxylate (38, 611 mg, 3.7 mmol). Resulting reaction mixture was heated at 110 °C for 16 h, filtered through a celite bed and concentrated under reduced pressure. The product was purified by column chromatography to afford 5-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (26, 500 mg). LCMS (ESI) Calcd. for C18H18N4O: 306.1, found [M+H]+= 360.8.

[0752] Synthesis of tert-butyl 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)propanoate, 40 [Step 3]: To a stirred solution of 5-(5-cyclopropyl-1H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (26, 250 mg, 0.8 mmol) in acetonitrile (10 mL) was added Cs2CO3 (399 mg, 1.2 mmol) and tert-butyl 3-bromopropanoate ( 205 mg, 0.9 mmol). The reaction mixture was stirred at 70 °C for 14 h, filtered, the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to afford tert-butyl 3-(5- cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoate (40, 175 mg). LCMS (ESI) Calcd. for C25H30N4O3: 434.2, found [M+H]+= 435.4.

[0753] Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propanoic acid, Example 25 [Step 4]: To a stirred solution of tert-butyl 3-(5- cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoate (40, 175 mg, 0.4 mmol) in dichloromethane (8 mL) at 0 °C was added trifluoroacetic acid (0.31 mL, 4.0 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford

[0754] 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)propanoic acid (Example 25, 95 mg). LCMS (ESI) Calcd. for C21H22N4O3: 378.1, found [M+H]+= 379.2.1H NMR (400 MHz, DMSO-d6): δH7.36 (d, 1H), 7.21-7.19 (m, 3H), 6.55 (s, 1H), 4.43 (t, 2H), 2.77 (t, 2H), 2.24 (s, 3H), 2.07-2.03 (m, 1H), 1.62 (brs, 2H), 1.35 (brs, 2H), 0.98-0.96 (m, 2H), 0.74-0.73 (m, 2H). Structure was confirmed by 2D NMR analysis. Example 26: Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 26)

[0755] Synthesis of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole, 32 [Step 1]: To a stirred solution of (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 410 mg, 2.2 mmol) and ethyl 5-(trifluoromethyl)-1H-pyrazole-3- carboxylate (450 mg, 2.2 mmol) in toluene (6 mL) was added potassium carbonate (600 mg, 4.3 mmol) at ambient temperature and reaction mixture was allowed to stir at 110 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature and diluted with water and extracted with dichloromethane. The organic extract was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H- pyrazol-3-yl)-1,2,4-oxadiazole (32, 450 mg). LCMS (ESI) Calcd. for C16H13F3N4O: 334.1, [M+H]+= 335.3.

[0756] Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 175 [Step 2]: To a stirred solution of 3-(1-(o- tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 250 mg, 0.7 mmol) in THF (5 mL) was added NaH (60% in oil suspension) (35 mg, 0.9 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred for 10 min at same condition. To this reaction mixture was added 1-bromo-2-(methylsulfonyl)ethane (170 mg, 0.9 mmol) and the reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic extract wasdried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford 5-(1-(2-(methylsulfonyl)ethyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 175, 80 mg). LCMS (ESI) calcd. for C19H19F3N4O3S: 440.1, [M+H]+= 441.0.1H NMR (400 MHz, DMSO- d6) δH7.72 (s, 1H), 7.38-7.37 (m, 1H), 7.23-7.20 (m, 3H), 5.12 (t, 2H), 3.78 (t, 2H), 3.00 (s, 3H), 2.29 (s, 3H), 1.75 (s, 2H), 1.43 (s, 2H). NOTE: The exact structure was confirmed by HMBC.

[0757] Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 26 [Step 3]: To a stirred solution of 3-(1-(o- tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (32, 220 mg, 0.7 mmol) in THF (5 mL) was added K2CO3(182 mg, 1.3 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred for 10 min at same condition. To this reaction mixture was added 1-bromo-2-(methylsulfonyl)ethane (185 mg, 1 mmol) and the reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford 5-(1-(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 26, 25 mg). LCMS (ESI) calcd. for C19H19F3N4O3S: 440.11, [M+H]+= 441.0,1H NMR (400 MHz, DMSO-d6) δH 7.69 (s, 1H), 7.39- 7.37 (m, 1H), 7.26-7.18 (m, 3H), 4.77 (t, 2H), 3.85 (t, 2H), 3.08 (s, 3H), 2.26 (s, 3H), 1.66 (s, 2H), 1.41 (s, 2H). NOTE: The exact structure was confirmed by HMBC. Example 27: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 27)

[0758] Synthesis of ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-5-(difluoromethyl)-1H-pyrazole-3- carboxylate, 43 [Step 1]: To a stirred solution of ethyl 5-(difluoro methyl)-1H-pyrazole-3- carboxylate (42, 800 mg, 4.2 mmol) in dimethylformamide (5 mL) at 0 °C, sodium hydride (200 mg, 5.1 mmol, 60% dispersion in mineral oil) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h and tert-butyl 2-bromoacetate (985 mg, 5.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with crushed ice, extracted with ethyl acetate. The organic extract was washed with ice cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-5- (difluoromethyl)-1H-pyrazole-3-carboxylate (43, 500 mg).1H NMR (400 MHz, DMSO-d6) δH 7.41-7.11 (m, 2H), 5.19 (s, 2H), 4.32-4.27 (m, 2H), 1.41 (s, 9H), 1.30 (t, 3H). Note: Isolated 300 mg of ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-3-(difluoromethyl)-1H-pyrazole-5-carboxylate (43a) and the structure of desired isomer was confirmed by NOE experiment.1H NMR (400 MHz, DMSO-d6) δH 7.20-6.93 (m, 2H), 5.25 (s, 2H), 4.32-4.27 (m, 2H), 1.41 (s, 9H), 1.29 (t, 3H).

[0759] Synthesis of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid, 44 [Step 2]: To a stirred solution of ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-5-(difluoromethyl)-1H- pyrazole-3-carboxylate (43, 200 mg, 0.7 mmol) in dichloromethane (1 mL), trifluoroacetic acid (1.0 mL, 13.5 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at ambienttemperature for 3 h. After completion the volatiles were evaporated under reduced pressure to afford 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 120 mg). LCMS (ESI) Calcd. for C9H10F2N2O4: 248.0, found [M+H]+= 249.2.

[0760] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 45 [Step 3]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H- pyrazol-1-yl)acetic acid (44, 400 mg, 1.6 mmol) in dry tetrahydrofuran (3 mL), 4- methylmorpholine (0.6 mL, 5.6 mmol) and isobutyl chloroformate (0.3 mL, 2.4 mmol) were added. The reaction mixture was stirred at -15 °C for 15 min and methanamine hydrochloride (545 mg, 8.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for additional 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 5-(difluoromethyl)-1- (2-(methylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylate (45, 110 mg). LCMS (ESI) Calcd. C10H13F2N3O3: 261.1, found [M+H]+= 262.2.

[0761] Synthesis of 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylic acid, 46 [Step 4]: To a cold solution of ethyl 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)- 1H-pyrazole-3-carboxylate (45, 110 mg, 0.4 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL), a solution of lithium hydroxide (26.5 mg, 0.6 mmol) in water (2 mL) was added drop-wise. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of ethyl acetate and isopropyl alcohol (9:1). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(difluoromethyl)-1-(2-(methylamino)-2- oxoethyl)-1H-pyrazole-3-carboxylic acid (46, 80 mg).1H NMR (400 MHz, DMSO-d6) δH 13.03 (brs, 1H), 8.19 (d, 1H), 7.23 (t, 1H), 7.01 (s, 1H), 4.97 (s, 2H), 2.62 (d, 3H).

[0762] Synthesis of (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-methylacetamide, 47 [Step 5]: To a stirred solution of 5- (difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylic acid (46, 80 mg, 0.3 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 105 mg, 0.6 mmol) in dichloromethane (5 mL), N,N-diisopropylethylamine (0.3 mL, 1.7 mmol), 1-Hydroxy-7- azabenzotriazole (9.3 mg, 0.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98.7 mg, 0.5 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate andwashed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-2-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N- methylacetamide (47, 130 mg). LCMS (ESI) Calcd. for C19H21F2N5O3: 405.2, found [M+H]+= 406.4.

[0763] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-methylacetamide, Example 27 [Step 6]: To a stirred solution of (Z)-2-(3- ((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)-N-methylacetamide (47, 130 mg, 0.3 mmol) in tetrahydrofuran (2 mL), tetra butyl ammonium hydroxide (41.6 mg, 0.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC purification to afford 2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 27, 15 mg). LCMS Calcd. for C19H19F2N5O2: 387.2, found [M+H]+= 388.3.1H NMR (400 MHz, DMSO- d6) δH 8.22-8.21 (m, 1H), 7.42-7.15 (m, 6H), 5.06 (s, 2H), 2.62 (d, 3H), 2.26 (s, 3H), 1.67-1.65 (m, 2H), 1.41-1.38 (m, 2H). Example 28: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Example 28)

[0764] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 48 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H- pyrazol-1-yl)acetic acid (44, 350 mg, 1.4 mmol) in dry dimethylformamide (5 mL), N,N- diisopropylethylamine (0.9 mL, 4.9 mmol) and N-methylmethanamine hydrochloride (1.2 g, 14.1 mmol) were added. After 10 min, T3P (1.3 mL, 4.2 mmol, 50 % in ethyl acetate) was added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Combined organic extract was washed with ice-cold water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 5-(difluoromethyl)-1-(2-(dimethylamino)-2- oxoethyl)-1H-pyrazole-3-carboxylate (48, 180 mg). LCMS (ESI) Calcd. C11H15F2N3O3: 275.1, found [M+H]+= 276.2.

[0765] Synthesis of 5-(difluoromethyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylic acid, 49 [Step 2]: To a cold solution of ethyl 5-(difluoromethyl)-1-(2-(dimethylamino)- 2-oxoethyl)-1H-pyrazole-3-carboxylate (48, 180 mg, 0.7 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) mixture, a solution of lithium hydroxide monohydrate (40 mg, 1.0 mmol) in water (1 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of ethyl acetate and isopropyl alcohol (9:1). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5- (difluoromethyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylic acid (49, 110 mg).1H NMR (400 MHz, DMSO-d6) δH 13.05 (brs, 1H), 7.41-7.00 (m, 2H), 5.34-5.16 (s, 1H), 3.04- 2.89 (m, 3H), 2.85-2.73 (s, 3H).1H NMR indicated the product as mixture of rotamers.

[0766] Synthesis of (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, 50 [Step 3]: To a stirred solution of 5- (difluoromethyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylic acid (49, 110 mg, 0.5 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 85.5 mg, 0.5 mmol) in dichloromethane (2 mL), N,N-diisopropylethylamine (0.3 mL, 1.6 mmol), 1-Hydroxy-7- azabenzotriazole (12.3 mg, 0.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112.1 mg, 0.6 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N,N- dimethylacetamide (50, 160 mg). LCMS (ESI) Calcd. for C20H23F2N5O3: 419.2 found [M+H]+= 420.4.

[0767] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N,N-dimethylacetamide, Example 28 [Step 4]: To a stirred solution of (Z)-2-(3- ((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)-N,N-dimethylacetamide (50, 130 mg, 0.3 mmol) in tetrahydrofuran (2 mL), tetra butyl ammonium hydroxide (41.6 mg, 0.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC purification to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-methylacetamide (Example 28, 25 mg). LCMS (ESI) Calcd. for C20H21F2N5O2: 401.1, found [M+H]+= 402.3.1H NMR (400 MHz, DMSO-d6) δH 7.38 (d, 1H), 7.34-7.08 (m, 5H), 5.44 (s, 2H), 3.05 (s, 3H), 2.85 (s, 3H), 2.26 (s, 3H), 1.67-1.66 (m, 2H), 1.41-1.38 (m, 2H). Example 29: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Example 29)

[0768] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 3 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H- pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dry tetrahydrofuran (10 mL), n-methyl morpholine (245 mg, 2.4 mmol) and isobutyl chloroformate (165 mg, 1.2 mmol) were added at - 15 °C. After 15 min, oxetan-3-amine (105 mg, 1.5 mmol) was added at -15 °C and the reaction mixture was stirred at same temperature for additional 2 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by combi flash chromatography to afford ethyl 5- (difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylate (51, 340 mg).1H NMR (400 MHz, DMSO-d6) δH 9.11 (d, 1H), 7.36-7.07 (m, 2H), 5.06 (s, 2H), 4.82-4.77 (m, 1H), 4.75-4.70 (m, 2H), 4.43 (t, 2H), 4.31-4.26 (m, 2H), 1.29 (t, 3H).

[0769] Synthesis of 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylic acid, 52 [Step 2]: To a cold solution of ethyl 5-(difluoromethyl)-1-(2-(oxetan-3- ylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylate (51, 170 mg, 0.6 mmol) in tetrahydrofuran (3 mL), a solution of lithium hydroxide (45 mg, 1.1 mmol) in water (1 mL) was added drop-wise. The reaction mixture was stirred at ambient temperature for 3 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with ethyl acetate (twice). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole- 3-carboxylic acid (52, 140 mg). LCMS (ESI) Calcd. for C10H11F2N3O4: 275.1 found [M+H]+= 276.2.

[0770] Synthesis of (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(oxetan-3-yl)acetamide, 53 [Step 3]: To a stirred solution of 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3-carboxylic acid (52, 160 mg, 0.6 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (185 mg, 1.5 mmol), 1- hydroxy-7-azabenzotriazole (15.8 mg, 0.1 mmol), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (145 mg, 0.8 mmol) and (Z)-N'-hydroxy-1-(o- tolyl)cyclopropane-1-carboximidamide (11, 135 mg, 0.7 mmol) were added at 30 °C. The reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(oxetan- 3-yl)acetamide (53, 260 mg). LCMS (ESI) Calcd. for C21H23F2N5O4: 447.2, found [M+H]+= 448.4.

[0771] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(oxetan-3-yl)acetamide, Example 29 [Step 4]: To a stirred solution of (Z)-2-(3- ((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)-N-(oxetan-3-yl)acetamide (53, 260 mg, 0.6 mmol) in tetrahydrofuran (5 mL), tetra butyl ammonium hydroxide (30 mg, 0.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford 2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(oxetan-3-yl)acetamide (Example 29, 75 mg). LCMS (ESI) Calcd. for C21H21F2N5O3: 429.1, found [M+H]+= 430.35.1H NMR (400 MHz, DMSO-d6) δH 9.15 (d, 1H), 7.41-7.38 (m, 1H), 7.31-7.14 (m, 5H), 5.29 (s, 2H), 4.82-4.77 (m, 1H), 4.74-4.70 (m, 2H), 4.45-4.42 (m, 2H), 2.26 (s, 3H), 1.60 (brs, 2H), 1.31 (brs, 2H). Example 30: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Example 30)

[0772] Synthesis of tert-butyl 4-(2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1- yl)acetyl)piperazine-1-carboxylate, 55 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3- (ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dichloromethane (5 mL), N,N-diisopropylethylamine (0.04 mL, 0.2 mmol) and propane phosphonic acid anhydride (0.06 mL, 0.20 mmol, 50% in ethyl acetate) were added. After 15 min, tert-butyl piperazine-1- carboxylate (54, 225 mg, 1.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with dichloromethane, washed with saturated solution of aqueous sodium bicarbonate followed by brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford tert-butyl 4-(2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (55, 450 mg). LCMS (ESI) Calcd. for C18H26F2N4O5: 416.2, found [M+H]+= 417.1.1H NMR (400 MHz, DMSO-d6) δH 7.30-7.03 (m, 2H), 5.43 (s, 2H), 4.31-4.26 (m, 2H), 3.49-3.47 (m, 2H), 3.43- 3.42 (m, 4H), 3.32-3.30 (m, 2H), 1.42 (s, 9H), 1.29 (t, 3H).

[0773] Synthesis of 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-(difluoromethyl)- 1H-pyrazole-3-carboxylic acid, 56 [Step 2]: To an ice cold solution of tert-butyl 4-(2-(5- (difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (55, 100 mg, 0.2 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL), a solution of lithium hydroxide (10 mg, 0.2 mmol) in water (1 mL) was added drop-wise. The reaction mixture was stirred at ambient temperature for 3 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of ethyl acetate and isopropyl alcohol (9:1). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5- (difluoromethyl)-1H-pyrazole-3-carboxylic acid (56, 90 mg). LCMS (ESI) Calcd. for C16H22F2N4O5: 388.2, found [M-H]- = 387.1.1H NMR (400 MHz, DMSO-d6) δH7.16-7.01 (m, 2H), 5.40 (s, 2H), 3.49-3.42 (m, 8H), 1.42 (s, 9H).

[0774] Synthesis of tert-butyl (Z)-4-(2-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)acetyl)piperazine-1-carboxylate, 57 [Step 3]: To a stirred solution of 1-(2-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (56, 40 mg, 0.10 mmol), and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 20 mg, 0.1 mmol) in dichloromethane (2 mL), N,N-diisopropylethylamine (0.05 mL, 0.3 mmol), 1-Hydroxy-7-azabenzotriazole (2.8 mg, 0.02 mmol) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (23.7 mg, 0.1 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford tert-butyl (Z)-4-(2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (57, 80 mg). LCMS (ESI) Calcd. for C27H34F2N6O5: 560.3, found [M+H]+= 561.5.

[0775] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one, Example 30 [Step 4]: To a stirred solution of tert- butyl (Z)-4-(2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (57, 80 mg, 0.1 mmol) in toluene (2 mL), propane phosphonic acid anhydride (0.05 mL, 0.2 mmol, 50% in ethyl acetate) was added. The resulting reaction mixture was heated at 90 °C for 12 h and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC purification to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-1- (piperazin-1-yl)ethan-1-one (Example 30, 12 mg). LCMS (ESI) Calcd. for C22H24F2N6O2: 442.1, found [M+H]+= 443.2.1H NMR (400 MHz, DMSO-d6 and two drops of D2O) δH 7.37-7.05 (m, 6H), 5.41 (s, 2H), 3.41-3.35 (m, 4H), 2.74-2.72 (m, 2H), 2.65-2.63 (m, 2H), 2.24 (s, 3H), 1.66- 1.63 (m, 2H), 1.39-1.36 (m, 2H). Example 31: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide (Example 31)

[0776] Synthesis of ethyl 5-(difluoromethyl)-1-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)- 1H-pyrazole-3-carboxylate, 58 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dichloromethane (5 mL) were added DIPEA (0.6 mL, 3.6 mmol) and propyl phosphonic anhydride (50% in ethyl acetate) (0.9 mL, 3.02 mmol). After 15 min, N,N-dimethylethane-1,2-diamine (106 mg, 1.2 mmol) was added and the resulting reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction mixture was diluted with dichloromethane, washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by combiflash chromatography to afford ethyl 5-(difluoromethyl)-1-(2-((2- (dimethylamino)ethyl)amino)-2-oxoethyl)-1H-pyrazole-3-carboxylate (58, 200 mg). LCMS (ESI) Calcd. for C13H20F2N4O3: 318.1, found [M+H]+= 319.1

[0777] Synthesis of 5-(difluoromethyl)-1-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-1H- pyrazole-3-carboxylic acid, 59 [Step 2]: To a stirred solution of ethyl 5-(difluoromethyl)-1-(2-((2- (dimethylamino)ethyl)amino)-2-oxoethyl)-1H-pyrazole-3-carboxylate (58, 200 mg, 1.5 mmol) in a mixture of THF (3 mL) and methanol (1 mL), was added a solution of lithium hydroxide monohydrate (52 mg, 1.2 mmol) in water (2 mL). The reaction mixture was stirred at ambient temperature for 2 h and volatiles were evaporated under reduced pressure. The residue was acidified with 1 (N) HCl and white precipitate was filtered and dried under reduced pressure to afford 5-(difluoromethyl)-1-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-1H-pyrazole-3- carboxylic acid (59, 160 mg). The product was carried to next step without further purification.

[0778] Synthesis of (Z)-2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide, 60 [Step 3]: To a stirred solution of 5-(difluoromethyl)-1-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-1H-pyrazole-3- carboxylic acid (59, 160 mg, 0.5 mmol) in DMF (3 mL), DIPEA (0.3 mL, 1.65 mmol), EDC.HCl (158 mg, 0.8 mmol) and HOAt (15 mg, 0.1 mmol) were added at ambient temperature. After 15 min, (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 105 mg, 0.5 mmol) was added. Resulting reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate and washed with water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(5-methoxy-2- methylphenyl)cyclopropane-1-carboximidamide (60, 220 mg). LCMS (ESI) Calcd. for C22H28F2N6O3: 462.2, found [M+H]+= 462.8. The product was carried to next step without further purification.

[0779] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide, Example 31 [Step 4]: A solution of (Z)-N'- ((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(5-methoxy-2- methylphenyl)cyclopropane-1-carboximidamide (60, 100 mg, 0.2 mmol) in toluene (2 mL), was added propyl phosphonic anhydride (50% in ethyl acetate) ( 0.1 mL,0.3 mmol). Resulting reaction mixture was stirred at 90 °C for 16 h, diluted with ethyl acetate and washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give 2-(5-(difluoromethyl)-3-(3- (1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2- (dimethylamino)ethyl)acetamide (Example 31, 16 mg). LCMS (ESI) Calcd. for C22H26F2N6O2: 444.2, found [M+H]+= 445.2.1H NMR (400 MHz, DMSO-d6 at HT): δH 8.17 (brs, 1H), 7.39-7.12 (m, 6H), 5.10 (s, 2H), 3.31 (t, 2H), 2.67 (brs, 2H), 2.43 (s, 6H), 2.30 (s, 3H), 1.70-1.67 (m, 2H), 1.41-1.38 (m, 2H). Example 32: Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)acetamide (Example 32)

[0780] Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1H- pyrazole-3-carboxylate, 61 [Step 1]: To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole- 3-carboxylate (13, 200 mg, 1.0 mmol) in tetrahydrofuran (5 mL), potassium tert-butoxide (355 mg, 3.1 mmol) was added. The reaction mixture was heated at 80 °C for 30 min and tert-butylN-(2-bromoethyl)carbamate (235 mg, 1.0 mmol) was added. The resulting reaction mixture was heated at 80 °C for 6 h. After completion, the reaction mixture was quenched with crushed ice, extracted with ethyl acetate and washed with ice cold water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford ethyl 1-(2-((tert- butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylate (61, 50 mg). LCMS (ESI) Calcd. for C14H21F2N3O4: 333.1, found [M+H]+= 334.1.1H NMR (400 MHz, DMSO-d6) δH 7.27 (t, 1H), 7.03 (s, 1H), 6.97-6.94 (m, 1H), 4.30-4.25 (m, 4H), 3.36-3.34 (m, 2H), 1.32 (s, 9H), 1.30 (t, 3H). Note: Structure of desired regio-isomer was confirmed by NOE experiment.

[0781] Synthesis of ethyl 1-(2-aminoethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylate 2,2,2- trifluoroacetate, 62 [Step 2]: To a stirred solution of ethyl 1-(2-((tert- butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylate (61, 200 mg, 0.6 mmol) in dichloromethane (2 mL), trifluoroacetic acid (0.1 mL, 1.2 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the volatiles were evaporated under reduced pressure to afford ethyl 1-(2-aminoethyl)-5- (difluoromethyl)-1H-pyrazole-3-carboxylate 2,2,2-trifluoroacetate (62, 150 mg). LCMS (ESI) Calcd. for C14H21F2N3O4: 233.1 found [M+H]+= 234.1.

[0782] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 63 [Step 3]: To a stirred solution of ethyl 1-(2-aminoethyl)-5-(difluoromethyl)-1H- pyrazole-3-carboxylate 2,2,2-trifluoroacetate (62, 250 mg, 0.8 mmol) in tetrahydrofuran at 0oC, triethyl amine (0.3 mL, 2.3 mmol) and acetyl chloride (0.1 mL, 2.3 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate (63, 150 mg). LCMS (ESI) Calcd. for C11H15F2N3O3: 275.1, found [M+H]+= 276.3.

[0783] Synthesis of 1-(2-acetamidoethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylic acid, 64 [Step 4]: To a cold solution of ethyl 5-(difluoromethyl)-1-(2-(methylamino)-2-oxoethyl)-1H- pyrazole-3-carboxylate (63, 250 mg, 0.9 mmol) in tetrahydrofuran (4 mL), a solution of lithium hydroxide monohydrate (76.3 mg, 1.8 mmol) in water (2 mL) was added drop-wise. The reaction mixture was stirred at ambient temperature for 3 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of dichloromethane andisopropyl alcohol (9:1). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 1-(2-acetamidoethyl)-5- (difluoromethyl)-1H-pyrazole-3-carboxylic acid (64, 140 mg). LCMS (ESI) Calcd. for C9H11F2N3O3: 247.1, found [M+H]+= 248.0.

[0784] Synthesis of (Z)-N-(2-(3-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)ethyl)acetamide, 65 [Step 5]: To a stirred solution of 1-(2- acetamidoethyl)-5-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (64, 130 mg, 0.5 mmol), and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (120 mg, 0.6 mmol) in dichloromethane (15 mL), N,N-diisopropylethylamine (0.3 mL, 1.6 mmol), 1-Hydroxy-7- azabenzotriazole (15 mg, 0.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.7 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-N-(2-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)ethyl)acetamide (65, 120 mg). LCMS (ESI) Calcd. for C20H23F2N5O3: 419.2, found [M+H]+= 420.2.

[0785] Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)ethyl)acetamide, Example 32 [Step 6]: A solution of (Z)-N-(2-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)ethyl)acetamide (65, 100 mg, 0.2 mmol) in toluene (3 mL) was heated at 80°C for 16 h After completion, the reaction mixture was concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford N-(2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)acetamide (Example 32, 71 mg). LCMS (ESI) Calcd. for C20H21F2N5O2: 401.1, found [M+H]+= 402.3.1H NMR (400 MHz, DMSO- d6) δH7.97-7.96 (m, 1H), 7.45-7.19 (m, 6H), 4.36 (t, 2H), 3.49 (t, 2H), 2.27 (s, 3H), 1.74 (s, 3H), 1.66-1.65 (m, 2H), 1.40-1.39 (m, 2H). Example 33: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (Example 33)

[0786] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H- pyrazole-3-carboxylate, 66 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3- (ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 200 mg, 0.8 mmol) in dichloromethane (5 mL), N,N-Diisopropylethylamine (0.4 mL, 2.4 mmol) and propane phosphonic acid anhydride (0.4 mL, 1.2 mmol, 50% in ethyl acetate) were added. After 15 min, 1-methylpiperazine (95 mg, 1.0 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with dichloromethane, washed with saturated solution of aqueous sodium bicarbonate followed by brine wash. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford 5-(difluoromethyl)-1-(2-(4- methylpiperazin-1-yl)-2-oxoethyl)-1H-pyrazole-3-carboxylate (66, 280 mg). LCMS (ESI) Calcd. for C14H20F2N4O3: 330.2, found [M+H]+= 331.2.1H NMR (400 MHz, DMSO-d6) δH7.30-7.03 (m, 2H), 5.40 (s, 2H), 4.33-4.26 (m, 2H), 3.48-3.34 (m, 4H), 2.37 (brs, 2H), 2.27 (brs, 2H), 2.20 (s, 3H), 1.29 (t, 3H).

[0787] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one, Example 33 [Step 2]: To a stirred solution of ethyl 5-(difluoromethyl)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-pyrazole-3-carboxylate (66, 280 mg, 0.9 mmol) in toluene (8 mL), potassium carbonate (140 mg, 1.0 mmol) and (Z)-N'- hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (160 mg, 0.8 mmol) were added. The reaction mixture was stirred at 90 °C for 16 h and concentrated under reduced pressure. The resultant residue was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC purification to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(4- methylpiperazin-1-yl)ethan-1-one (Example 33, 51 mg). LCMS (ESI) Calcd. for C23H26F2N6O2:456.2, found [M+H]+= 457.3.1H NMR (400 MHz, methanol-d4) δH7.38 (d, 1H), 7.23-6.90 (m, 5H), 5.42 (s, 2H), 3.68 (brs, 4H), 2.75-2.67 (m, 4H), 2.49 (s, 3H), 2.31 (s, 3H), 1.75-1.74 (m, 2H), 1.40-1.38 (m, 2H). Example 34: Synthesis of 5-(5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 34)

[0788] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carboxylate, 67 [Step 1]: To a stirred suspension of ethyl 5-(difluoromethyl)-1H-pyrazole-3- carboxylate (13, 1.0 g, 5.3 mmol) and potassium carbonate (2.9 g, 21.0 mmol) in DMF (60 mL) at 0 °C, 1-bromo-2-(methylsulfonyl)ethane (1.5 g, 7.9 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford ethyl 5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylate (67, 420 mg). LCMS (ESI) calcd. for C10H14F2N2O4S: 296.0, found [M+H]+= 297.0.1H NMR (400 MHz, DMSO-d6) δH7.38 (t, 1H), 7.09 (s, 1H), 4.70 (t, 2H), 4.32-4.27 (m, 2H), 3.78-3.74 (m, 2H), 3.07 (s, 3H), 1.29 (t, 3H). Note: Structure was confirmed based on NOE experiment of compounds 67 and 67a.

[0789] Synthesis of 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylic acid, 68 [Step 2]: To an ice cold solution of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylate (67, 420 mg, 1.4 mmol) in tetrahydrofuran (6 mL) and methanol (1 mL), an aqueous solution (2 mL) of lithium hydroxide (120 mg, 2.8 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of dichloromethane and isopropyl alcohol (9:1). Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylic acid (68, 350 mg). LCMS (ESI) Calcd. for C8H10F2N2O4S: 268.0, found [M+H]+= 269.0.

[0790] Synthesis of (Z)-N'-((5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carbonyl)oxy)-1-(o-tolyl)cyclopropane-1-carboximidamide, 69 [Step 3]: To a stirred solution of 5- (difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylic acid (68, 350 mg, 1.3 mmol), and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 248.2 mg, 1.3 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (335 mg, 2.6 mmol), 1-hydroxy-7- azabenzotriazole (36 mg, 0.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (325 mg, 1.7 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-N'-((5-(difluoromethyl)- 1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1- carboximidamide (69, 300 mg). LCMS (ESI) Calcd. for C19H22F2N4O4S: 440.1, found [M+H]+= 441.4.1H NMR (400 MHz, DMSO-d6) δH 7.51-7.24 (m, 4H), 7.17-7.16 (m, 2H), 6.12 (brs, 2H), 4.68 (t, 2H), 3.76 (t, 2H), 3.04 (s, 3H), 2.40 (s, 3H), 1.43 (brs, 2H), 1.00 (brs, 2H).

[0791] Synthesis of 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole, 70 [Step 4]: To a stirred solution of (Z)-N'-((5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazole-3-carbonyl)oxy)-1-(o-tolyl)cyclopropane-1-carboximidamide (69, 300 mg, 0.7 mmol) in tetrahydrofuran (10 mL), tetra butyl ammonium hydroxide (35 mg, 0.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(5-(difluoromethyl)-1H- pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 200 mg). LCMS (ESI) Calcd. for C16H14F2N4O: 316.1, found [M+H]+= 317.2.

[0792] Synthesis 5-(5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 34 and 5-(3-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 176 [Step 5]: To a stirred suspension of 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 200 mg, 0.6 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (10 mL) at 0 °C, 1-bromo-2-(methylsulfonyl)ethane (175 mg, 1.0 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product were purified by reverse phase preparative HPLC to afford the first product as 5-(5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol- 3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 34, 46 mg) as Peak-1 and the second product as 5-(3-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-5-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 176, 30 mg) as Peak-2.

[0793] 5-(5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 34 (Peak-1): LCMS (ESI) Calcd. for C19H20F2N4O3S: 422.1, found [M+H]+= 423.3.1H NMR (400 MHz, DMSO-d6) δH 7.55-7.29 (m, 3H), 7.24-7.20 (m, 3H), 4.76 (t, 2H), 3.80 (t, 2H), 3.07 (s, 3H), 2.26 (s, 3H), 1.66-1.65 (m, 2H), 1.41-1.39 (m, 2H). Note: The structure of the final oxadiazoles was confirmed by NOE experiments and another isomer was formed during alkylation. Example 35: Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoic acid (Example 35)

[0794] Synthesis of tert-butyl 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)propanoate, 71 [Step 1]: To a stirred suspension of 5-(5-(difluoromethyl)- 1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 400 mg, 1.3 mmol) and potassium carbonate (1.2 g, 8.9 mmol) in dimethylformamide (10 mL) at 0 °C, tert-butyl 3- bromopropanoate (395 mg, 1.9 mmol) was added. The resulting reaction mixture was allowed to stir at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford tert-butyl 3-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoate (71, 130 mg). LCMS (ESI) Calcd. for C23H26F2N4O3: 444.2, found [M+H]+= 445.4.1H NMR (400 MHz, DMSO-d6) δH 7.37- 7.22 (m, 5H), 4.51 (t, 2H), 2.86 (t, 2H), 2.26 (s, 3H), 1.65 (brs, 2H), 1.39 (brs, 3H), 1.35 (s, 9H). Note: Structure was confirmed based on NOE experiment.

[0795] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propanoic acid, Example 35 [Step 2]: To a stirred solution of tert-butyl 3-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoate (71, 120 mg, 0.3 mmol) in dichloromethane (15 mL), trifluoroacetic acid (0.4 mL, 5.4 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 6 h. After completion, the volatiles were removed under reduced pressure. The product was purified by reverse phase prep HPLC to afford 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoic acid (Example 35, 35 mg). LCMS (ESI) Calcd. for C19H18F2N4O3: 388.1, found [M+H]+= 389.3.1H NMR (400 MHz, DMSO-d6) δH12.54 (brs, 1H), 7.56-7.29 (m, 2H), 7.26-7.18 (m, 4H), 4.52 (t, 2H), 2.90 (t, 2H), 2.26 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H). Note: Another isomer was formed during alkylation. Examples 36a & 36b: 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (Example 36a) & 2-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1- amine (Example 36b)

[0796] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N,N-dimethylethan-1-amine, 36a & 2-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine, 36b [Step 1]: To a stirred solution of 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole (70, 120 mg, 0.38 mmol) in dimethylformamide (3 mL), potassium carbonate (105 mg, 0.76 mmol) and 2-bromo-N,N-dimethyl-ethanamine hydrobromide (106 mg, 0.46 mmol) were added. The resulting reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with ethyl acetate, washed with ice-cold water and brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The products were purified by reverse phase preparative HPLC to afford peak-1 as 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N- dimethylethan-1-amine (36a, 14 mg) and peak-2 as 2-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (36b, 25 mg).

[0797] 2-(5-(Difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)- N,N-dimethylethan-1-amine, Example 36a: LCMS (ESI) Calcd. for C20H23F2N5O: 387.1, found [M + H]+= 388.2,1H NMR (400 MHz, DMSO-d6): δH7.51-7.20 (m, 6H), 4.42 (t, 2H), 2.70-2.68 (m, 2H), 2.27 (s, 3H), 2.18 (s, 6H), 1.66 (brs, 2H), 1.39 (brs, 2H).

[0798] 2-(3-(Difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)- N,N-dimethylethan-1-amine, 36b: LCMS (ESI) Calcd. for C20H23F2N5O: 387.1, found [M + H]+= 388.2,1H NMR (400 MHz, DMSO-d6): δH 7.39-7.36 (m, 2H), 7.25-6.97(m, 4H), 4.68 (t, 2H), 2.65 (t, 2H), 2.28 (s, 3H), 2.11 (s, 6H), 1.70-1.67 (m, 2H), 1.45-1.43 (m, 2H). Example 37: Synthesis of N-(2-amino-2-oxoethyl)-2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetamide (Example 37)

[0799] Synthesis of tert-butyl-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)acetate, 72 [Step 1]: To a stirred suspension of 5-(5-(difluoromethyl)-1H- pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 600 mg, 1.9 mmol) and potassium carbonate (265 mg, 1.9 mmol) in dimethylformamide (20 mL) at 0 °C, tert-butyl 2-bromoacetate (72, 555 mg, 2.9 mmol) was added. The resulting reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford tert-butyl-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate (70, 120 mg) and tert-butyl 2-(3-(difluoromethyl)-5-(3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate (72a, 200 mg).

[0800] Analytical data of tert-butyl-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate, 72: LCMS (ESI) Calcd. for C22H24F2N4O3: 430.2, found [M+H]+= 431.2.1H NMR (400 MHz, DMSO-d6) δH7.46-7.19 (m, 6H), 5.26 (s, 2H), 2.27 (s, 3H), 1.67 (brs, 2H), 1.41 (s, 9H), 1.25 (brs, 2H). Note: Structure was confirmed based NOE experiment.

[0801] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)acetic acid, 73 [Step 2]: To a stirred solution of tert-butyl 2-(5-(difluoromethyl)-3-(3- (1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate (72, 120 mg, 0.3 mmol) in dichloromethane (15 mL), trifluoroacetic acid (317.9 mg, 2.8 mmol) was added at 0oC. The reaction mixture was stirred at ambient temperature for 6 h and the volatiles were reduced under reduced pressure to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (73, 100 mg). LCMS (ESI) Calcd. for C18H16F2N4O3: 374.1, found [M+H]+= 375.2.

[0802] Synthesis of N-(2-amino-2-oxoethyl)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetamide, Example 37 [Step 3]: To a stirred solution of 2- (5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (73, 90 mg, 0.2 mmol) and 2-aminoacetamide hydrochloride (35 mg, 0.3 mmol) in dichloromethane (10 mL) and dimethylformamide (0.5 mL), N,N-Diisopropylethylamine (155 mg, 1.2 mmol) and propane phosphonic acid anhydride (0.1 mL, 0.4 mmol, 50% in ethyl acetate) were added. The resulting reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with dichloromethane and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford N-(2-amino-2-oxoethyl)-2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetamide (Example 37, 26 mg). LCMS (ESI) Calcd. for C20H20F2N6O3: 430.2, found [M+H]+= 431.3.1H NMR (400 MHz, DMSO-d6) δH 8.55 (t, 1H), 7.41-7.37 (m, 2H), 7.30-7.28 (m, 2H), 7.24-7.20 (m, 3H), 7.14-7.12 (m, 1H), 5.18 (s, 2H), 3.70 (d, 2H), 2.26 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H). Note: Another isomer was formed during alkylation. Example 38: Synthesis of 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid (Example 38)

[0803] Synthesis of ethyl 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylate, 74 [Step 1]: To a stirred solution of 5-[5-(difluoromethyl)-1H-pyrazol-3-yl]-3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazole (70, 200 mg, 0.632 mmol) in acetonitrile (6 mL) was added Cs2CO3(515 mg, 1.6 mmol). After 5 min, ethyl 1- (bromomethyl)cyclopropanecarboxylate (262 mg, 1.3 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted ethyl acetate and washed with water followed by brine wash. Combined organic extracts were dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to give ethyl 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylate (74, 130 mg). Structure of regiomers were confirmed by NOE experiment. LCMS (ESI) Calcd. for C23H24F2N4O3:422.18, found [M+H]+= 443.4. Note: Other regio-isomer was also formed.

[0804] Synthesis of 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid, Example 38 [Step 2]: To a solution of ethyl 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)methyl)cyclopropane-1-carboxylate (74, 110 mg, 0.3 mmol) in THF (2 mL) and water (2 mL), lithium hydroxide monohydrate (32 mg, 0.770 mmol) was added. The reaction mixture was stirred at 70 °C for 4 h and volatiles were evaporated under reduced pressure. The residual aqueous phase was acidified with 1(N) HCl and extracted with ethyl acetate (thrice). Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give 1-((5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)methyl)cyclopropane-1-carboxylic acid (Example 38, 37 mg). LCMS (ESI) Calcd. for C21H20F2N4O2: 414.2, found [M+H]+= 415.3.1H NMR (400 MHz, DMSO-d6): δH 12.62 (brs, 1H), 7.64-7.20 (m, 6H), 4.52 (s, 2H), 2.27 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H), 1.23 (brs, 2H),1.14 (brs, 2H). Example 39: Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid (Example 39)Scheme 26

[0805] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-2,2-dimethylpropanoic acid, Example 39 and 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid, Example 178 [Step 1]: To a stirred solution of 5-[5-(difluoromethyl)-1H-pyrazol-3-yl]-3-[1-(o- tolyl)cyclopropyl]-1,2,4-oxadiazole (220 mg, 0.7 mmol) in DMA (2 mL), Cs2CO3( 680 mg, 2.09 mmol) and 3-bromo-2,2-dimethylpropanoic acid (227 mg, 1.25 mmol) were added. Resulting reaction mixture was stirred at 90 °C for 16 h, diluted with ethyl acetate and washed with water followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give the first product as 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid, Peak 1 (Example 39, 29 mg) and the second product as 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid, Peak 2 (Example 178, 38 mg).

[0806] 3-(5-(Difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)- 2,2-dimethylpropanoic acid (Example 39): LCMS (ESI) Calcd. for C21H22F2N4O3: 416.2, found [M+H]+= 417.3.1H NMR (400 MHz, DMSO-d6): δH 12.67 (brs, 1H),7.54-7.19 (m, 6H), 4.46 (s, 2H), 2.27 (s, 3H), 1.67- 1.65 (m, 2H), 1.40-1.37 (m, 2H), 1.13 (s, 6H). Examples 40a & 40b: Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 40a) and 3-(3- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 40b)Scheme 27

[0807] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)thietane 1,1-dioxide, Example 40a & 3-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide, Example 40b [Step 1]: 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 200 mg, 0.6 mmol) in acetontrile (2 mL), cesium carbonate (410 mg, 1.3 mmol) was added at 0 °C. After 15 min, 3-bromothietane 1,1-dioxide (290 mg, 1.6 mmol) was added to the reaction mixture and the reaction mixture was heated at 100 °C for 16 h. After completion, the mixture was diluted with water and partitioned with ethyl acetate. The combined organic layer was collected,washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC to afford 3-(5-(difluoromethyl)- 3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 40a, 25 mg) as peak 1 and 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 40b, 20 mg) as peak 2.

[0808] 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)thietane 1,1-dioxide, Example 40a [Peak-1]: LCMS (ESI) Calcd for C19H18F2N4O3S: 420.1, found [M+H]+= 421.1.1H NMR (400 MHz, DMSO-d6) δH 7.53-7.20 (m, 6H), 5.65-5.61 (m, 1H), 4.84-4.82 (m, 4H), 2.27 (s, 3H), 1.68-1.67 (brs, 2H), 1.42-1.39 (brs, 2H).

[0809] 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)thietane 1,1-dioxide, Example 40b [Peak-2]: LCMS (ESI) Calcd for C19H18F2N4O3S: 420.1, found [M+H]+= 421.3.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.43-7.10 (m, 6H), 5.97 (brs, 1H), 4.85-4.74 (m, 4H), 2.33 (s, 3H), 1.77 (s, 2H), 1.45 (s, 2H). Example 41: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine (Example 41)

[0810] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate, 75 [Step 1]: To a stirred solution of triphenylphosphine (1.2g , 1.9 mmol) in THF (15 mL) and DIAD (383.6 mg, 1.9 mmol) at 0 °C, 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 400 mg, 1.3 mmol) and tert-butyl (2-hydroxyethyl)(methyl)carbamate (332 mg, 1.9 mmol) were added. Resulting reaction mixture was allowed to stir at ambient temperature for 16 h and filtered through a celite pad. Combined filtrate was evaporated under reduced pressure. The product was purified by flash column chromatography to afford first product as tert-butyl (2-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)(methyl)carbamate (75a, 230 mg) and second product was tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)(methyl)carbamate (75, 230 mg). LCMS (ESI) Calcd. for C24H29F2N5O3: 473.2 found [M+H]+= 474.2. The structure of these regio-isomer was determined in the next step.

[0811] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-methylethan-1-amine, Example 41 [Step 2]: To a stirred solution of tert-butyl (2- (5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)(methyl)carbamate (75, 230 mg, 0.5 mmol) in dichloromethane (10 mL), trifluoroacetic acid (114.0 mg, 2.4 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h and volatiles were reduced under reduced pressure. The product was purified by reverse phase preparative HPLC to give 2-(5-(difluoro methyl)-3-(3-(1-(o-tolyl) cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine, (Example 41, 15 mg). LCMS (ESI) Calcd. for C19H21F2N5O: 373.17, found [M+H]+= 374.2,1H NMR (400 MHz, DMSO-d6) δH 7.52-7.720 (m, 6H), 4.37 (t, 2H), 2.91 (t, 2H), 2.26 (s, 6H), 1.66 (brs, 2H), 1. (brs, 2H). The structure was confirmed based on NOE experiment. Example 42: Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (Example 42)

[0812] Synthesis of methyl 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate, 76a and methyl 3-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate, 76 [Step 1]:To a stirred solution of DIAD (330 mg, 1.9 mmol) in THF (15 mL) at 0 °C, triphenylphosphine (1.1 g, 1.9 mmol) was added. After 5 min., methyl 3-hydroxycyclobutanecarboxylate (247 mg, 1.9 mmol) and 5-[5-(difluoromethyl)-1H-pyrazol-3-yl]-3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazole (70, 400 mg, 1.3 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 12 h, filtered through a celite bed and combined filtrate was concentrated under reduced pressure. The products were purified by column chromatography to give the first product as methyl 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)cyclobutane-1-carboxylate, Peak 1 (76a, 220 mg) and the second product as methyl 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)cyclobutane-1-carboxylate, Peak 2 (76, 110 mg). The structure of regiomers were confirmed by NOE experiment.

[0813] Methyl 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)cyclobutane-1-carboxylate, Peak 1 (76a): LCMS (ESI) Calcd. for C22H22F2N4O3: 428.2, found [M+H]+= 429.4.

[0814] Methyl 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)cyclobutane-1-carboxylate, Peak 2 (76): LCMS (ESI) Calcd. for C22H22F2N4O3: 428.2, found [M+H]+= 429.4.

[0815] Synthesis of 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)cyclobutane-1-carboxylic acid, Example 180 [Step 2]: To a solution of methyl 3-(3- (difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane- 1-carboxylate (76a, 220 mg, 0.5 mmol) in THF (2 mL), a solution of lithium hydroxide monohydrate (65 mg, 1.5 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70 °C for 4 h and volatiles were evaporated under reduced pressure, acidified with 1(N) HCl, and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give 3-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (Example 180, 45 mg). LCMS (ESI) Calcd. for C21H20F2N4O3: 414.1, found [M+H]+= 415.2.1H NMR (400 MHz, DMSO-d6): δH7.39-7.00 (m, 6H), 5.79 (t, 1H), 3.11-3.07 (d, 1H), 2.85-2.78 (m, 2H), 2.67-2.63 (m, 2H), 2.30 (s, 3H), 1.71 (brs, 2H), 1.44 (brs, 2H). One acid proton is exchangeable.

[0816] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)cyclobutane-1-carboxylic acid, Example 42 [Step 3]: To a solution of methyl 3-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (76, 100 mg, 0.2 mmol) in THF (2 mL), a solution of lithium hydroxide monohydrate (29 mg, 0.7 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70 °C for 4 h and volatiles were evaporated under reduced pressure, acidified with 1(N) HCl, and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (Example 42, 25 mg). LCMS (ESI) Calcd. for C21H20F2N4O3: 414.15, found [M+H]+= 415.25.1H NMR (400 MHz, DMSO-d6): δH 7.53-7.20 (m, 6H), 5.24-5.20 (m, 1H), 3.13-3.10 (m, 1H), 2.89-2.81 (m, 2H), 2.67-2.62 (m, 2H), 2.27 (s, 3H), 1.67 (brs, 2H), 1.40 (brs, 2H). One acid proton is exchangeable. Example 43: Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide (Example 43)

[0817] Synthesis of ethyl tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)carbamate, 77 [Step 1]: To a stirred solution of 5-(5- (difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 340 mg, 1.0 mmol) in acetonitrile (15 mL) was added Cs2CO3(1.0 g, 3.2 mmol) and tert-butyl (2- bromoethyl)carbamate (482 mg, 2.1 mmol). Resulting reaction mixture was allowed to stir at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography to afford ethyl tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)ethyl)carbamate (77, 170 mg). LCMS (ESI) Calcd. for C23H27F2N5O3: 459.2, found [M+H]+= 460.4. Note: Other regio-isomer (77a) was also formed.

[0818] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)ethan-1-amine, 78 [Step 2]: To a stirred solution of ethyl tert-butyl (2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)carbamate (77, 170 mg, 0.37 mmol) in dichloromethane (5 mL), was added TFA (0.2 mL, 2.6 mmol). Resulting reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated under reduced pressure to afford 2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-amine (78, 120 mg). The product was carried to next step without further purification. LCMS (ESI) Calcd. for C18H19F2N5O: 359.1, found [M+H]+= 360.1

[0819] Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)ethyl)methanesulfonamide, Example 43 [Step 3]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-amine (78, 120 mg, 0.3 mmol) in THF (5 mL), triethylamine (0.13 mL, 19.7 mmol) and methanesulfonyl chloride (0.04 mL, 0.5 mmol )were added at 0 °C. Resulting reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate and washed with saturated solution of sodium bicarbonate followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford N-(2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide (Example 43, 50 mg). LCMS (ESI) Calcd. for C19H21F2N5O3S: 437.1, found [M+H]+= 438.1.1H NMR (400 MHz, DMSO-d6): δH 7.49-7.20 (m, 7H), 4.21(t, 2H), 3.44-3.42 (m, 2H), 2.87 (s, 3H), 2.32 (s, 3H), 1.67 (brs, 2H), 1.40 (brs, 2H). Example 44: Synthesis of 2-[5-(difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]- 1H-pyrazol-1-yl]acetic acid (Example 44)Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol- 1-yl)acetic acid, Example 44 [Step 1]: To a stirred solution of tert-butyl 2-(5-(difluoromethyl)-3- (3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate (72, 200 mg, 0.5 mmol) in dichloromethane (10 mL), trifluoroacetic acid (0.36 mL, 4.7 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h and volatiles were reduced under reduced pressure. The product was purified by reverse phase preparative HPLC to give 2-[5- (difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]-1H-pyrazol-1-yl]acetic acid (Example 44, 176 mg). LCMS (ESI) Calcd. For C18H16F2N4O3: 374.1, found [M+H]+= 375.2,1H NMR (400 MHz, DMSO-d6): δH 7.39-7.12 (m, 6H), 4.83 (brs, 2H), 2.27 (s, 3H), 1.67-1.65 (m, 2H), 1.39 (brs, 2H). One acid proton is exchangeable. Example 45: Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)-N-methylacetamide (Example 45)Sc e e 3

[0820] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate, 79 [Step 1]: To a stirred solution of triphenylphosphine (1.2g , 1.9 mmol) in THF (15 mL) and DIAD (383.6 mg, 1.9 mmol) at 0 °C, 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 400 mg, 1.3 mmol) and tert-butyl (2-hydroxyethyl)(methyl)carbamate (332 mg, 1.9 mmol) were added. Resulting reaction mixture was allowed to stir at ambient temperature for 16 h and filtered through a celite pad. Combined filtrate was evaporated under reduced pressure. The product was purified by flash column chromatography to afford first product as tert-butyl (2-(3-(difluoromethyl)-5-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate (79a, 230 mg) and second product was tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)(methyl)carbamate (79, 230 mg). LCMS (ESI) Calcd. for C24H29F2N5O3: 473.2 found [M+H]+= 474.2. The structure of these regio-isomer was determined in the next step.

[0821] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-methylethan-1-amine, 80 [Step 2]: To a stirred solution of tert-butyl (2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)ethyl)(methyl)carbamate (79, 230 mg, 0.5 mmol) in dichloromethane (10 mL), trifluoroacetic acid (114.0 mg, 2.4 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h and volatiles were reduced under reduced pressure. The product was purified by reverse phase preparative HPLC to give 2-(5-(difluoro methyl)-3-(3-(1-(o-tolyl) cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine, (80, 15 mg). LCMS (ESI) Calcd. for C19H21F2N5O: 373.17, found [M+H]+= 374.2,1H NMR (400 MHz, DMSO-d6) δH 7.52-7.720 (m, 6H), 4.37 (t, 2H), 2.91 (t, 2H), 2.26 (s, 6H), 1.66 (brs, 2H), 1. (brs, 2H). The structure was confirmed based on NOE experiment.

[0822] Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)ethyl)-N-methylacetamide, Example 45 [Step 3]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N- methylethan-1-amine (80, 250 mg, 0.7 mmol) in dichloromethane (10 mL) were added triethylamine (0.5 mL, 3.4 mmol) and acetyl chloride (0.14 mL, 2.0 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 6 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to give N-(2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)-N- methylacetamide (Example 45, 24 mg). LCMS (ESI) Calcd. for C21H23F2N5O2: 415.18, found [M+H]+= 416.29.1H NMR (400 MHz, DMSO-d6at 100 °C) δH7.44-7.17 (m, 6H), 4.48 (brs, 2H), 3.75 (brs, 2H), 2.82 (brs, 3H), 2.31 (s, 3H), 1.90 (s, 3H), 1.71-1.68 (m, 2H), 1.40-1.37 (m, 2H). Example 46: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-morpholinoethan-1-one (Example 46)

[0823] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-1-morpholinoethan-1-one, Example 46 [Step 1]: To a stirred solution of 2-[5- (difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]-1H-pyrazol-1-yl]acetic acid (Example 44, 120 mg, 0.321 mmol) in dichloromethane (10 mL) were added DIPEA (0.6 mL, 3.6 mmol) and propyl phosphonic anhydride (50% in ethyl acetate) (0.16 mL, 0.962 mmol). After 15 min, morpholine (2, 34.4 mg, 0.4 mmol) was added and the resulting reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with dichloromethane and washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by prep HPLC to give 2-[5-(difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]- 1,2,4-oxadiazol-5-yl]pyrazol-1-yl]-1-morpholinoethanone (Example 46, 42 mg). LCMS (ESI) Calcd. for C22H23F2N5O3: 443.2 found [M+H]+= 444.3.1H NMR (400 MHz, DMSO-d6): δH 7.39- 7.06 (m, 6H), 5.49 (s, 2H), 3.66 (t, 2H), 3.58 (t, 2H), 3.51 (t, 2H), 3.44 (t, 2H), 2.27 (s, 3H), 1.67- 1.66 (m, 2H), 1.41-1.38 (brs, 2H). Example 47: Synthesis of (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)glycine (Example 47)

[0824] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)acetyl)glycinate, 81 [Step 1]: To a stirred solution of 2-[5-(difluoromethyl)- 3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]-1H-pyrazol-1-yl]acetic acid (Example 44, 220 mg, 0.6 mmol) in dichloromethane (15 mL) were added DIPEA ( 227 mg, 1.8 mmol) and propylphosphonic anhydride (50% in ethyl acetate) (0.45 mL, 1.5 mmol). After 15 min, tert-butyl glycinate (157 mg, 1.2 mmol) was added and the resulting reaction mixture was allowed to stirat ambient temperature for 16 h. The reaction mixture was diluted with dichloromethane, washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give tert- butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)acetyl)glycinate (81, 76 mg). LCMS (ESI) Calcd. for C24H27F2N5O4: 487.2, found [M+H]+= 488.4.

[0825] Synthesis of (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)acetyl)glycine, Example 47 [Step 2]: To a stirred solution of tert-butyl (2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)acetyl)glycinate (81, 60 mg, 0.1 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL, 13.0 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h and volatiles were reduced under reduced pressure. The product was purified by reverse phase preparative HPLC to give 2-[[2-[5-(difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5- yl]pyrazol-1-yl]acetyl]amino]acetic acid (Example 47, 37 mg,). LCMS (ESI) Calcd. for C20H19F2N5O4: 431.1, found [M+H]+= 432.2.1H NMR (400 MHz, DMSO-d6): δH 12.80 (brs, 1H), 8.64 (brs, 1H) 7.41-7.14 (m, 6H), 5.17 (s, 2H), 3.81 (s, 2H), 2.26 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H). Example 48: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-methoxyethyl)acetamide (Example 48)

[0826] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-methoxyethyl)acetamide, Example 48 [Step 1]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 70 mg, 0.18 mmol) in dichloromethane (3 mL), N,N-diisopropylethylamine (0.10mL, 0.56 mmol) and propane phosphonic acid anhydride (50% in ethyl acetate) (0.08 mL, 0.28 mmol) were added. After 15 min, 2-methoxyethan-1-amine (17 mg, 0.22 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane, washed with saturated solution of aqueous sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-methoxyethyl)acetamide (Example 48, 20 mg). LCMS (ESI) Calcd. for C21H23F2N5O3: 431.2, found [M + H]+= 432.3, ,1H NMR (400 MHz, DMSO-d6): δH 8.44 (t, 1H), 7.41-7.14 (m, 6H), 5.09 (s, 2H), 3.38-3.35 (m, 2H), 3.32-3.26 (m, 5H), 2.26 (s, 3H), 1.66 (brs, 2H), 1.39 (brs, 2H). Example 49: Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide (Example 49)Scheme 36

[0827] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide, Example 49 [Step 1]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 120 mg, 0.3 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.2 mL, 1.0 mmol) and T3P (0.1 mL, 0.5 mmol, 50% in ethyl acetate) were added. After 15 min, 2-aminoethan-1-ol (0.04 mL, 0.6 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate, washed with ice cold water followed by brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N- (2-hydroxyethyl)acetamide (Example 49, 20 mg). LCMS (ESI) Calcd. for C20H21F2N5O3: 417.2, found [M+H]+= 418.3.1H NMR (400 MHz, DMSO-d6) δH 8.36 (t, 1H), 7.41-7.14 (m, 6H), 5.09 (s,2H), 4.75 (t, 1H), 3.45-3.40 (m, 2H), 3.18-3.14 (m, 2H), 2.26 (s, 3H) 1.68-1.65 (m, 2H), 1.41- 1.38 (m, 2H). Example 50: Synthesis of (S)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one (Example 50)

[0828] Synthesis of (S)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide, Example 50 [Step 1]: To a stirred solution of 2- (5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 100 mg, 0.3 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.1 mL, 0.8 mmol) and T3P (0.1 mL, 0.4 mmol, 50% in ethyl acetate) were added. After 15 min, (S)-N,N-dimethylpyrrolidin-3-amine (60 mg, 0.5 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h, diluted with ethylacetate, washed with ice cold water followed by brine. Combined organic extract were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford (S)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one (Example 50, 36 mg). LCMS (ESI) Calcd. for C24H28F2N6O2: 470.2, found [M+H]+= 471.2.1H NMR (400 MHz, DMSO-d6, 100 °C) δH 7.40-7.38 (m, 1H), 7.32-7.06 (m, 5H), 5.31 (brs, 2H), 3.78-3.71 (m, 1H), 3.56-3.52 (m, 1H), 3.32 (m, 1H), 2.88-2.86 (m, 1H), 2.76 (m, 1H), 2.30 (m, 3H), 2.22-2.13 (m, 6H), 2.03-2.00 (m, 1H), 1.87 (m, 1H), 1.69 (m, 2H), 1.39 (m, 2H). Example 51: Synthesis of (R)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one (Example 51)

[0829] Synthesis of (R)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one, Example 51 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)acetic acid (Example 44, 100 mg, 0.3 mmol) in DMF (2 mL), DIPEA (0.13 mL, 0.8 mmol) and propane phosphonic acid anhydride (50% in ethyl acetate) (0.12 mL, 0.40 mmol) were added. After 15 mins, (R)-N,N-dimethylpyrrolidin-3-amine (30 mg, 0.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane, washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC method to afford (R)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one (Example 51, 38 mg). LCMS (ESI) Calcd. for C24H28F2N6O2: 470.2, found [M+H]+= 471.2.1H NMR (400 MHz, DMSO-d6at 100 °C): 7.40-7.05 (m, 6H), 5.34-5.31 (m, 2H), 3.78-3.72 (m, 1H), 3.55-3.50 (m, 1H), 3.36-3.31 (m, 1H), 2.91-2.87 (m, 1H), 2.76-2.72 (m, 1H), 2.30 (m, 3H), 2.22-2.12 (m, 6H), 2.02 (m, 1H), 1.89-1.86 (m, 1H), 1.69 (m, 2H), 1.39 (m, 2H). Example 52 & Example 53: Synthesis of (S)-1-(3-aminopyrrolidin-1-yl)-2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-one (Example 52 & Example 53)

[0830] Synthesis of tert-butyl (S)-(1-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate, 83 and tert-butyl (S)-(1-(2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)acetyl)pyrrolidin-3-yl)carbamate, 83 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3- (3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 300 mg, 0.8 mmol) in DMF (5 mL), DIPEA (0.42 mL, 2.4 mmol) and propane phosphonic acid anhydride (50% in ethyl acetate) (0.48 mL, 1.6 mmol) were added. After 15 min, tert-butyl pyrrolidin-3-ylcarbamate (299 mg, 1.6 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate, washed with ice cold water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford tert-butyl (1-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate (380 mg). The enantiomers were separated by normal phase chiral HPLC to afford the first product as tert-butyl (S)-(1-(2-(5-(difluoromethyl)- 3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)pyrrolidin-3- yl)carbamate, Peak 1 (82, 150 mg) and the second product as tert-butyl (R)-(1-(2-(5- (difluoromethyl)-3-(3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1- yl)acetyl)pyrrolidin-3-yl)carbamate, Peak 2 (83, 150 mg). The absolute stereochemistries of these compounds were not determined.

[0831] tert-butyl (S)-(1-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate, Peak 1 (82): LCMS (ESI) Calcd. for C27H32F2N6O4: 542.2, found [M+H]+= 543.3,

[0832] tert-butyl (R)-(1-(2-(5-(difluoromethyl)-3-(3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate, Peak 2 (83): LCMS (ESI) Calcd. for C27H32F2N6O4: 542.2, found [M+H]+= 543.4.

[0833] Chiral HPLC method: Chiral separation was performed on an Agilent 1200 series instrument. Column: CHIRALPAK IC (250 X 20 mm) 5µ, operating at ambient temperature with a flow rate of 18.0 mL / min. Mobile phase: 70% Hexane, 15% EtOH and 15% dichloromethane, held isocratic mixture up to 16 min at a wavelength of 250 nm.

[0834] Synthesis of (S)-1-(3-aminopyrrolidin-1-yl)-2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-one, Example 52, [Step 3]: To a stirred solution of tert-butyl (S)-(1-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate (82, 150 mg, 0.3 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid ( 1.0 mL, 13.1 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at ambient temperature for 2 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-1-(3-aminopyrrolidin-1-yl)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-one (Example 52, 47 mg). LCMS (ESI) Calcd. for C22H24F2N6O2: 442.19, found [M+H]+= 443.20.1H NMR (400 MHz, DMSO-d6 and 2 drops of D2O): δH 7.37-7.35 (m, 1H), 7.32-7.05 (m, 5H), 5.30-5.27 (m, 2H), 3.62-3.31 (m, 4H), 3.15-3.06 (m, 1H), 2.24 (s, 3H), 2.08-1.97 (m, 1H), 1.72-1.60 (m, 3H), 1.39-1.36 (m, 2H). Two amine protons are exchangeable.

[0835] Synthesis of (R)-1-(3-aminopyrrolidin-1-yl)-2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-one, Example 53 [Step 4]: To a stirred solution of tert-butyl (R)-(1-(2-(5-(difluoromethyl)-3-(3-(1-phenylcyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)pyrrolidin-3-yl)carbamate (83, 150 mg, 0.3 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid ( 1.0 mL, 13.1 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at ambient temperature for 2 h and volatiles were evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (R)-1-(3-aminopyrrolidin-1-yl)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)ethan-1-one (Example 53, 48 mg). LCMS (ESI) Calcd. for C22H24F2N6O2: 442.19, found [M+H]+= 443.20.7.37-7.35 (m, 1H), 7.32-7.05 (m, 5H), 5.30-5.27(m, 2H), 3.62-3.31 (m, 4H), 3.15-3.06 (m, 1H), 2.24 (s, 3H), 2.08-1.97 (m, 1H), 1.72-1.60 (m, 3H), 1.39-1.36 (m, 2H). Two amine protons are exchangeable. Example 54: Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propenamide (Example 54)

[0836] Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propenamide, Example 54 [Step 5]: To a stirred solution of 3-(5-cyclopropyl-3-(3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoic acid (Example 22, 60 mg, 0.16 mmol) in DMF (3 mL), were added HATU (90 mg, 0.24 mmol), DIPEA (0.14 mL, 0.8 mmol) and ammonium chloride (25 mg, 0.5 mmol). The reaction mixture was stirred at ambient temperature for 14 h, diluted ethyl acetate and washed with water followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford 3-(5- cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propenamide (Example 54, 47 mg). LCMS (ESI) Calcd. for C21H23N5O2: 377.19, found [M+H]+= 378.10.1H NMR (400 MHz, DMSO-d6): δH 7.44 (brs, 1H), 7.37 (d, 1H), 7.23-7.19 (m, 3H), 6.92 (brs,1H), 6.55 (s, 1H), 4.44 (t, 2H), 2.70 (t, 2H), 2.25 (s, 3H), 2.04 (brs,1H), 1.64-1.61 (m, 2H), 1.37-1.35 (m, 2H), 0.99-0.96 (m, 2H), 0.76-0.73 (m, 2H). Examples 55a & 55b: Synthesis of 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55a) and 5-(4-(difluoromethyl)-1-methyl-1H- pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55b)

[0837] Synthesis of 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazole & 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)- 1,2,4-oxadiazole, Example 55a and Example 55b [Step 1]: To a stirred solution of methyl 4- (difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylate (86, 200 mg, 1 mmol) (along with other regioisomer) in toluene (2 mL), K2CO3(270 mg, 2.0 mmol) and N'-hydroxy-1-(o- tolyl)cyclopropanecarboxamidine (180 mg, 1.0 mmol) were added and reaction mixture was allowed to stir at 90 °C for 16 h. After completion the reaction mixture was diluted with ethyl acetate and partitioned with water. Combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The product was purified and separated by reverse phase prep-HPLC to afford 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55a, 65 mg) as peak 1 and 5-(4-(difluoromethyl)-1- methyl-1H-pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55b, 90 mg) as peak 2.

[0838] Analytical data of 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 55a: LCMS (ESI) Calcd for C17H16F2N4O: 330.3, found [M+H]+= 331.0.1H NMR (400 MHz, DMSO-d6) δH8.39 (s, 1H), 7.41-7.13 (m, 5H), 4.00 (s, 3H), 2.27 (s, 3H), 1.69-1.66 (m, 2H), 1.41-1.38 (m, 2H).

[0839] Analytical data of 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole, Example 55b: LCMS (ESI) Calcd for C17H16F2N4O: 330.3, found [M+H]+= 331.0.1H NMR (400 MHz, DMSO-d6) δH 7.97 (s, 1H), 7.38 (d, 1H), 7.27-7.11 (m, 4H), 4.18 (s, 3H), 2.30 (s, 3H), 1.73-1.70 (m, 2H), 1.45-1.42 (s, 2H). Note: The exact structure of peak 1 & peak 2 was confirmed by NOE experiments. Example 56: Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- tolyl)cyclopropyl)oxazole (Example 56)

[0840] Synthesis of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl chloride, 88 [Step 1]: To a stirred solution of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (87, 140 mg, 0.8 mmol) in SOCl2(5.0 mL, 70 mmol) was heated at 60 °C added and stirred for 2 h. After completion volatiles was evaporated under reduced pressure to afford 5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl chloride (88, 150 mg) which was confirmed in next step.

[0841] Synthesis of 2-diazo-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one, 89 [Step 2]: To a solution of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl chloride (88, 150 mg, 0.8 mmol) in Toluene (2 mL), (Trimethylsilyl)diazomethane (2M in hexane) (2.0 mL, 4 mmol) was added dropwise at 0 °C. The reaction was stirred at ambient temperature for 16 h. Reaction mixture was directly forwarded to next step. LCMS Calcd. for C7H6F2N4O: [M] = 200.15, found [M+H]+= 201.2.

[0842] Synthesis of 2-bromo-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one, 90 [Step 3]: To a stirred solution of 2-diazo-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1- one (150 mg, 0.8 mmol) in 1,4-Dioxane (2mL), HBr in H2O (48%) (1.0 mL, 20 mmol) was added slowly at 0 °C and stirred for 1 h at ambient temperature. The reaction was concentrated to dryness and the residue was taken up in EtOAc and the organic extracts were washed with water then saturated brine solution. The organic ectracts were then separated and dried (MgSO4) under reduced pressure which was purified by flash column chromatography to afford 2-bromo-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one (90, 190 mg). LCMS Calcd. for C7H7BrF2N2O: [M] = 253, found [M+H]+= 255. Synthesis of 2-amino-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one, 91 [Step 4]: To a solution of 2-bromo-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one (150 mg, 0.6 mmol) in Chloroform (2 mL), Hexamethylentetramine (0.06 mL, 1 mmol) was added and stirred for 4 hours at ambient temperature. The reaction mixture was filtered through celite bed to afford the precipitated hexamine adduct. The adduct was then heated with Methanol (4 mL) and Conc. HCl (0.40 mL) for 16 h under reflux. The reaction mixture was cooled, fitered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford 2-amino-1-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)ethan-1-one (91, 200 mg). LCMS Calcd. For C7H9F2N3O: [M] = 189.16, found [M+H]+= 190.1.Example 56: Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- tolyl)cyclopropyl)oxazole (Example 56)

[0843] Synthesis of 1-(o-tolyl)cyclopropane-1-carboxylic acid, 92 [Step 1]: To a stirred solution of 1-(o-tolyl)cyclopropane-1-carbonitrile (10, 1.00 g, 6 mmol) in 4M LiOH.H2O aq. solution (8.0 mL, 25 mmol) was refluxed at 100 °C for 24h with continue stirring. Reaction mixture was cooled at 0 °C, washed with ethyl acetate and aqueous layer was acidified by 5N HCl solution and extracted with ethyl acetate (thrice). Organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-(o- tolyl)cyclopropane-1-carboxylic acid (92, 600 mg).1H NMR (400 MHz, DMSO-d6) δH12.19 (brs, 1H), 7.21-7.08 (m, 4H), 2.27 (s, 3H), 1.50 (d, 2H), 1.10-1.08 (m, 2H). Notes: Extra peak present in1H NMR.

[0844] Synthesis of 1-(o-tolyl)cyclopropane-1-carboxylic chloride, 93 [Step 2]: A stirred solution of 1-(o-tolyl)cyclopropane-1-carboxylic acid (92, 350 mg, 2 mmol) in SOCl2(6 mL, 80 mmol) was heated at 60 °C added and stirred for 2 h. After completion volatiles was evaporated under reduced pressure to afford 1-(o-tolyl)cyclopropanecarbonyl chloride (93, 350 mg) which was confirmed in next step.

[0845] Synthesis of N-(2-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-oxoethyl)-1-(o- tolyl)cyclopropane-1-carboxamide, 94 [Step 3]: To a stirred solution of 1-(o-tolyl)cyclopropane-1- carboxylic chloride (200 mg, 1.2 mmol) in 1,2 dichloromethane (4mL), triethyl amine (0.4 mL, 3 mmol) in 1,2 dichloromethane (2 ml) and 2-amino-1-[5-(difluoromethyl)-1-methyl-pyrazol-3- yl]ethanone (230 mg, 1.2 mmol) in 1,2 dichloromethane(2 ml) was added portionwise at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with 1,2 dichloromethane. The organic extracts were then separated and under reduced pressure. The product was purified by reverse phase prep HPLC purification to afford N-(2-(5-(difluoromethyl)- 1-methyl-1H-pyrazol-3-yl)-2-oxoethyl)-1-(o-tolyl)cyclopropane-1-carboxamide (94, 120 mg).1H NMR (400 MHz, DMSO-d6) δH 7.44-6.81 (m, 7H), 4.39 (d, 2H), 3.99 (s, 3H), 2.39 (s, 3H), 1.42(d, 2H), 0.97 (d, 2H). LC / MS: calculated for C18H19F2N3O2[M]: 347.36, found [M+H]+: 348. Notes: 15mg of compound shipped. Rest amount were forwarded to next step.

[0846] Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- tolyl)cyclopropyl)oxazole, Example 56 [Step 4]: In a round buttom flask, POCl3(1.5 mL, 15 mmol) was added in a stirred solution of N-(2-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2- oxoethyl)-1-(o-tolyl)cyclopropane-1-carboxamide (94, 100 mg, 0.3 mmol) at 0 °C. The resulting reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic extracts were then separated and dried under reduced pressure. The product was purified by reverse phase prep HPLC purification to afford 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- tolyl)cyclopropyl)oxazole (Example 56, 30 mg).1H NMR (400 MHz, DMSO-d6) δH 7.44-6.81 (m, 7H), 3.90 (s, 3H), 2.24 (s, 3H), 1.67-1.65 (m, 2H), 1.36-1.33 (m, 2H). LC / MS: calculated for C18H17F2N3O [M]: 329.34, found [M+H]+: 330.2. Examples 57-64: Synthesis of (Z)-1-(2-chloro-5-fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide, 97

[0847] Synthesis of 1-(2-chloro-5-fluorophenyl)cyclopropane-1-carbonitrile, 96 [Step 1]: To a stirred solution of NaOH (1.4 g, 35.4 mmol) in water (5 mL), 2-(2-chloro-5-fluoro- phenyl)acetonitrile (95, 500 mg, 3.0 mmol), TBAB (190 mg, 0.6 mmol) and 1,2-dibromoethane (2.2 mL, 14.7 mmol) were added and the reaction mixture was heated at 60 °C for 12h. After completion, the reaction mixture was poured into cold water and extracted with ethyl acetate (thrice). Combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-(2-chloro-5-fluorophenyl)cyclopropane-1- carbonitrile (96, 510 mg ).1H NMR (400 MHz, DMSO-d6) δH 7.63-7.59 (m, 1H), 7.50-7.47 (m, 1H), 7.34-7.29 (m, 1H), 1.99-1.69 (m, 2H), 1.52-1.41 (m, 2H).

[0848] Synthesis of (Z)-1-(2-chloro-5-fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide, 97 [Step 2]: To a stirred solution of 1-(2-chloro-5-fluorophenyl)cyclopropane-1-carbonitrile (96, 500 mg, 2.6 mmol) in ethanol (25mL), sodium carbonate (540 mg, 5.1 mmol) andhydroxylamine hydrochloride (355 mg, 5.1 mmol) were added and the reaction was heated at 70 °C for 12h. After completion, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate and washed with water and brine. Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford (Z)-1-(2-chloro-5-fluorophenyl)-N'-hydroxycyclopropane-1- carboximidamide (97, 550 mg). LCMS (ESI) Calcd for C10H10ClFN2O: 228.6, found [M+H]+= 229.2. Examples 57a & 57b: Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 57a)

[0849] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carboxylate, 67 [Step 1]: To a stirred suspension of ethyl 5-(difluoromethyl)-1H-pyrazole-3- carboxylate (13, 1 g, 5.3 mmol) and potassium carbonate (2.9 g, 21.03 mmol) in dimethylformamide (60 mL) at 0 °C, 1-bromo-2-(methylsulfonyl)ethane (1.48 g, 7.89 mmol) was added. The resulting reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with ethyl acetate and washed with ice-cold water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford ethyl 5- (difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylate (67, 420 mg). LCMS (ESI) calcd. for C10H14F2N2O4S: 296.0 found [M+H]+= 297.0,1H NMR (400 MHz, DMSO-d6): δH7.38 (t, 1H), 7.09 (s, 1H), 4.70 (t, 2H), 4.32-4.27 (m, 2H), 3.78-3.74 (m, 2H), 3.07 (s, 3H), 1.29 (t, 3H). Note: Structure was confirmed based NOE experiment on compound 67a.

[0850] Synthesis of 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylic acid, 68 [Step 2]: To a cold solution of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H- pyrazole-3-carboxylate (67, 420 mg, 1.42 mmol) in tetrahydrofuran (6 mL) and methanol (1 mL), a solution of lithium hydroxide (119 mg, 2.84 mmol) in water (2 mL) was added drop-wise. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated under reduced pressure. The aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ~pH-5 and extracted with a mixture of dichloromethane and isopropyl alcohol (9:1). Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)- 1H-pyrazole-3-carboxylic acid (68, 350 mg). The product was carried to next step without further purification. LCMS (ESI) Calcd. for C8H10F2N2O4S: 268.03 found [M+H]+= 269.09.

[0851] Synthesis of (Z)-1-(4-chloro-2-fluorophenyl)-N'-((5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide, 98 [Step 3]: To a stirred solution of 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carboxylic acid (68, 600 mg, 2.2 mmol), and (Z)-1-(2-chloro-4-fluorophenyl)-N'- hydroxycyclopropane-1-carboximidamide (565 mg, 2.5 mmol) in dichloromethane (10 mL), N,N- diisopropylethylamine (1.9 mL, 11.2 mmol), 1-hydroxy-7-azabenzotriazole (60 mg, 0.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (645 mg, 3.4 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (Z)-1-(4-chloro-2-fluorophenyl)-N'-((5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide (98, 500 mg). LCMS (ESI) Calcd. for C18H18ClF3N4O4S: 478.1, found [M+H]+= 479.1.

[0852] Synthesis of 3-(1-(4-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1H-pyrazol- 3-yl)-1,2,4-oxadiazole, 99 [Step 4]: To a stirred solution of (Z)-1-(4-chloro-2-fluorophenyl)-N'-((5- (difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide (98, 450 mg, 0.9 mmol) in tetrahydrofuran (8 mL), tetra butyl ammonium hydroxide (1.9 mL, 1.9 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. Combined organic extract was dried overanhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 3-(1-(4- chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (99, 250 mg). LCMS (ESI) Calcd. for C15H10ClF3N4O: 354.1, found [M+H]+= 354.8.

[0853] Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, Example 57a [Step 5]: To a stirred suspension of 3-(1-(4-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1H-pyrazol-3-yl)- 1,2,4-oxadiazole (99, 130 mg, 0.4 mmol) and potassium carbonate (100 mg, 0.7 mmol) in THF (2 mL) at 0 °C, 2-bromo-N,N-dimethylacetamide (73 mg, 0.4 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product were purified by reverse phase prep HPLC to afford 2-(3-(3-(1- (2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)- N,N-dimethylacetamide (Example 57a, 35 mg). LCMS (ESI) Calcd. for C19H17ClF3N5O2: 439.1, found [M+H]+= 440.1.1H NMR (400 MHz, DMSO-d6) δH 7.65-7.61 (m, 1H), 7.51-7.48 (dd, 1H), 7.34-7.08 (m, 3H), 5.44 (s, 2H), 3.05 (s, 3H), 2.86 (s, 3H), 1.73-1.70 (m, 2H), 1.49-1.46(m, 2H). Note: Example 57b was isolated as other regio-isomer.

[0854] Examples 58-64 were synthesized in a manner similar to Example 57 from the corresponding pyrazole carboxylic acid. Example 58: Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Examples 58)

[0855] 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 45 using 1-bromo-2-(methylsulfonyl)ethane. LCMS (ESI) Calcd. for C18H16ClF3N4O3S: 460.1, found [M+H]+= 461.0.1H NMR (400 MHz, DMSO-d6) δH 7.65-7.61 (m, 1H), 7.55-7.42 (m, 2H), 7.32 (s, 1H), 7.29-7.23 (m, 1H), 4.78-4.74 (m, 2H), 3.82-3.78 (m, 2H), 3.06 (s, 3H), 1.71 (s, 2H), 1.48 (s, 2H). Examples 59 & 60: Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)propanamide, (Example 59) and (R)-2-(3-(3- (1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propenamide (Example 60)

[0856] (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)propenamide and (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)propenamide were synthesized following Scheme 45 using 2-bromopropanamide. The absolute stereochemistries were not determined and was arbitrarily assigned.

[0857] (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)propanamide, Example 59 (Peak 1): LCMS (ESI) Calcd. for C18H15ClF3N5O2: 425.7, found [M+H]+= 426.2.1H NMR (400 MHz, DMSO-d6): δH7.63-7.25 (m, 7H), 5.26 (s, 1H), 1.73 (d, 5H), 1.47 (s, 2H).

[0858] (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)propenamide, Example 60 (Peak 2): LCMS (ESI) Calcd. for C18H15ClF3N5O2: 425.7, found [M+H]+= 426.2.1H NMR (400 MHz, DMSO-d6): δH 7.65-7.61 (m, 1H), 7.50-7.25 (m, 6H), 5.26 (d, 1H), 1.73 (d, 5H), 1.47 (s, 2H).

[0859] Chiral Prep HPLC method: HPLC SFC prep purification was performed on Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralcel-OX-H (21.0 mm x 250 mm), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 70 ml / min, using 80% CO2 in super critical state & 20% of 100% methanol as mobile phase. Run this isocratic mixture up to 10 minutes and also maintained the isobaric condition of 100 bar at 254 nm wavelength. Example 61: Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(3- (methylsulfonyl)propyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 61)

[0860] 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(3- (methylsulfonyl)propyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 61)was synthesized following Scheme 45 using 1-bromo-3-(methylsulfonyl)propane. LCMS (ESI) Calcd. for C19H18ClF3N4O3S: 474.1, found [M+H]+= 475.1.1H NMR (400 MHz, DMSO-d6): δH 7.64-7.61 (m, 1H), 7.53-7.48 (m, 1H), 7.40-7.23 (m, 3H), 4.49-4.45 (t, 2H), 3.20- 3.17 (t, 2H), 2.99 (s, 3H), 2.33-2.22 (m, 2H), 1.72 (brs, 2H), 1.47 (brs, 2H). Example 62: Synthesis of 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 62)

[0861] 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 62) was synthesized following Scheme 45 using 3-bromothietane 1,1-dioxide. LCMS (ESI) Calcd for C18H14ClF3N4O3S: 458.0, found [M+H]+= 459.0.1H NMR (400 MHz, DMSO-d6): δH7.65-7.61 (m, 1H), 7.53-7.24 (m, 4H), 5.65-5.61 (m,1H), 4.84-4.82 (m, 4H), 1.73 (s, 2H), 1.48 (s, 2H).Example 63: Synthesis of 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)propenamide (Example 63)

[0862] 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)propenamide (Example 63) was synthesized following Scheme 45 using 3- bromopropanamide. LCMS (ESI) Calcd for C18H15ClF3N5O2: 425.7; found [M+H]+= 426.3.1H NMR (400 MHz, DMSO-d6): δH7.64-7.60 (m, 1H), 7.56-7.24 (m, 5H), 6.97 (brs, 1H), 4.48 (t, 2H), 2.73 (t, 2H), 1.72-1.70 (m, 2H), 1.48-1.45 (m, 2H). Example 64: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 64)

[0863] 2-(5-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)acetamide (Example 64) was synthesized following Scheme 45 using 3-2- bromoacetamide. LCMS (ESI) Calcd. for C17H13ClF3N5O2: 411.1, found [M+H]+= 412.0.1H NMR (400 MHz, DMSO-d6): δH 7.71 (s, 1H), 7.64-7.60 (m, 1H), 7.51-7.49 (dd, 1H), 7.42 (s, 1H), 7.34(s, 1H), 7.26-6.97 (m, 2H), 5.25 (s, 2H), 1.74-1.72 (m, 2H), 1.50-1.47 (m, 2H). Example 65: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-phenylacetamide (Example 65)

[0864] Synthesis of tert-butyl 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetate, 100 [step 1]: tert-Butyl 2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)99-5-(difluoromethyl)-1H-pyrazol-1-yl)acetate was synthesized following Scheme 45 using tert-butyl 2-bromoacetate. LCMS (ESI) Calcd. for C21H20ClF3N4O3: 468.1, found [M+H]+= 469.2.1H NMR (400 MHz, DMSO-d6): δH7.65-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.46-7.19 (m, 3H) 5.26 (s, 2H), 1.74-1.71 (m, 2H), 1.49-1.46 (m, 2H), 1.40 (s, 9H).

[0865] Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetic acid, Example 109 [Step 2]: To a stirred solution of tert- butyl 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)acetate (100, 100 mg, 0.2 mmol) in dichloromethane (2 mL), trifluoroacetic acid(16 equiv.0.3 mL, 3.2 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 6 h and the volatiles were removed under reduced pressure and purified by reverse phase prep-HPLC to afford 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid (Example 109, 23 mg). Structure was confirmed by NOE experiment. LCMS (ESI) Calcd for C17H12ClF3N4O3: 412.1, found [M+H]+= 413.0.1HNMR (400 MHz, DMSO-d6) δH7.65-7.61 (m, 1H), 7.50-7.47 (dd, 1H), 7.27-7.10 (m, 3H), 4.79 (s, 2H), 1.77-1.74 (m, 2H), 1.47-1.44 (m, 2H).

[0866] Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-phenylacetamide, Example 65: [Step 3]: To a stirred solution of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H- pyrazol-1-yl)acetic acid (Example 109, 70 mg, 0.2 mmol) in dichloromethane ( 2 mL), aniline (0.023 mL, 0.3 mmol ) and DIPEA ( 0.089 mL, 0.5 mmol) were added followed by addition of T3P (50% in ethyl acetate) (3 equiv.). Resulting reaction mixture was stirred for 16 h at ambient temperature, diluted with dichloromethane and washed with water. Combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford 2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N- phenylacetamide (Example 65, 40 mg ). LCMS (ESI) Calcd for C23H17ClF3N5O2: 487.1, found [M-H]-: 486.2.1H NMR (400 MHz, DMSO-d6,100 °C): δH 10.13 (s, 1H), 7.64-7.60 (t, 1H), 7.55 (d, 2H), 7.42-16 (m, 6H), 7.11-7.09 (m, 1H), 5.29 (s, 2H), 1.75 (brs, 2H), 1.47 (brs, 2H).

[0867] Examples 66-92 were synthesized in a manner similar to Example 65. Example 66: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2,2,2 trifluoroethyl)acetamide (Example 66)

[0868] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamid (Example 66) was synthesized following Scheme 46 using 2,2,2-trifluoroethan-1-amine. LCMS Calcd. for C19H14ClF6N5O2:493.7, found [M+H]+= 494.1HNMR (400 MHz, DMSO-d6): δH9.03-8.99 (m, 1H), 7.64-7.61 (m, 1H),7.51-7.48 (m, 1H),7.33-7.15(m, 3H), 5.21 (s, 2H), 4.02-3.92 (brs, 2H), 1.73-1.70 (brs, 2H), 1.49-1.46 (brs, 2H). Example 67: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide (Example 67)

[0869] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide (Example 67) was synthesized following Scheme46 using 2-aminoethan-1-ol. LCMS (ESI) Calcd for C19H17ClF3N5O3: 455.1, found [M+H]+= 456.1.1H NMR (400 MHz, DMSO-d6at 100 °C): δH8.01 (brs, 1H), 7.62 (t, 1H), 7.39 (d, 1H), 7.23-7.19 (m, 2H), 5.07 (s, 2H), 4.39 (brs, 1H), 3.48-3.46 (m, 2H), 3.21 (q, 2H), 1.75 (s, 2H), 1.47-1.45 (m, 2H). Example 68: Synthesis of N-(2-amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 68)

[0870] N-(2-Amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 68) was synthesized following Scheme 46 using 2-aminoacetamide. LCMS (ESI) Calcd for C19H16ClF3N6O3: 468.1, found [M+H]+= 469.1.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 8.24 (s, 1H), 7.64-7.60 (t, 1H), 7.39 (d, 1H), 7.24-6.96 (m, 5H), 5.16 (s, 2H), 3.73-3.72 (brs, 2H), 1.75 (s, 2H), 1.47 (s, 2H). Example 69: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 69)

[0871] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 69) was synthesized following Scheme 46 using 2-(methylamino)ethan-1-ol. LCMS (ESI) Calcd for C20H19ClF3N5O3: 469.1, found [M+H]+= 470.1.1H NMR (400 MHz, DMSO-d6): δH 7.62 (d, 1H), 7.46 (d, 1H), 7.24- 7.19 (m, 3H), 5.50 (s, 2H), 5.38 (s, 1H), 3.65 (d, 1H), 3.48-3.40 (m, 2H), 3.35-3.21 (m, 1H), 3.05 (s, 1H), 2.83 (s, 2H), 1.79 (t, 2H), 1.46 (t, 2H). Example 70: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide (Example 70)

[0872] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide Example 70 was synthesized following Scheme 46 using N1,N1-dimethylethane-1,2-diamine. LCMS (ESI) Calcd. for C21H22ClF3N6O2: 482.1, found [M+H]+= 483.1.1HNMR (400 MHz, DMSO-d6at 100 °C): δH7.88 (s, 1H), 7.64-7.60 (t, 1H), 7.39-7.10 (m, 4H), 5.06 (s, 2H), 3.22-3.19 (brs, 2H), 2.37-2.34 (brs, 2H), 2.18 (s, 6H), 1.75 (s, 2H), 1.47 (s, 2H). Example 71: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-methoxyethyl)acetamide (Example 71)

[0873] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-methoxyethyl)acetamide (Example 71) was synthesized following Scheme 3 using 2-methoxyethan-1-amine. LCMS (ESI) Calcd for C20H19ClF3N5O3: 469.1, found [M+H]+= 470.1.1H NMR (400 MHz, DMSO-d6): δH8.43 (t, 1H), 7.62 (q, 1H), 7.49 (dd, 1H), 7.41-7.14 (m, 3H), 5.10 (s, 2H), 3.38-3.24 (m, 7H), 1.73-1.70 (m, 2H), 1.48-1.46 (m, 2H). Example 72: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Example 72)

[0874] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Example 72) was synthesized following Scheme 46 using 2,2,2-trifluoro-N-methylethan-1-amine. LCMS (ESI) Calcd. for C20H16ClF6N5O2: 507.1, found [M+H]+= 508.1.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.64- 7.60 (t, 1H), 7.40 (d, 1H), 7.31-7.04 (m, 3H), 5.53 (s, 2H), 4.18 (s, 2H), 3.20 (s, 3H), 1.75 (s, 2H), 1.47 (s, 2H). Example 73: Synthesis of (R)-2-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)propenamide (Example 73)

[0875] (R)-2-(2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetamido)propanamide (Example 73) was synthesized following Scheme 46 using (R)-2-aminopropanamide. LCMS (ESI) Calcd for C20H18ClF3N6O3: 482.1, found [M+H]+= 483.0.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 8.20 (s, 1H), 7.63- 7.62 (t, 1H), 7.40-7.37 (m, 1H), 7.22-6.93 (m, 5H), 5.14 (s, 2H), 4.27(s, 1H), 1.75 (s, 2H), 1.47 (s, 2H), 1.27 (d, 3H). Example 74: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylacetamide (Example 74)

[0876] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylacetamide (Example 74) was synthesized following Scheme 46 using N1,N1,N2-trimethylethane-1,2-diamine. LCMS (ESI) Calcd for C22H24ClF3N6O2: 496.1, found [M+H]+= 497.1.1H NMR (400 MHz, DMSO-d6): δH 7.61 (t, 1H), 7.39-7.37 (m, 1H), 7.28-7.01 (m, 3H), 3.48-3.43 (m, 2H), 2.44 (brs, 1H), 2.21 (brs, 5H), 1.92 (s, 3H), 1.78-1.74 (m, 2H), 1.47-1.45 (m, 2H). Example 75: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-methoxyethyl)-N-methylacetamide (Example 75)

[0877] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-methoxyethyl)-N-methylacetamide (Example 75) was synthesized following Scheme 46 using 2-methoxy-N-methylethan-1-amine. LCMS (ESI) Calcd for C21H21ClF3N5O3: 483.2, found [M+H]+= 484.1.1H NMR (400 MHz, DMSO-d6at 100 °C): δH7.63-7.60 (m, 1H), 7.37 (dd, 1H), 7.27-7.00 (m, 3H), 5.40 (s, 2H), 3.53 (brs, 4H), 3.31 (brs, 3H), 3.04- 2.93 (m, 2H), 1.83-1.70 (m, 2H), 1.52-1.45 (m, 2H). Example 76: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (Example 76)

[0878] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (Example 76) was synthesized following Scheme 46 using 1-amino-2-methylpropan-2-ol. LCMS (ESI) Calcd for C21H21ClF3N5O3: 483.1, found [M+H]+= 484.1.1H NMR (400 MHz, DMSO-d6): δH 7.82 (brs, 1H),7.63-7.60 (m, 1H), 7.39-7.36 (m, 1H), 7.23-7.09 (m, 3H), 5.13 (s, 2H), 4.10 (s, 1H), 3.11 - 3.10 (brs, 2H), 1.77-1.75 (brs, 2H), 1.48-1.45 (brs, 2H), 1.10 (s, 6H). Example 77: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-((1-methylpiperidin-4-yl)methyl)acetamide (Example 77)

[0879] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-((1-methylpiperidin-4-yl)methyl)acetamide (Example 77) was synthesized following Scheme 46 using (1-methylpiperidin-4-yl)methanamine. LCMS (ESI) Calcd for C24H26ClF3N6O2: 522.1, found [M+H]+= 523.1.1HNMR (400 MHz, DMSO-d6 at 100 °C): δH 7.97 (brs, 1H), 7.63-7.60 (t, 1H), 7.39-7.09 (m, 4H), 5.06 (s, 2H), 3.04-3.01 (m, 2H), 2.73-2.67 (m, 2H), 2.15 (s, 3H), 1.88-1.82 (t, 2H), 1.76-1.75 (brs, 2H), 1.63-1.59 (m, 2H), 1.52-1.47 (brs, 2H), 1.43-1.38 (brs, 1H), 1.28-1.14 (m, 2H). Example 78: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(1-cyanocyclopropyl)acetamide (Example 78)

[0880] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(1-cyanocyclopropyl)acetamide (Example 78) was synthesized following Scheme 46 using 1-aminocyclopropane-1-carbonitrile. LCMS (ESI) Calcd for C21H16ClF3N6O2: 476.1, found [M+H]+= 477.2.1H NMR (400 MHz, DMSO-d6): δH 9.27 (s, 1H), 7.65-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.40-7.14 (m, 3H), 5.12 (s, 2H), 1.73-1.71 (m, 2H),1.52-1.46 (m, 4H), 1.18- 1.14 (m, 2H). Example 79: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(methylamino)-2-oxoethyl)acetamide (Example 79)

[0881] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-(methylamino)-2-oxoethyl)acetamide (Example 79) was synthesized following Scheme 46 using 2-amino-N-methylacetamide. LCMS (ESI) Calcd. for C20H18ClF3N6O2: 482.1, found [M-H]- = 481.2.1H NMR (400 MHz, DMSO-d6): δH8.61 (t, 1H),7.86 (d, 1H), 7.64-7.60 (m, 1H), 7.50-7.47 (m, 1H), 7.31-7.14 (m, 3H), 5.17 (s, 2H), 3.72 (d, 2H), 2.60 (d, 3H), 1.71 (s, 2H), 1.47 (s, 2H). Example 80: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 80)

[0882] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 80) was synthesized following Scheme 46 using cyclopropylmethanamine. LCMS (ESI) Calcd. For C21H19ClF3N5O2: 465.2, found [M+H]+= 466.2.1H NMR (400 MHz, DMSO-d6): δH 8.42 (t, 1H), 7.64 (t, 1H), 7.50-7.48 (m, 1H), 7.41-7.14 (m, 3H), 5.08 (s, 2H), 2.99 (t, 2H), 1.71 (s, 2H), 1.47 (s, 2H), 0.90 (s, 1H), 0.43 (d, 2H), 0.17 (d, 2H). Example 81: Synthesis of N-(2-amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N- methylacetamide (Example 81)

[0883] N-(2-Amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 81) was synthesized following Scheme 46 using 2-(methylamino)acetamide. LCMS (ESI) Calcd. for C20H18ClF3N6O3: 482.1, found [M+H]+= 483.0.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.63-7.60 (m, 1H), 7.40-7.37 (m, 1H), 7.27-7.0 (m, 5H), 5.43 (brs, 2H), 4.04-3.91 (m, 2H), 3.09 (brs, 2H), 2.86 (brs, 1H), 1.76-1.73 (m, 2H), 1.48-1.45 (m, 2H). Example 82: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(cyclobutylmethyl)acetamide (Example 82)

[0884] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(cyclobutylmethyl)acetamide was synthesized following Scheme 46 using cyclobutylmethanamine. LCMS (ESI) Calcd. for C22H21ClF3N5O2: 479.1, found [M+H]+= 480.1.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.93 (brs, 1H), 7.63-7.59 (m, 1H), 7.39-7.36 (m, 1H), 7.22-7.09 (m, 3H), 5.05 (s, 2H), 3.18-3.15 (m, 2H), 2.44-2.41 (m, 1H), 2.04-1.97 (m, 2H), 1.85-1.66 (m, 6H), 1.47-1.45 (m, 2H). Example 83: Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 83)

[0885] (S)-2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 83) was synthesized following Scheme 46 using (S)-3-methoxypyrrolidine. LCMS (ESI) Calcd. for C22H21ClF3N5O3: 495.1, found [M+H]+= 496.1.1H NMR (400 MHz, DMSO-d6): δH7.64-7.60 (t,1H), 7.39 (d, 1H), 7.33-7.06 (m, 3H), 5.36-5.28 (brs, 2H), 4.09-3.99 (m, 1H), 3.67-3.58 (m, 2H), 3.44 (s, 2H), 3.35-3.27 (m, 3H), 2.07 (s, 1H),1.95 (s, 1H), 1.75 (s, 2H), 1.47-1.45 (brs, 2H). Example 84: Synthesis of (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 84)

[0886] (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 84) was synthesized following Scheme 46 using (R)-3-methoxypyrrolidine. LCMS (ESI) Calcd. for C22H21ClF3N5O3: 495.2, found [M+H]+= 496.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.63-7.59 (m, 1H), 7.39-7.32 (m, 1H), 7.22-7.06 (m, 3H), 5.36-5.28 (m, 2H), 4.09-3.99 (m, 1H), 3.66-3.59 (m, 2H), 3.43-3.36 (m, 2H), 3.30-3.27 (m, 3H), 2.06-1.94 (m, 2H), 1.76-1.73 (m, 2H), 1.48-1.45 (m, 2H). Example 85: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxyazetidin-1-yl)ethan-1-one (Example 85)

[0887] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3-methoxyazetidin-1-yl)ethan-1-one (Example 85) was synthesized following Scheme 46 using 3-methoxyazetidine. LCMS (ESI) Calcd. for C21H19ClF3N5O3: 481.8, found [M+H]+= 482.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 7.62 (t, 1H), 7.40 (d, 1H), 7.35- 7.08 (m, 3H), 5.16 (s, 2H), 4.39-4.28 (m, 3H), 4.09 (brs, 1H), 3.76 (brs, 1H), 3.26 (s, 3H), 1.74 (s, 2H), 1.47 (s, 2H). Example 86: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3,3-difluoropyrrolidin-1-yl)ethan-1-one (Example 86)

[0888] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3,3-difluoropyrrolidin-1-yl)ethan-1-one (Example 86) was synthesized following Scheme 46 using 3,3-difluoropyrrolidine. LCMS (ESI) Calcd. for C21H17ClF5N5O2: 501.8, found [M+H]+= 502.4.1H NMR (400 MHz, DMSO-d6at 100 °C): δH7.62 (t, 1H), 7.39 (d, 1H), 7.32-7.06 (m, 3H), 5.36 (s, 2H), 4.07-3.62 (m, 4H), 2.32 (brs, 1H), 1.75-1.69 (m, 2H), 1.52- 1.47 (m, 2H). Example 87: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 87)

[0889] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 87) was synthesized following Scheme 46 using pyrrolidine. LCMS (ESI) Calcd. for C21H19ClF3N5O2: 465.1, found [M+H]+= 466.1.1HNMR (400 MHz, DMSO-d6): δH7.65-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.36-7.09 (m, 3H), 5.35 (s, 2H), 3.54-3.51 (m, 2H), 3.31 (d, 2H), 1.96-1.90 (m, 2H), 1.83-1.76 (m, 2H), 1.71 (s, 2H), 1.47 (s, 2H). Example 88: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one (Example 88)

[0890] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one (Example 88) was synthesized following Scheme 46 using 3,3-difluoroazetidine. LCMS (ESI) Calcd. for C20H15ClF5N5O2: 487.1, found [M+H]+= 488.0.1H NMR (400 MHz, DMSO-d6): δH 7.65-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.38-7.11 (m, 3H), 5.33 (s, 2H), 4.78-4.72 (m, 2H), 4.42-4.36 (m, 2H), 1.71 (s, 2H), 1.47 (brs, 2H). Example 89: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)-N-methylacetamide (Example 89)

[0891] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)-N-methylacetamide (Example 89) was synthesized following Scheme 46 using 2-methyl-1-(methylamino)propan-2-ol. LCMS (ESI) Calcd. for C22H23ClF3N5O3: 497.1, found [M+H]+= 498.1.1H NMR (400 MHz, DMSO-d6): δH 7.63-7.60 (t, 1H), 7.38 (d, 1H), 7.27-7.00 (m, 3H), 5.46 (s, 2H), 4.55-4.16 (brs, 1H), 3.34 (s, 2H), 3.17 (brs, 3H), 1.75 (s, 2H), 1.47 (s, 2H), 1.12 (s, 6H). Examples 90 & 91: Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 90) & (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 91)

[0892] (S)-2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 90) and (R)-2-(3- (3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol- 1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 91) were synthesized following Scheme 46 using tetrahydrofuran-3-amine. The absolute stereochemistries were assigned by matching the chiral HPLC SFC data of both peaks with the compound synthesized using chiral amine (S- isomer) with known absolute stereochemistry.

[0893] (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 90) (Peak 1):1HNMR (400 MHz, DMSO-d6): δH8.63 (d, 1H), 7.64-7.61 (m, 1H), 7.49 (dd, 1H), 7.31 (s, 1H), 7.27-7.23 (m, 2H), 5.08 (s, 2H), 4.24 (brs, 1H), 3.81-3.67 (m, 3H), 3.51-3.47 (m, 1H), 2.13-2.08 (m, 1H), 1.73 (d, 3H), 1.47 (s, 2H). LCMS (ESI) Calcd for C21H19ClF3N5O3: 481.8, found [M+H]+= 482.1.

[0894] (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 91) (Peak 2): LCMS (ESI) Calcd. for C21H19ClF3N5O3: 481.8, found [M+H]+= 482.1.1H NMR (400 MHz, DMSO-d6): δH 8.63 (d, 1H), 7.64-7.61 (m, 1H), 7.49 (dd, 1H), 7.41-7.14 (m, 3H), 5.08 (s, 2H), 4.24 (brs, 1H), 3.81-3.67 (m, 3H), 3.51-3.47 (m, 1H), 2.13-2.08 (m, 1H), 1.73 (d, 3H), 1.47 (s, 2H).

[0895] Preparative chiral HPLC method: SFC preparative purification was performed on Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using C Amylose A (30.0 mm x 250mm ), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 110 ml / min, using 75 % CO2 in super critical state & 25% of methanol as mobile phase, Run this isocratic mixture up to 14.0 minutes and also maintained the isobaric condition of 100 bar at 254 nm wavelength. Example 92: Synthesis of (S)-2-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)propenamide (Example 92)

[0896] (S)-2-(2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetamido) propanamide (Example 92) was synthesized following Scheme 46 using 2-aminopropanamide. LCMS (ESI) Calcd for C20H18ClF3N6O3: 482.1, found [M+H]+= 483.1.1H NMR (400 MHz, DMSO-d6): δH 8.53 (d, 1H), 7.65-7.61 (t, 1H), 7.51- 7.50 (m,1H), 7.48 (s, 1H), 7.43-7.13 (m, 3H), 7.06 (s, 1H), 5.21-5.11 (m, 2H), 4.24-4.21 (m, 1H), 1.72 (s, 2H), 1.47 (brs, 2H), 1.24-1.22(m, 3H).

[0897] Preparative chiral HPLC method: SFC preaparative purification was performed on Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using I Cullulose J (30.0 mm x 250 mm), 5 min column operating at 35 °C temperature, maintaining flow rate of 90 mL / min, using 85% CO2 in super critical state and 15% of MeOH mobile phase. Run this isocratic mixture up to 14 min and also maintained the isobaric condition of 100 bar at 220 nm. Note: Reaction with (2R)-2-aminopropanamide was performed to obtain (R)-2-(2-(3-(3-(1- (2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1- yl)acetamido)propenamide (Example 92) with known absolute configuration. After comparingthe chiral HPLC of both isomers (Peak 1 & Peak 2) with this R-isomer, it is confirmed that Peak 1 is R-isomer and Peak 2 is S-isomer. Example 93: Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)acetamide (Example 93)Scheme 47

[0898] Synthesis of tert-butyl 4-((2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)methyl)...

Claims

CLAIMS What is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, according to Formula (IId):wherein X1-X5are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C1-C6alkyl, a substituted C1-C6alkyl, a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, a C1-C6alkoxy, optionally substituted with an aryl, a C3-C10cycloalkyl, -C(O)NH2, -C(O)NHY1, - C(O)NY1Y2, -COOH, -C(O)OY1, -Y1COOH, or -Y1OY2; Y1and Y2are each independently a C1-C6alkyl optionally substituted with one or more halogen or hydroxy; R3is a halogen, a hydrogen, a C1-C6alkyl, a C1-C6alkyl substituted with one or more halogen, or a C3-C10cycloalkyl; and R4is a hydrogen, a C1-C6alkyl, or a C1-C6alkyl substituted with one or more halogen; if R3and R4are optionally interconnected they form a C3-C6cycloalkyl, a substituted C3-C6cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring andR30-R34are each independently a hydrogen, a carboxylic acid, an ester, a halogen, an amide, a substituted amide, a cyano, an ether, or a C1-C6alkyl.

2. The compound of claim 1, wherein X1is a C1-C6alkyl or a halogen.

3. The compound of claim 2, wherein the C1-C6alkyl is methyl.

4. The compound of claim 2, wherein the halogen is chlorine.

5. The compound of claim 1, wherein X2and X4are each independently a hydrogen or a halogen.

6. The compound of claim 1, wherein X3 is a hydrogen, a C1-C6alkyl or a halogen.

7. The compound of claim 6, wherein the C1-C6alkyl is methyl.

8. The compound of claim 6, wherein the halogen is chlorine or fluorine.

9. The compound of claim 1, wherein X5 is a C1-C6alkyl or a hydrogen.

10. The compound of claim 1, wherein at least two of X2-X5 are hydrogen.

11. The compound of claim 1, wherein at least three of X2-X5 are hydrogen.

12. The compound of claim 1, wherein X2-X5 are hydrogen.

13. The compound of claim 1, wherein R3 is C1-C6alkyl or C1-C6alkyl substituted with one or more halogen.

14. The compound of claim 13, wherein the C1-C6alkyl substituted with one or more halogen is -CHF2.

15. The compound of claim 13, wherein the C1-C6alkyl is methyl.

16. The compound of claim 1, wherein R4 is hydrogen.

17. The compound of claim 1, wherein R30-R34 are hydrogen.

18. The compound of claim 1, wherein R30is methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

19. The compound of claim 1, wherein R31is methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

20. The compound of claim 1, wherein R32is methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

21. The compound of claim 1, wherein R33 is methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

22. The compound of claim 1, wherein R34 is methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.

23. The compound of claim 1, wherein at least two of R30-R34 are hydrogen, -OCH3, - COOH, -C(O)NH2, -C(O)NHCH3, cyano, methyl, - C(O)OCH3, or fluorine.

24. The compound of claim 1, wherein X1-X5 are each independently hydrogen, halogen, Cl, F, or methyl, and R3-R4 are independently H, methyl, -CHF2, or -CF3.

25. The compound of claim 1, wherein at least one of R30-R34 is carboxylic acid.

26. The compound of claim 1, wherein at least one of R30-R34 is amide.

27. The compound of claim 1, wherein at least one of R30-R34 is ester.

28. The compound of claim 1, wherein at least one of R30-R34 is ether.

29. The compound of claim 1, wherein at least one of R30-R34 is cyano.

30. The compound of claim 1, wherein at least one of R30-R34 is methyl.

31. The compound of claim 1, wherein at least two of R30-R34 is carboxylic acid, amide, ester, ether, cyano, or methyl.

32. The compound of claim 1, wherein the compound comprises one of the following compounds:

33. A composition comprising one of the following compounds:

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