Polycyclic amides as UBE2K modulators for treating cancer

Abstract

Formula (I): [Formula 1] Compounds of TIFF2023509452000161.tif19131, and pharmaceutically acceptable salts and compositions thereof, are provided, which are useful for treating conditions associated with modulation of UBE2K.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 956,802, filed January 3, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Cancer progression is a global concern, and metastasis constitutes the second leading cause of death worldwide. The ubiquitin-proteasome system (UPS) has recently attracted attention as an important target for cancer therapy due to its role in cell proliferation and survival. Ubiquitin (Ub) is a small, highly conserved regulatory protein that is covalently tagged to proteins as a signal for proteasomal degradation. Ubiquitination is a multistep process that transfers Ub to specific target proteins. Ub conjugation occurs through an enzymatic cascade involving Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3) enzymes. See, for example, Cancer Biol Ther. 2010 Oct 15; 10(8): 737-747. Because the addition and removal of Ub is a fundamental process in all eukaryotic cells, it is not surprising that Ub metabolic enzymes feature prominently as oncogenes or tumor suppressors in various cancers and in many cancer-related signaling / regulatory pathways. See Cell Cycle 2017; 16(7): 634-648. Summary of the Invention [Problem to be solved by the invention]

[0003] Although progress has been made in this area (eg, as with the FDA-approved proteasome inhibitor bortezomib), there remains a need for improved small molecule modulators of the UPS. [Means for solving the problem]

[0004] As used herein, Formula I:

[0005] [ka] (In the formula, R 1 , R 2 , p, Z 1 , Z 2 , X, ring A, and p are as described herein), as well as pharmaceutically acceptable salts and compositions thereof. The disclosed compounds and compositions modulate (e.g., inhibit) UBE2K and modified forms of UBE2K, including, but not limited to, monoubiquitinated UBE2K, di-, tri-, and tetraubiquitinated UBE2K, and are useful for treating various cancers. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 shows UBE2K polyubiquitination activity by certain compounds of the invention. [Figure 2] FIG. 1 shows the selective stabilization of monoubiquitinated UBE2K by certain compounds of the invention. [Figure 3] FIG. 1 shows the UBE2K-Ub releasing activity of certain compounds of the present invention. [Figure 4] FIG. 1 shows the antitumor efficacy of compound 131 in an MV.4.11 cell (B myelomonocytic leukemia) line-induced xenograft model in nude mice. DETAILED DESCRIPTION OF THE INVENTION

[0007] 1. General description of the compound As used herein, Formula I:

[0008] [ka] (Z 1 and Z 2 are each independently N or CH; X is N or CH; Ring A is phenyl or 5- to 9-membered heteroaryl, each of which is R 5 optionally substituted with 1 to 3 groups selected from; Y is CH2, -CHR a , -CR a R b , or SO; R a and R b are each independently halo, (C1-C6)alkyl, or halo(C1-C6)alkyl; or R a and R b together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which is optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1-C6)alkylOH, (C1-C6)alkylO(C1-C6)alkyl, and OH; R 1 is halo(C1-C6)alkyl, halo(C1-C6)alkoxy, or -NR c R d wherein two available hydrogen atoms on said halo(C1-C6)alkyl and halo(C1-C6)alkoxy may, together with the carbon atoms to which they are attached, form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkoxy; R c and R d are each independently hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkylO(C1-C6)alkyl, halo(C1-C6)alkylO(C1-C6)alkyl, (C1-C6)alkyl-O-halo(C1-C6)alkyl, halo(C1-C6)alkyl-O-halo(C1-C6)alkyl, or (C1-C6)alkylOH; or R c and R dtogether with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, and oxo; R 2 is CN, halo, OH, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1-C6)alkoxy; or R 1 and R 2 when on adjacent carbon atoms, together with the carbon atoms to which they are attached form a 5- or 6-membered oxygen-containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, and halo(C1-C6)alkyl; R 3 is hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl; R 4 is CN, halo, OH, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, or 5- or 6-membered heterocyclyl; and p is 0 or 1.

[0009] 2.Definition When used in connection with describing a chemical group that may have multiple points of attachment, a hyphen (-) refers to the point of attachment of that group to the defined variable. For example, -NH(C1-C6)alkyl means that the point of attachment of the group is on the nitrogen atom.

[0010] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0011] The term "alkyl," when used alone or as part of a larger moiety, such as "haloalkyl," means a saturated, straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl.

[0012] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0013] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0014] A "haloalkoxy" is a haloalkyl group attached to another moiety via an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0015] "Oxo" refers to the divalent functional group =O, ie, an oxygen atom connected to another atom (typically carbon or sulfur) by a double bond.

[0016] The term "heteroaryl" refers to an aromatic ring of a specified size (e.g., a 5-, 6-, 7-, 8-, or 9-membered ring) containing 1 to 4 heteroatoms independently selected from N, O, and S. Heteroaryl groups can be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, etc. When specified, optional substituents on a heteroaryl group may be located at any substitutable position.

[0017] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic ring of a specified size (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) containing from 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. When specified, optional substituents on a heterocyclyl group may be located at any substitutable position, including, for example, the position at which the heterocyclyl is attached.

[0018] The term "cycloalkyl" refers to a monocyclic hydrocarbon ring of the specified size (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. When specified, optional substituents on a cycloalkyl group may be located at any substitutable position, including, for example, the position at which the cycloalkyl is attached.

[0019] The disclosed compounds exist in various tautomeric forms and are part of this disclosure. The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds / substituents resulting from the formal migration of at least one hydrogen atom and at least one change in valence. Exemplary tautomers include, for example:

[0020] [ka] All such isomeric forms of such compounds are expressly included. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all other tautomeric forms that may exist for that compound are encompassed by the structural formula. This includes compounds of Formula I where X is N or C.

[0021] The compounds described herein can exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teachings having an acidic group, such as carboxylic acids, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include, for example, ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts). Compounds with a quaternary ammonium group also include a counteranion, such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids, such as glutamic acid.

[0022] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0023] As used herein, the terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a particular organism or other susceptibility factor), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, e.g., to delay their recurrence.

[0024] The term "pharmaceutically acceptable" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0025] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that elicits a biological or medical response in a subject, for example, a dosage of 0.01 to 100 mg / kg body weight / day.

[0026] 3.Compound As used herein, in a first embodiment, a compound of formula I:

[0027] [ka]

[0013] Provided is a compound of the formula: wherein the variables are as defined above, or a pharmaceutically acceptable salt thereof.

[0028] In a second embodiment, the compound of formula I has formula II or III:

[0029] [ka] wherein the remaining variables are as described above for Formula I, or a pharmaceutically acceptable salt thereof.

[0030] In a third embodiment, the compound of formula I has formula IV:

[0031] [ka] wherein the remaining variables are as described above for Formula I, or a pharmaceutically acceptable salt thereof.

[0032] In a fourth embodiment, R in a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof 3 is hydrogen, and the remaining variables are as described in relation to Formula I or the second embodiment.

[0033] In a fifth embodiment, Y in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is CH, SO, or cyclopropyl, and the remaining variables are as described with respect to Formula I or the fourth embodiment. Alternatively, as part of the fifth embodiment, Y in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is CH, and the remaining variables are as described with respect to Formula I or the fourth embodiment.

[0034] In a sixth embodiment, Z in the compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, 1 is N and Z 2 is CH;Z 1 is CH and Z 2 is N; or Z 1 and Z 2 are each CH, and the remaining variables are as described with respect to Formula I or the fourth or fifth embodiment. Alternatively, as part of the sixth embodiment, Z in a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, 1 and Z 2 are each CH, and the remaining variables are as described in relation to Formula I or the fourth or fifth embodiment.

[0035] In a seventh embodiment, ring A in the compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is phenyl or a 5- to 6-membered heteroaryl, each of which is selected from the group consisting of R 5 and the remaining variables are as described with respect to Formula I, or the fourth, fifth, or sixth embodiment. Alternatively, as part of the seventh embodiment, Ring A in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is phenyl, pyridyl, furanyl, or pyrazolyl, each of which is selected from R 5 and the remaining variables are as described with respect to Formula I, or the fourth, fifth, or sixth embodiment. In another alternative, as part of the seventh embodiment, ring A in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is phenyl or furanyl, each of which is selected from R 5 and the remaining variables are as described with respect to Formula I, or the fourth, fifth, or sixth embodiment. In another alternative, as part of the seventh embodiment, ring A in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is optionally substituted with 1 to 3 groups selected from R 5and the remaining variables are as described in relation to Formula I or the fourth, fifth or sixth embodiment.

[0036] In an eighth embodiment, R in a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof 1 and R 2 are on adjacent carbon atoms and, together with the carbon atom to which they are attached, form a 5-membered oxygen-containing heterocyclyl optionally substituted with one or two halo, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth or seventh embodiment. Alternatively, R in a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, 1 and R 2 are on adjacent carbon atoms and together with the carbon atom to which they are attached form a dioxolanyl optionally substituted with 1 or 2 halo, and the remainder of the variables are as described in relation to Formula I or the fourth, fifth, sixth or seventh embodiment.

[0037] In a ninth embodiment, R in a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof 1 is halo(C1-C4)alkyl, halo(C1-C4)alkoxy, or -NR c R d and;R c is hydrogen and R d is halo(C1-C4)alkyl; or R c and R d and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 1is -OCF3, -OCHF2, -OCH2CF3, -CF3, -CH2CF3, -CHF2, piperidinyl, pyrrolidinyl, azapanyl, morpholinyl, thiomorpholinyl, piperazinyl, or azetidinyl, each of said heterocycles being optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, and oxo, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth, or seventh embodiment.

[0038] In a tenth embodiment, R in a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof 2 is CN, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, or (C1-C4)alkoxy, and the remaining variables are as described with respect to Formula I or the fourth, fifth, sixth, seventh, or ninth embodiment. Alternatively, as part of the tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 2 is CN or halo, and the remaining variables are as described with respect to Formula I or the fourth, fifth, sixth, seventh, or ninth embodiment. In another alternative, as part of the tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 2 is fluoro, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth, seventh or ninth embodiment.

[0039] In an eleventh embodiment, p in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 0, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth, seventh, ninth or tenth embodiment.

[0040] In a twelfth embodiment, R in a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof 5is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, —N[(C1-C4)alkyl]2, or 6-membered heterocyclyl, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. Alternatively, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 5 is F, Br, Cl, —OCH, —OCHCH, OH, —O(CH)CH, —NMe, —CH(CH), —C(CH), —OCH(CH), morpholinyl, —CH, or —CF, and the remaining variables are as described in relation to Formula I or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0041] Specific examples of compounds are provided in the Examples section and are included herein as part of the thirteenth embodiment. Pharmaceutically acceptable salts and neutral forms of these compounds are also included.

[0042] Also provided herein are pharmaceutical compositions comprising a compound described herein; and a pharmaceutically acceptable carrier.

[0043] 4. Uses, Formulation and Administration The compounds and compositions described herein are generally useful for modulating the activity of UBE2K. In some embodiments, the compounds and compositions described herein inhibit the activity of UBE2K.

[0044] In some aspects, the compounds and compositions described herein are useful for the treatment of cancer. Accordingly, provided herein is a method of treating cancer, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Also provided is the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. Also provided is a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, or a disclosed compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0045] Cancers treatable by this method include, but are not limited to, liquid cancers such as acute myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia, or solid tumors such as pancreatic cancer, ovarian cancer, breast cancer, colon cancer, and gastrointestinal cancer.

[0046] In certain aspects, the compositions described herein are formulated for administration to a subject in need of such a composition. The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0047] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend on the particular compound in the composition.

[0048] [Example] Representative examples of the disclosed compounds are shown in the following non-limiting methods, schemes, and examples.

[0049] General synthetic route

[0050] [ka]

[0051] Compounds of Formula I can be prepared according to General Scheme 1 above, for example, by reacting an appropriate cyano starting material with ammonium sulfide (e.g., [NH4]2S) optionally in the presence of a base and at elevated temperature to form the corresponding sulfide amine. See Step 1. Cyclization to the corresponding heteroaryl with a suitably protected amine then occurs in Step 2, where PG is an amine protecting group, e.g., an acid-labile protecting group. The amine is then exposed (e.g., with an acid) and then coupled with a suitable acid (Step 3), for example, using a diimide-based reagent or the like, to form a compound of Formula I. The variables have the same meanings as described herein.

[0052] [ka]

[0053] Compounds of formula I can also be prepared according to general scheme 2 above, for example, in step 1, appropriate amino and carboxylic acid starting materials are reacted (e.g., in the presence of a base and optionally in the presence of an additive) to form the cyano product. The cyano can then be cyclic in step 2, for example, at elevated temperature and optionally in the presence of an inorganic base, to form a compound of formula 1. The variables have the same meanings as described herein.

[0054] Exemplary Synthesis Synthesis of N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound 2):

[0055] [ka]

[0056] To a solution of 2-(trifluoromethyl)benzoic acid (500 mg, 2.626 mmol) in DMF (2 mL) cooled to 0 °C, (5-(thiophen-2-yl)-1H-pyrazol-3-yl)methanamine (662 mg, 2.629 mmol, 1 equiv.), HATU (380 mg, 5.258 mmol), and DIPEA (129 mg, 8.097 mmol) were added. The solution was stirred at room temperature for 16 h. After completion of the reaction, the solvent was evaporated, followed by the addition of water (10 mL), extraction with EtOAc (50 mL x 2), and drying over Na2SO4. It was then concentrated under reduced pressure to give the crude product. The crude product was then purified by flash column chromatography (eluent: 20% EtOAc / n-hexane) to give the title compound (650 mg, 70%) as N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethyl)benzamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.94 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.40-7.70 (m, 2H), 7.40 (m, 2H), 7.32(s, 1H), 7.05(m, 1H), 6.40-6.48(m, 1H), 4.40 (s, 2H). LCMS:M / Z 352.1[M+H] +

[0057] Using procedures similar to those described above for Compound 1 and using the appropriate starting materials, the compounds in Table 1 below were prepared.

[0058] [Table 1] TIFF0007827626000011.tif253153TIFF0007827626000012.tif153162

[0059] Synthesis of 5-fluoro-2-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)benzamide (compound 80):

[0060] [ka]

[0061] Step 1: Methyl 5-fluoro-2-(piperidin-1-yl)benzoate

[0062] [ka]

[0063] To a stirred solution of methyl 2,5-difluorobenzoate (500 mg, 2.906 mmol) in DMF (10 mL) was added piperidine (0.37 ml, 3.488 mmol), followed by K2CO3 (1 g, 7.267 mmol), and the reaction mixture was stirred at 80 °C for 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, diluted with water (10 mL), and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography (eluent: 40% EtOAc in hexane) to obtain methyl 5-fluoro-2-(piperidin-1-yl)benzoate as a brown solid (350 mg, 50.87%). 1 H NMR (400 MHz, DMSO-d6): δ 7.33-7.36 (m, 1H), 7.26-7.31 (m, 1H), 7.10-7.13 (m, 1H), 3.79 (s, 3H), 2.82-2.87 (m, 4H), 1.58 (s, 4H), 1.48 (s, 2H). LC-MS m / z (MH): 238.0

[0064] Step 2: 5-Fluoro-2-(piperidin-1-yl)benzoic acid

[0065] [ka]

[0066] To a stirred solution of methyl 5-fluoro-2-(piperidin-1-yl)benzoate (250 mg, 1.054 mmol) in THF:HO (10 mL + 5 mL) was added LiOH (200 mg, 4.219 mmol). The reaction was then stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated, diluted with EtOAc (10 mL), the organic layer was separated, and the aqueous layer was acidified with 1N HCl solution (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over NaSO and concentrated on a rotary evaporator to give 5-fluoro-2-(piperidin-1-yl)benzoic acid (200 mg, 75.47%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) Rotamer δ 18.55 (s, 1H), 11.97 (s, 1H), 7.82-7.85 (m, 1H), 7.69-7.72 (m, 1H), 7.51-7.56 (m, 1H), 3.07 (t, LC-MS m / z (MH): 238.0

[0067] Step 3: 5-Fluoro-2-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)benzamide

[0068] [ka]

[0069] To a stirred solution of 5-fluoro-2-(piperidin-1-yl)benzoic acid (300 mg, 1.345 mmol) in DCM (20 mL) was added EDC.HCl (385 mg, 2.015 mmol) and HOBt (308 mg, 2.281 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes, (5-(thiophen-2-yl)-1H-pyrazol-3-yl)methanamine (310 mg, 1.614 mmol) was added, and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, diluted with water (10 mL), and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over Na SO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography (eluent: 40% EtOAc in hexane) to give 5-fluoro-2-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)benzamide as an off-white solid (11 mg, 21.31%). 1H NMR (400 MHz, DMSO-d6) Rotamer δ 12.84 (s, 1H), 10.53 (s, 1H), 7.54-7.64 (m, 1H), 7.32-7.40 (m, 4H), 7.04-7.11 (m, 1H), 6.54 (s, 1H), 4.47-4.56 (m, 2H), 2.78 (s, 4H), 1.47 (s, 4H), 1.39 (s, 2H). LC-MS m / z (MH): 385.0.

[0070] Using procedures similar to those described above for Compound 80 and using the appropriate starting materials, the compounds in Table 2 below were prepared.

[0071] [Table 2]

[0072] Synthesis of N-((5-(2-methoxyphenyl)-1H-pyrazol-3-yl)methyl)-2-(piperidin-1-yl)benzamide (compound 102):

[0073] [ka]

[0074] Step 1: Synthesis of ethyl 5-nitro-1H-pyrazole-3-carboxylate

[0075] [ka]

[0076] To a stirred solution of 5-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.84 mmol) in ethanol (50 mL) was added SOCl (8 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the solvent was evaporated, diluted with EtOAc (50 mL), washed once with saturated NaHCO solution (50 mL) followed by water (50 mL), and the organic layer was separated, dried over NaSO, and concentrated on a rotary evaporator to give the crude compound. The crude compound was triturated with diethyl ether (25 mL) to give ethyl 5-nitro-1H-pyrazole-3-carboxylate as an off-white solid (4.5 g, 77.58%). 1 H NMR (400 MHz, DMSO-d6) rotamer δ 15.19 (s, 1H), 7.48 (s, 1H), 4.32-4.37 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H). LC-MS m / z (MH): 186.1

[0077] Step 2: Synthesis of ethyl 5-amino-1H-pyrazole-3-carboxylate

[0078] [ka]

[0079] To a stirred solution of ethyl 5-nitro-1H-pyrazole-3-carboxylate (10 g, 54.05 mmol) in AcOH:THF (1:1) was added Pd / C (wt / wt, 100 mg), and the reaction mixture was hydrogenated at 50 psi for 12 h. After completion of the reaction, the mixture was filtered through a Celite bed, washed with methanol (2 × 50 ml), dried over anhydrous NaSO, and concentrated on a rotary evaporator to give ethyl 5-amino-1H-pyrazole-3-carboxylate as an off-white solid (8 g, 95.57%). 1H NMR (400 MHz, DMSO-d6) Rotamer δ 12.09 (s, 1H), 5.63 (s, 1H), 5.15 (s, 1H), 4.16 (s, 2H), 1.23 (s, 3H), LC-MS m / z (MH): 156.1

[0080] Step 3: Synthesis of ethyl 5-iodo-1H-pyrazole-3-carboxylate

[0081] [ka]

[0082] To a stirred solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.2 g, 7.74 mmol) in HCl (12 mL) was added NaNO (658 mg, 9.67 mmol) in HO (6 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, to which KI (1.6 g, 9.63 mmol) in HO (6 mL) was slowly added at the same temperature. The mixture was warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed once with saturated sodium thiosulfate solution (20 mL) followed by HO (20 ml). The organic layers were dried over NaSO and concentrated on a rotary evaporator to give the crude compound. The crude compound was purified by flash column chromatography (eluent: 10% EtOAc in hexanes) to give ethyl 5-iodo-1H-pyrazole-3-carboxylate as an off-white solid (320 mg, 16%). 1 H NMR (400 MHz, DMSO-d6) rotamer δ 14.23 (s, 1H), 6.88 (s, 1H), 4.27-4.32 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), LC-MS m / z (MH): 266.92

[0083] Step 4: Synthesis of ethyl 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylate

[0084] [ka]

[0085] To a stirred solution of ethyl 5-iodo-1H-pyrazole-3-carboxylate (100 mg, 0.273 mmol) in 1,4-dioxane-HO (8 mL + 2 mL) was added (2-methoxyphenyl)boronic acid (45 mg, 0.296 mmol) and NaCO (72 mg, 0.679 mmol). The reaction mixture was degassed with argon for 10 minutes, and palladium-tetrakis(triphenylphosphine) (31 mg, 0.026 mmol) was added to the mixture, which was then heated at 100 °C for 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, diluted with water (10 mL), and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography (eluent: 60% EtOAc in hexanes) to give ethyl 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylate as an off-white solid (47 mg, 70.14%). 1 H NMR (400 MHz, DMSO-d6) rotamer δ 13.56 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.30-7.39 (m, 1H), 7.11-7.20 (m, 3H), 7.01-7.05 (m, 1H), 4.25-4.33 (m, 2H), 3.89 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), LC-MS m / z (MH): 247

[0086] Step 5: Synthesis of 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylic acid

[0087] [ka]

[0088] To a stirred solution of ethyl 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylate (400 mg, 1.62 mmol) in THF:HO (20 mL + 10 mL) at 0 °C, LiOH.HO (260 mg, 6.504 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the solvent was evaporated, diluted with EtOAc (10 mL), the organic layer was separated, and the aqueous layer was acidified with 1 N HCl solution (5 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over NaSO and concentrated on a rotary evaporator to give 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylic acid as a brown solid (250 mg, 70.62%). 1 H NMR (400 MHz, DMSO-d6) rotamer δ 13.21 (s, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.11-7.14 (m, 2H), 7.01 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H). LC-MS m / z (MH): 219

[0089] Step 6: Synthesis of 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxamide

[0090] [ka]

[0091] To a stirred solution of 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (250 mg, 1.146 mmol) in DMF (6 mL), HATU (650 mg, 1.720 mmol), DIPEA (740 mg, 3.440 mmol), and NH4HCO3 (360 mg, 4.587 mmol) were added at room temperature and stirred for 12 hours. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by Grace column chromatography eluting with 80% EtOAc in petroleum ether to give 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxamide (80 mg, yield: 32.25%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) rotamer δ 13.24 (s, 1H), 7.88-7.94 (m, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.27-7.38 (m, 1H), 6.96-7.19 (m, 4H), 3.89 (s, 3H). LC-MS m / z (MH): 218

[0092] Step 7: Synthesis of (5-(2-methoxyphenyl)-1H-pyrazol-3-yl)methanamine

[0093] [ka]

[0094] To a stirred solution of 5-(2-methoxyphenyl)-1H-pyrazole-3-carboxamide (80 mg, 0.368 mmol) in THF (10 mL) was added lithium aluminum hydride (54 mg, 1.474 mmol) at 0° C., and the reaction mixture was stirred at 80° C. for 12 hours. After completion of the reaction, the reaction was quenched with a slurry of NaSO, followed by the addition of EtOAc (20 mL) and filtration through a Celite pad. The resulting filtrate was concentrated under reduced pressure to give (5-(2-methoxyphenyl)-1H-pyrazol-3-yl)methanamine as an off-white solid (45 mg, 60%), which was used in the next step without further purification. LC-MS m / z (MH): 204

[0095] Step 8: N-((5-(2-methoxyphenyl)-1H-pyrazol-3-yl)methyl)-2-(piperidin-1-yl)benzamide

[0096] [ka]

[0097] To a stirred solution of 2-(piperidin-1-yl)benzoic acid (45 mg, 0.22 mmol) in dichloromethane was added EDC.HCl (63 mg, 0.33 mmol) and HOBt (50 mg, 0.32 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, and to the resulting mixture was added (5-(2-methoxyphenyl)-1H-pyrazol-3-yl)methanamine (45 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, diluted with water (10 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative TLC (eluted with 5% MeOH / DCM) to give 5-fluoro-2-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)methyl)benzamide as an off-white solid (5.3 mg, 6.16%). 1H NMR (400 MHz, DMSO-d6) rotamer δ 12.80 (s, 1H), 10.22 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.64 (bs, 1H), 7.40-7.47 (m, 1H), 7.27-7.29 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.99 (bs, 1H), 6.66 (s, 1H), 4.51 (s, 2H), 3.85 (s, 3H), 2.80 (s, 4H), 1.49 (s, 4H), 1.38 (s, 2H). LC-MS m / z (M-H): 391.0

[0098] Using procedures similar to those described above for Compound 102 and using the appropriate starting materials, the compounds in Table 3 below were prepared.

[0099] [Table 3]

[0100] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 76):

[0101] [ka]

[0102] Step 1: Synthesis of methyl 2-bromobenzoate

[0103] [ka]

[0104] To a stirred solution of 2-bromobenzoic acid (10 gm, 50 mmol) in methanol (80 ml) at 0°C, concentrated sulfuric acid (8 ml, 150 mmol) was added and the reaction mixture was stirred at reflux temperature for 16 hours. After completion of the reaction, the reaction mixture was completely concentrated under reduced pressure. The crude product was quenched with cold water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), and dried over sodium sulfate. The organic layer was concentrated to give the pure yellow liquid product, methyl 2-bromobenzoate (9.0 gm, 83% yield). 1 H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.4, 1.9 Hz, 1H), 7.65 (dt, J = 25.6, 12.6 Hz, 1H), 7.42 - 7.29 (m, 2H), 3.94 (s, 3H).

[0105] Step 2: Synthesis of methyl 2-(4,4-difluoropiperidin-1-yl)benzoate

[0106] [ka]

[0107] To a stirred solution of methyl 2-bromobenzoate (250 mg, 1.162 mmol) in 1,4-dioxane (5 mL) was added 4,4-difluoropiperidine hydrochloride (202 mg, 1.2818 mmol), Xantphos (335 mg, 0.581 mmol), and CS2CO3 (944 mg, 2.905 mmol). The reaction mixture was degassed five times with argon, followed by the addition of Pd2dba3 (106 mg, 0.1166 mmol). The reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction, the mixture was cooled, quenched with water, and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The dried organic layers were concentrated under reduced pressure to give the crude product as a yellow liquid. This was purified by flash column chromatography using ethyl acetate and hexane as eluents. Pure material of methyl 2-(4,4-difluoropiperidin-1-yl)benzoate was obtained (40 mg, 16%). 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.73 (m, 1H), 7.42 (dd, J = 11.1, 4.4 Hz, 1H), 7.10 - 6.98 (m, 2H), 3.89 (s, 3H), 3.22 - 3.07 (m, 4H), 2.16 (ddd, J = 19.3, 13.8, 5.6 Hz, 4H).

[0108] Step 3: Synthesis of 2-(4,4-difluoropiperidin-1-yl)benzoic acid

[0109] [ka]

[0110] To a stirred solution of methyl 2-(4,4-difluoropiperidin-1-yl)benzoate (770 mg, 3.019 mmol) in ethanol (8 mL) was added water (2 mL) and NaOH (480 mg, 12.078 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate (2 × 50 mL). The product-containing aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give the product, 2-(4,4-difluoropiperidin-1-yl)benzoic acid (580 mg, 80%), as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 14.99 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 3.15 (s, 4H), 2.16 (t, J = 13.9 Hz, 4H). LC-MS m / z (M+H): 242.0.

[0111] Step 4: 2-(4,4-difluoropiperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)benzamide

[0112] [ka]

[0113] To a stirred solution of 2-(4,4-difluoropiperidin-1-yl)benzoic acid (25 mg, 0.104 mmol) in dichloromethane (5 mL) was added EDC.HCl (29 mg, 0.156 mmol), HOBt (23 mg, 0.156 mmol), and triethylamine (0.067 mL, 0.468 mmol), followed by 5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (24 mg, 0.114 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The organic layers were concentrated under reduced pressure to give the crude product as a red liquid. The crude product was purified by flash chromatography using ethyl acetate and hexane as the eluent to give 2-(4,4-difluoropiperidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as an off-white solid (10 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 0.4H), 13.97 (s, 0.6H), 9.81 (s, 0.4H), 9.73 (s, 0.6H), 7.87 - 7.66 (m, 2H), 7.53 (dd, J = 11.5, 4.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 13.9, 6.4 Hz, 1H), 7.14 - 7.07 (m, 1H), 4.66 (d, J = 5.6 Hz, 1.2H), 4.57 (d, J = 5.0 Hz, 0.8H), 3.04 (s, 4H), 2.15 (s, 4H). LC-MS m / z (M+H): 404.1.

[0114] Using procedures similar to those described above for Compound 76 and using the appropriate starting materials, the compounds in Table 4 below were prepared.

[0115] [Table 4] TIFF0007827626000034.tif253154TIFF0007827626000035.tif251165TIFF0007827626 000036.tif255155TIFF0007827626000037.tif253157TIFF0007827626000038.tif44162

[0116] Synthesis of 3-(3,3-difluoropyrrolidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)pyrazine-2-carboxamide (compound 87):

[0117] [ka]

[0118] Step 1: Synthesis of ethyl 3-(3,3-difluoropyrrolidin-1-yl)pyrazine-2-carboxylate

[0119] [ka]

[0120] To a stirred solution of ethyl 3-chloropyrazine-2-carboxylate (300 mg, 1.61 mmol) in DMF (10 mL) at 0 °C, CS2CO3 (1.2 g, 3.22 mmol) and Et3N (162.9 mg, 1.61 mmol) were added, followed by 3,3-difluoropyrrolidine.HCl (277.9 mg, 1.93 mmol). The reaction mixture was stirred in a sealed tube at 100 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was triturated with n-hexane, and the resulting product was dried to give ethyl 3-(3,3-difluoropyrrolidin-1-yl)pyrazine-2-carboxylate as a yellow syrup (260 mg, 62.95%).1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 2 Hz, 1H), 8.03 (d, J = 2 Hz, 1H), 4.50 (q, J = 6.4 Hz, 2H), 3.78 - 3.72 (m, 4H), 2.51 - 2.40 (m, 2H), 1.46 (t, J = 6.8 Hz, 3H).

[0121] Step 2: Synthesis of 3-(3,3-difluoropyrrolidin-1-yl)pyrazine-2-carboxylic acid

[0122] [ka]

[0123] To a stirred solution of ethyl 3-(3,3-difluoropyrrolidin-1-yl)pyrazine-2-carboxylate (250 mg, 0.97 mmol) in THF:HO (5 mL:2 mL) at 0 °C was added LiOH (244.67 mg, 5.83 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was acidified with 1N HCl and extracted with EtOAc (2 × 20 mL). The organic layer was dried over MgSO and concentrated in vacuo to give 3-(3,3-difluoropyrrolidin-1-yl)pyrazine-2-carboxylic acid as an off-white solid (200 mg, 90.17%). 1 H NMR (400 MHz, DMSO-d6): δ 13.50 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H), 3.80 (t, J = 12.8 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.56 - 2.49 (m, 2H).

[0124] Step 3: Synthesis of 3-(3,3-difluoropyrrolidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)pyrazine-2-carboxamide

[0125] [ka]

[0126] To a stirred solution of 3-((3,3-difluoropyrrolidin-1-yl)methyl)pyrazine-2-carboxylic acid (70 mg, 0.30 mmol) in CHCl (10 mL) was added EDC.HCl (87.57 mg, 0.45 mmol), HOBt (61.8 mg, 0.45 mmol), and EtN (92.62 mg, 0.91 mmol) at 0° C. The resulting mixture was stirred for 10 minutes, and then (5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methanamine.HCl (72.62 mg, 0.33 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was washed with water and extracted with CHCl (2×10 mL). The organic layer was dried over MgSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give 3-(3,3-difluoropyrrolidin-1-yl)-N-((5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl)methyl)pyrazine-2-carboxamide as an off-white solid (39 mg, 32.63%). 1 H NMR (400 MHz, DMSO-d6): δ 13.96 (brs, 1H), 9.26 (brs, 1H), 8.26 (s, 1H), 7.94 (s, 1H), 7.59 (d, J = 12 Hz, 2H), 7.14 (s, 1H), 4.55 (d, LC-MS (m / z): 391.10 (M+H) +

[0127] Using procedures similar to those described above for Compound 87 and using the appropriate starting materials, the following compounds in Table 5 were prepared.

[0128] [Table 5]

[0129] Synthesis of N-((5-(4-methylthiophen-3-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (compound 16):

[0130] [ka]

[0131] Step 1: N-((1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide:

[0132] [ka]

[0133] To a stirred solution of 2-(trifluoromethoxy)benzoic acid (25 g, 0.121 mmol) in DMF (250 mL) at 0 °C, HATU (46.1 g, 0.121) was added, followed by (2H-pyrazol-3-yl)methanamine (11.7 g, 0.1213) and DIPEA (39.1 g, 0.303 mmol). The reaction mixture was then stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water (2.5 L) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed once with HO (250 mL), saturated NaHCO solution (250 mL), and finally brine (250 mL). The organic layer was dried over NaSO and concentrated to give the crude compound. The crude compound was purified by flash column chromatography (eluent: 70% EtOAc / petroleum ether) to give N-((1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (18.3 g, 53.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 12.64 (d, J = 47.1 Hz, 1H), 8.87 (d, J = 42.1 Hz, 1H), 7.76 - 7.50 (m, 3H), 7.49 - 7.27 (m, 2H), 6.15 (d, J = 12.1 Hz, 1H), 4.42 (t, J = 11.1 Hz, 2H). LC-MS m / z (M+H): 286.1.

[0134] Step 2: N-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide:

[0135] [ka]

[0136] To a stirred solution of N-((1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (18.3 g, 64.15 mmol) in toluene (400 mL) at room temperature was added 3,4-dihydro-2H-pyran (5.39 g, 64.1 mmol). The reaction was then heated at 80 °C for 4 h. After completion of the reaction, the solvent toluene was distilled off, and the residue was diluted with EtOAc (250 mL) and washed once with saturated NaHCO solution (100 mL) and HO (100 mL). The organic layer was separated, dried over NaSO, and concentrated to give the crude compound. The crude product thus obtained was triturated with petroleum ether (200 mL) and stirred for 12 h. The solid was filtered and dried under vacuum to give N-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (12.57 g, 51.5%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.57 (t, J = 7.0 Hz, 2H), 7.46 - 7.38 (m, 2H), 6.20 (d, J = 2.2 Hz, 1H), 5.32 (d, J = 10.3 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.90 (d, J = 11.0 Hz, 1H), 3.67 - 3.52 (m, 1H), 2.07 (dd, J = 24.7, 11.0 Hz, 1H), 1.98 - 1.80 (m, 2H), 1.65 (s, 1H), 1.51 (d, J = 3.5 Hz, 2H). LC-MS m / z (M+H): 370.1.

[0137] Step 3: N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide:

[0138] [ka]

[0139] To a stirred solution of N-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (18.2 g, 49.30 mmol) in dry THF (200 mL) at −78° C., 1.6 M n-butyllithium in hexane (6.31 g, 98.61 mmol) was added over a period of 10 minutes. The reaction mixture was then stirred at the same temperature for 1 hour. To the resulting mixture, iodine (13.76 g, 54.2 mmol) in dry THF (200 mL) was added over 15 minutes. After completion of the addition of iodine, the reaction was slowly warmed to −20° C. and stirred for 45 minutes. After completion of the reaction, it was carefully quenched with saturated NaHSO3 solution (200 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude compound. The crude compound was purified by flash column chromatography (eluent: 20% EtOAc in petroleum ether) to give N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (12.57 g, 51.5%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.91 (t, J = 5.6 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.44 (dd, J = 14.6, 7.6 Hz, 2H), 6.43 (s, 1H), 5.33 (d, J = 9.8 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 3.90 (d, J = 10.9 Hz, 1H), 3.59 (dd, J = 17.3, 7.5 Hz, 1H), 2.27 (dd, J = 22.8, 9.5 Hz, 1H), 1.97 (d, J = 12.3 Hz, 1H), 1.83 (d, J = 12.1 Hz, 1H), 1.67 (s, 1H), 1.50 (s, 2H)., LC-MS m / z (M+H): 396.0.

[0140] Step 4: N-((5-(4-methylthiophen-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide

[0141] [ka]

[0142] To a stirred solution of N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (60 mg, 0.131 mmol) and 4-methylthiophene-3-boronic acid (20.66 mg, 0.157 mmol) in 1,4-dioxane:water (5 mL:1 mL) was added Na2CO3 (34.71 mg, 0.327 mmol). The reaction mixture was then degassed with argon for 10 minutes, followed by the addition of palladium-tetrakis(triphenylphosphine) (15.13 mg, 0.0130 mmol). The resulting mixture was heated at 100 °C for 12 hours. After completion of the reaction, the mixture was diluted with HO (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude compound. This was further purified by preparative TLC to give N-((5-(4-methylthiophen-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (34 mg, 57.74%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.57 (dd, J = 15.8, 5.4 Hz, 3H), 7.44 (dd, J = 15.6, 7.6 Hz, 2H), 7.34 (s, 1H), 6.26 (s, 1H), 5.02 (d, J = 9.5 Hz, 1H), 4.43 (s, 2H), 3.91 (d, J = 11.1 Hz, 1H), 3.43 (s, 1H), 2.33 (d, J = 14.2 Hz, 1H), 2.09 (d, J = 16.3 Hz, 3H), 1.90 (s, 1H), 1.47 (s, 3H), 1.22 (s, 2H). LC-MS m / z (M+H): 466.2.

[0143] Using procedures similar to those described above for compound 16 and using the appropriate starting materials, the intermediate compounds in Table 6 below were prepared.

[0144] [Table 6] TIFF0007827626000050.tif242149TIFF0007827626000051.tif254145TIFF0007827626000052.tif254146TIFF0007827626000053.tif200149

[0145] Step 5: N-((5-(4-methylthiophen-3-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide:

[0146] [ka]

[0147] To a stirred solution of N-((5-(4-methylthiophen-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (34 mg, 0.073 mmol) in dichloromethane (3 mL) at 0 °C was added 1,4-dioxane-HCl (4.0 M, 3 mL). The resulting reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the mixture was concentrated and further co-distilled with dichloromethane (2 × 10 mL) to give crude material. Further workup was carried out by addition of HO (10 mL), followed by basification with saturated NaHCO solution and extraction with EtOAc (2 × 5 mL). The combined organic layers were dried over NaSO and concentrated to give crude compound. It was then purified by preparative TLC (eluent: 30% EtOAc + hexane) to give N-((5-(4-methylthiophen-3-yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (19 mg, 68.24%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 12.77 (d, J = 41.1 Hz, 1H), 8.92 (d, J = 39.6 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 7.0 Hz, 2H), 7.43 (s, 2H), 7.24 LC-MS m / z (MH): 382.1.

[0148] Using procedures similar to those described above for compound 16 and using the appropriate starting materials, the compounds in Table 7 below were prepared.

[0149] [Table 7] TIFF0007827626000056.tif253155TIFF0007827626000057.tif241165TIFF00078276260 00058.tif254161TIFF0007827626000059.tif254156TIFF0007827626000060.tif253161

[0150] Synthesis of N-((5-(2,5-dihydroxyphenyl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (compound 40):

[0151] [ka]

[0152] To a stirred solution of N-((5-(2,5-dimethoxyphenyl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (90 mg, 0.365 mmol) in dichloromethane (5 mL) at 0 °C was added a solution of BBr3 in dichloromethane (1.0 M, 4 mL). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, it was quenched with aqueous NaHCO3 (5 mL) and extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude compound. It was purified by preparative TLC (3% MeOH in DCM) to give N-((5-(2,5-dihydroxyphenyl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide as an off-white solid (24 mg, 34.28%). 1 H NMR (400 MHz, DMSO) δ 12.80 (d, 1H), 9.85 (d, 1H), 8.93 (d, 2H), 7.62 (d, 2H), 7.45 (s, 2H), 6.99 (s, 1H), 6.71 (s, 1H), 6.59 (s, 2H), 4.47 (d, 2H) LC-MS (ESI): m / z 393.9 (M+H) +

[0153] Using procedures similar to those described above for Compound 40 and using the appropriate starting materials, the compounds in Table 8 below were prepared.

[0154] [Table 8] TIFF0007827626000063.tif255157TIFF0007827626000064.tif15163

[0155] Synthesis of 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 126):

[0156] [ka]

[0157] Step 1: Synthesis of 2-methoxybenzothioamide

[0158] [ka]

[0159] To a stirred solution of 2-methoxybenzonitrile (130 g, 977 mmol) in pyridine (1200 mL) at 0° C. was added ammonium sulfide solution (650 mL, 5 volumes), followed by triethylamine (150 mL, 1075 mmol). The reaction mixture was then stirred at 55° C. for 12 hours. The reaction was monitored by TLC (30% ethyl acetate / hexane). After completion of the reaction, it was diluted with cold water (4.0 L), and the solid was filtered and dried in vacuo to give 2-methoxybenzothioamide (145 g, 89% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94 br(s, 1H), 9.30 (brs, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H).

[0160] Step-2: Synthesis of tert-butyl ((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate

[0161] [ka]

[0162] A stirred solution of 2-methoxybenzothioamide (61 g, 365 mmol) and tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (207 g, 1095 mmol) in pyridine (300 mL) was heated at 120 °C for 48 h. After completion of the reaction by TLC, it was diluted with water (500 mL) and extracted with EtOAc (2 × 600 mL). The organic layer was separated, washed with saturated NH4Cl solution (500 mL), brine solution (500 mL), dried over Na2SO4, filtered, and evaporated to give the crude compound. The crude product was washed with diethyl ether to give tert-butyl ((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate (27 g, yield: 24%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 4.18 (d, J = 5.6 Hz, 2H), 3.94 (s, 3H), 1.38 (s, 9H). LC-MS m / z (M+H): 305.0.

[0163] Step-3: Synthesis of (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride:

[0164] [ka]

[0165] To a stirred solution of tert-butyl ((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate (27 g, 89 mmol) in DCM (150 mL) at 0° C., 4 M HCl in 1,4-dioxane-HCl (54 mL, 2 volumes) was added and left for 10 minutes. The reaction was stirred at room temperature for 4 hours. TLC showed the completion of starting material and the formation of a polar spot (5% MeOH / DCM). After completion of the reaction, it was diluted with petroleum ether (200 mL) and the free solid that formed was filtered. The solid was washed with diethyl ether (200 mL) and dried under vacuum to give (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (25 g, yield: 99%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (brs, 3H), 8.05 (d, J = 8.0 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.01 (brs, 3H), 4.13 (d, J = 5.6 Hz, 2H), 3.95 (s, 3H). LC-MS m / z (M+H): 205.1.

[0166] Step-4: Synthesis of 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide:

[0167] [ka]

[0168] To a stirred solution of 2-(difluoromethoxy)benzoic acid (20 g, 104 mmol) in DCM (500 mL) at 0 °C was added EDC.HCl (30 g, 156 mmol), HOBt (21 g, 156 mmol), (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (25 g, 104 mmol), followed by triethylamine (44 mL, 312 mmol). The reaction was stirred at room temperature for 12 h. After completion of the reaction, the solid was filtered through a Celite bed, and the resulting filtrate was washed once with saturated NaHCO solution (500 mL), saturated NH Cl solution (1 L), and brine solution. The organic layer was separated, dried over Na SO , and concentrated under reduced pressure to give the crude product. The resulting crude was triturated with acetonitrile (500 mL), stirred for 1 h, filtered, washed with diethyl ether (100 mL), and dried under vacuum to give 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (19 g, yield: 56%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.55 (s, 1H), 8.76 (bs, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.36-6.99 (m, 5H), 4.53 (d, J = 5.6 Hz, 2H), 3.94 (s, 3H). LC-MS m / z (M+H): 374.9.

[0169] Alternative preparation of 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide, compound 126:

[0170] [ka]

[0171] Step 1: Synthesis of N-(cyanomethyl)-2-(difluoromethoxy)benzamide

[0172] [ka]

[0173] To a stirred solution of 2-(difluoromethoxy)benzoic acid (5 g, 26 mmol) in DMF (20 mL) at 0 °C, HATU (15.1 g, 39.8 mmol), DIPEA (10.3 g, 79 mmol), and 2-aminoacetonitrile HCl (2.4 g, 26 mmol) were added. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water (50 mL), extracted with EtOAc (2 × 50 mL), and the organic layer was separated and washed with ice-cold water (3 × 100 mL), followed by brine solution (2 × 100 mL), and finally dried over Na SO and concentrated under reduced pressure to give the crude compound. The resulting crude material was dissolved in diethyl ether (50 mL) and subsequently triturated with pentane (2×50 mL), and the precipitated solid was filtered and dried under vacuum to give N-(cyanomethyl)-2-(difluoromethoxy)benzamide (3.5 g, ∼58% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): 8.98 (t, J = 5.2 Hz, 10.4 Hz, 1H), 7.56 (t, J = 8 Hz, 16.4 Hz, 2H), 7.33 (t, J = 8 Hz, 15.6 Hz, 1H), 7.26 (d, J = 8 Hz, 1H) 6.99 (d, J = 73.6 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H). LC-MS m / z (MH): 227.1

[0174] Step-2: Synthesis of 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide

[0175] [ka]

[0176] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)benzamide (3.5 g, 13.78 mmol) and 2-methoxybenzohydrazide (3.44 g, 20.6 mmol) in n-BuOH (20 mL) was added potassium carbonate (0.95 g, 6.89 mmol). The resulting reaction mixture was heated at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated in vacuo, diluted with water (50 mL), extracted with EtOAc (2×50 mL), and the organic layer was separated, washed with brine solution (20 mL), water (50 mL), and finally dried over NaSO and concentrated to give the crude brown compound. The resulting crude was diluted with acetonitrile (5 mL), stirred for 15 minutes, and the precipitated white solid was filtered and washed with diethyl ether (2×20 mL) to give 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (BRG-0399) (1.9 g, approximately 37% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.5 (s, 1H), 8.76 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 15.2 Hz, LC-MS m / z (MH): 375.1.

[0177] Using procedures similar to those described above for Compound 126 and using the appropriate starting materials, the following compounds in Table 9 were prepared.

[0178] [Table 9] TIFF0007827626000074.tif211165

[0179] Synthesis of N-((5-(3-methoxypyridin-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (compound 34):

[0180] [ka]

[0181] Step 1: Methyl 3-methoxypicolinate

[0182] [ka]

[0183] To a stirred solution of 3-methoxypicolinic acid (1 g, 7.19 mmol) in acetone (10 mL) at 0 °C, K2CO3 (2.48 g, 17.97 mmol) was added, followed by methyl iodide (2.23 g, 15.75 mmol). The mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated, diluted with HO (25 mL), and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over Na2SO4 and concentrated on a rotary evaporator to give the crude compound. The crude product was purified by flash column chromatography to give methyl 3-methoxypicolinate as a yellow syrup (570 mg, 47.50%). 1 H NMR (400 MHz, DMSO): δ 8.16 (dd, J = 4.5, 1.1 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 8.6, 4.5 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H). LC-MS (ESI): m / z 168.1 (M+H) +

[0184] Step 2: 3-Methoxypicolinohydrazide

[0185] [ka]

[0186] To a stirred solution of methyl 3-methoxypicolinate (560 mg, 3.33 mmol) in ethanol (10 mL) at room temperature, hydrazine hydrate (213 mg, 6.66 mmol) was added and stirred for 12 hours at 70° C. After completion of the reaction, the mixture was concentrated and the crude compound thus obtained was triturated with petroleum ether to give 3-methoxypicolinohydrazide as a brown syrup (530 mg, 94.6%). 1 H NMR (400 MHz, DMSO): δ 9.40 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.5, 4.6 Hz, 1H), 4.43 (s, 2H), 3.79 (s, 3H). LC-MS (ESI): m / z 168.2 (M+H) +

[0187] Step 3: N-(cyanomethyl)-2-(trifluoromethoxy)benzamide

[0188] [ka]

[0189] To a stirred solution of 2-(trifluoromethoxy)benzoic acid (2 g, 9.7 mmol) in DMF (10 mL) was added HATU (5.5 g, 14.56 mmol) and DIPEA (3.76 g, 29.12 mmol) at 0 °C. The resulting mixture was stirred for 10 min, and 2-aminoacetonitrile 2 (897 mg, 9.70 mmol) was added and stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The resulting crude product was purified by CombiFlash column chromatography (eluent: 40% ethyl acetate in hexane) to give N-(cyanomethyl)-2-(trifluoromethoxy)benzamide as a white solid (1.8 g, 82.19%). 1 H NMR (400 MHz, DMSO): δ 9.18 (s, 1H), 7.65-7.60 (m, 2H), 7.48 (dd, J = 14, 3.5 Hz, 2H), 4.30 (d, J = 5.6 Hz 2H). LC-MS (ESI): m / z 245.1 (M+H) +

[0190] Step 4: N-((5-(3-methoxypyridin-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-2-(trifluoromethyl)benzamide

[0191] [ka]

[0192] To a stirred solution of N-(cyanomethyl)-2-(trifluoromethoxy)benzamide in n-butanol (2 mL), 3-methoxypicolinohydrazide (44.34 mg, 0.26 mmol) and K2CO3 (15.20 mg, 0.11 mmol) were added and stirred at 165 °C under microwave irradiation for 30 minutes. After completion of the reaction, the reaction mixture was diluted with cold water and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude compound. The crude compound was purified by preparative TLC to give N-((5-(3-methoxypyridin-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-2-(trifluoromethyl)benzamide as an off-white solid (30 mg, 34.5%). 1 H NMR (400 MHz, DMSO): δ 14.01 (s, 1H), 8.95 (s, 1H), 8.27 (s, 1H), 7.69 - 7.56 (m, 3H), 7.52 - 7.39 (m, 3H), 4.54 (s, 2H), 3.92 (s, 3H). LC-MS (ESI): m / z 394.1 (M+H) +

[0193] Synthesis of 2-(difluoromethoxy)-N-(1-(5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)cyclopropyl)benzamide (compound 118):

[0194] [ka]

[0195] Step 1: N-(1-cyanocyclopropyl)-2-(difluoromethoxy)benzamide

[0196] [ka]

[0197] To a stirred solution of 2-(difluoromethoxy)benzoic acid (1 g, 5.32 mmol) and 1-aminocyclopropane-1-carbonitrile hydrochloride (747 mg, 6.40 mmol) in DMF (20 mL) at 0 °C, TEA (3.0 mL, 21.28 mmol), EDC.HCl (1.52 mg, 7.98 mmol), and HOBt (1.07 mg, 7.98 mmol) were added. The resulting reaction mixture was then stirred at room temperature for 12 h. After completion of the reaction, the mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with ice-cold water (3 × 100 mL), brine (2 × 100 mL), and dried over NaSO. Concentration followed by purification of the crude product using flash column chromatography afforded N-(1-cyanocyclopropyl)-2-(difluoromethoxy)benzamide (560 mg, 42% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO): δ 9.20 (s, 1H), 7.51-7.56 (m, 2H), 6.94-7.34 (m, 3H), 1.53-1.57 (m, 2H), 1.18-1.22(m, 2H). LC-MS (ESI): m / z 400.1 (M+H) +

[0198] Step 2: 2-(Difluoromethoxy)-N-(1-(5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)cyclopropyl)benzamide

[0199] [ka]

[0200] To a stirred solution of N-(1-cyanocyclopropyl)-2-(difluoromethoxy)benzamide (200 mg, 0.79 mmol) and 2-methoxybenzohydrazide (200 mg, 1.2 mmol) in n-BuOH was added K2CO3 (100 mg, 0.72 mmol) at room temperature. The resulting reaction mixture was heated at 120 °C for 16 h. Upon completion of the reaction, the mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc. The organic material was washed with brine, water, and finally dried over Na2SO4. Concentration on a rotary evaporator followed by purification by flash column chromatography afforded 2-(difluoromethoxy)-N-(1-(5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)cyclopropyl)benzamide (50 mg, 16% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO): δ 13.37 (s, 1H), 9.04 (s, 1H), 7.99 (d, J = 7.6Hz, 1H), 7.58 (d, J = 7.6Hz, 1H), 7.52(t, J = 8.0 Hz, 1H), 7.44 (t, J LC-MS (ESI): m / z 400.1 (M+H) +

[0201] Synthesis of 2-(difluoromethoxy)-5-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 138):

[0202] [ka]

[0203] Step 1: 2-(difluoromethoxy)-5-fluorobenzaldehyde:

[0204] [ka]

[0205] To a stirred solution of KOH (8.09 g, 142.8 mmol) in acetonitrile (20 mL) and water (20 mL) at −20° C., 4-fluoro-2-hydroxybenzaldehyde (1 g, 7.14 mmol) was added, followed by dropwise addition of diethyl(bromodifluoromethyl)phosphonate (3.80 g, 14.28 mmol) over a period of 30 minutes. After completion of the reaction, the mixture was diluted with EtOAc (20 mL), and the organic layer was separated and dried over Na2SO4. Concentration of the organic material followed by purification of the crude compound by flash column chromatography (eluent: 10% EtOAc in hexane) afforded 2-(difluoromethoxy)-5-fluorobenzaldehyde as a yellow syrup (700 mg, 51.8%). 1 H NMR (400 MHz, DMSO): δ 10.20 (d, J = 2.8 Hz, 1H), 7.65 (ddd, J = 9.0, 8.0, 3.3 Hz, 1H), 7.59 (dd, J = 8.3, 3.2 Hz, 1H), 7.46 (dd, J = 9.0, 4.2 Hz, 1H), 7.32 (t, J = 73.6 Hz, 1H).

[0206] Step 2: 2-(difluoromethoxy)-5-fluorobenzoic acid:

[0207] [ka]

[0208] To a vigorously stirred solution of 2-(difluoromethoxy)-5-fluorobenzaldehyde (500 mg, 2.62 mmol) in THF:t-butanol:HO (10 mL) at 0 °C, monobasic sodium phosphate (1.02 g, 6.56 mmol) was added, followed sequentially by 2-methyl-2-butene (473.4 mL, 2.29 mmol) and NaClO. The mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was acidified with 1 N HCl (5 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over NaSO and concentrated to give 2-(difluoromethoxy)-5-fluorobenzoic acid as a white solid (400 mg, 73.93%). 1 H NMR (400 MHz, DMSO): δ 13.49 (s, 1H), 7.61 (dd, J = 8.7, 3.2 Hz, 1H), 7.49 (ddd, J = 8.9, 8.0, 3.3 Hz, 1H), 7.34 (dd, J = 9.0, 4.5 Hz, 1H), 7.10 (t, J = 74.3 Hz, 1H). GC-MS (ESI): m / z 206 (M) +

[0209] Step 3: 2-(difluoromethoxy)-5-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide:

[0210] [ka]

[0211] To a stirred solution of 2-(difluoromethoxy)-5-fluorobenzoic acid (100 mg, 0.48 mmol) in dichloromethane (10 mL) at 0 °C was added EDC.HCl (113.02 mg, 0.72 mmol), HOBt (98.37 mg, 0.72 mmol), and TEA (147.07 mg, 1.45 mmol). The resulting mixture was stirred for 10 minutes, followed by the addition of (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (139.8 mg, 0.58 mmol). The mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was washed successively with saturated NH4Cl (20 mL), saturated NaHCO3 solution (20 mL), and brine (20 mL) once. The combined organic layers were dried over Na2SO4 and concentrated. The crude product thus obtained was purified by flash column chromatography (eluent: 40% ethyl acetate in hexane) to give the compound 2-(difluoromethoxy)-5-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as an off-white solid (60 mg, 31.5%). 1 H NMR (400 MHz, DMSO): δ 13.56 (s, 1H), 8.89 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.49 - 7.36 (m, 4H), 7.31 (t, J = 4.3 Hz, 1H), 7.19 (d, J = 7.07 (t, J = 7.5 Hz, 1H), 6.94 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 3.95 (s, 3H). LC-MS (ESI): m / z 393.3 (M+H) +

[0212] Synthesis of 2-(difluoromethoxy)-5-fluoro-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide

[0213] [ka]

[0214] To a stirred solution of 2-(difluoromethoxy)-5-fluorobenzoic acid (100 mg, 0.48 mmol) in dichloromethane (10 mL) at 0 °C, EDC.HCl (113.02 mg, 0.72 mmol), HOBt (98.37 mg, 0.72 mmol), and TEA (147.07 mg, 1.45 mmol) were added. The resulting mixture was stirred for 10 minutes, followed by the addition of (5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methoxamine hydrochloride (129.36 mg, 0.58 mmol). The mixture was warmed to room temperature and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was washed successively with saturated NH4Cl (20 mL), saturated NaHCO3 solution (20 mL), and brine (20 mL) once. The combined organic layers were dried over Na2SO4 and concentrated. The crude product thus obtained was purified by flash column chromatography (eluent: 40% ethyl acetate in hexane) to give 2-(difluoromethoxy)-5-fluoro-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as an off-white solid (40 mg, 20.10%). 1 H NMR (400 MHz, DMSO): δ 13.70 (s, 1H), 8.90 (s, 1H), 7.77 (s, 1H), 7.46 - 7.37 (m, 2H), 7.31 (t, J = 4.4 Hz, 2H), 7.21 (dd, J = 8.8, 4.3 Hz, 1H), 7.13(t, J = 64 Hz, 1H), 4.53 (d, J = 5.5 Hz, 2H), 3.94 (s, 3H). LC-MS (ESI): m / z 411.1 (M+H) + .

[0215] Synthesis of 2-(difluoromethoxy)-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)nicotinamide (Compound 143) and 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)nicotinamide (Compound 144)

[0216] [ka]

[0217] Step 1: Methyl 2-hydroxynicotinate:

[0218] [ka]

[0219] To a stirred solution of 2-hydroxynicotinic acid (5 g, 27.8 mmol) in methanol (75 mL) at 0 °C, thionyl chloride (5 mL) was added and stirred at 75 °C for 12 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give the crude product. The mixture was basified with saturated NaHCO solution (20 mL) and extracted with 10% methanol in dichloromethane (2 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give methyl 2-hydroxynicotinate as an off-white solid (2.3 g, 41.8%). 1 H NMR (400 MHz, DMSO): δ 12.08 (s, 1H), 8.04 (dd, J = 7.1, 2.2 Hz, 1H), 7.65 (dd, J = 6.3, 2.2 Hz, 1H), 6.25 (t, J = 6.7 Hz, 1H), 3.71 (s, 3H). LC-MS (ESI): m / z 154.1 (M+H)

[0220] Step 2: Methyl 2-(difluoromethoxy)nicotinate:

[0221] [ka]

[0222] To a stirred solution of methyl 2-hydroxynicotinate (1.9 g, 12.4 mmol) in DMF at 0 °C, sodium hydride (357 mg, 14.9 mmol) was added portionwise and stirred for 10 minutes, followed by the addition of 2-chloro-2,2-difluoroacetic acid (1.94 g, 14.9 mmol) and stirring at 125 °C for 2 hours. After completion of the reaction, the mixture was diluted with ice-cold water (25 mL) and extracted with 10% methanol in dichloromethane (2 × 10 mL). The combined organic layers were concentrated under reduced pressure to give the crude compound. This was purified by flash column chromatography to give methyl 2-(difluoromethoxy)nicotinate as a light brown solid (500 mg, 19.84%). 1 H NMR (400 MHz, DMSO): δ 8.48 (dd, J = 4.9, 1.9 Hz, 1H), 8.33 (dd, J = 7.6, 1.9 Hz, 1H), 7.79 (t, J = 72.2 Hz, 2H), 7.42 (dd, J = 7.6, 4.9 Hz, 1H), 3.87 (s, 3H). LC-MS (ESI): m / z 154.1 (M+H)

[0223] Step 3: 2-(difluoromethoxy)nicotinic acid:

[0224] [ka]

[0225] To a stirred solution of methyl 2-(difluoromethoxy)nicotinate (260 mg, 1.27 mmol) in THF:HO (10 mL:5 mL) at 0 °C, LiOH (122.8 mg, 5.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated, diluted with HO (10 mL), and extracted with EtOAc (2 × 10 mL). The aqueous layer was separated, acidified with 1N HCl solution (5 mL), and then extracted with 10% methanol in dichloromethane (2 × 15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 2-(difluoromethoxy)nicotinic acid as an off-white solid (60 mg, 24.7%). 1 H NMR (400 MHz, DMSO): δ 13.44 (s, 1H), 8.43 (dd, J = 4.9, 1.9 Hz, 1H), 8.30 (dd, J = 7.6, 1.9 Hz, 1H), 7.78 (t, J = 72.4 Hz, 1H), 7.39 (dd, J = 7.6, 4.9 Hz, 1H).

[0226] Step 4: 2-(difluoromethoxy)-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)nicotinamide (compound 143):

[0227] [ka]

[0228] To a stirred solution of 2-(difluoromethoxy)nicotinic acid (70 mg, 0.37 mmol) in CHCl (10 mL) at 0 °C, EDC.HCl (106.4 mg, 0.55 mmol), HOBt (75.01 mg, 0.55 mmol), and triethylamine (112 mg, 1.11 mmol) were added. The resulting mixture was stirred for 10 minutes, and (5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (95.74 mg, 0.37 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was washed successively with saturated NHCl (20 mL), saturated NaHCO solution (20 mL), and brine (20 mL). The combined organic layers were dried over NaSO and concentrated to give the crude compound. The resulting crude was then purified by flash column chromatography (eluent: 50% ethyl acetate in hexane) to give the product 2-(difluoromethoxy)-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)nicotinamide as an off-white solid (60 mg, 41.23%). 1 H NMR (400 MHz, DMSO): δ 13.73 (s, 1H), 8.83 (s, 1H), 8.35 (dd, J = 4.9, 1.9 Hz, 1H), 8.11 (dd, J = 7.5, 1.8 Hz, 1H), 7.74 (t, J = 72.1 Hz, 1H), 7.81 (dd, J = 9.4, 3.2 Hz, 1H), 7.42 - 7.29 (m, 2H), 7.22 (dd, J = 9.1, 4.5 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.95 (s, 3H).LC-MS (ESI): m / z 394.2 (M+H)

[0229] Step 5: 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)nicotinamide (compound 144):

[0230] [ka]

[0231] To a stirred solution of 2-(difluoromethoxy)nicotinic acid (50 mg, 0.26 mmol) in CHCl (10 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (76.02 mg, 0.39 mmol), hydroxybenzotriazole (53.58 mg, 0.39 mmol), and triethylamine (80.10 mg, 0.79 mmol) were added. The resulting mixture was stirred for 10 minutes, followed by the addition of (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (63.6 mg, 0.26 mmol) and stirring at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with aqueous NHCl and extracted with dichloromethane. The organic material was washed successively with 1 N HCl, aqueous NHCO, and brine. The organic layer was dried over MgSO4, concentrated under vacuum and the crude compound so obtained was purified by flash column chromatography to give the product as a white solid (60 mg, 76%). 1 H NMR (400 MHz, DMSO): δ 13.58 (s, 1H), 8.82 (s, 1H), 8.35 (dd, J = 4.9, 1.8 Hz, 1H), 8.09 (t, J = 8.1 Hz, 2H), 7.73 (t, J = 72.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.37 (dd, J = 7.5, 4.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 4.56 (d, J = 5.4 Hz, 2H), 3.95 (s, 3H). LC-MS (ESI): m / z 376.1 (M+H)

[0232] Using procedures similar to those described above and using the appropriate starting materials, the compounds in Table 10 below were prepared.

[0233] [Table 10] TIFF0007827626000095.tif233165

[0234] Synthesis of 2-(difluoromethoxy)-3-fluoro-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 135) and 2-(difluoromethoxy)-3-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 136):

[0235] [ka]

[0236] Step 1: Methyl 2-(difluoromethoxy)-3-fluorobenzoate

[0237] [ka]

[0238] To a cold, stirred solution of KOH (6.58 g, 117.5 mmol) in water (30 mL), acetonitrile (30 mL) was added, and the solution was further cooled to −20° C. To the resulting mixture, methyl 2-fluoro-6-hydroxybenzoate (1 g, 5.87 mmol) was added, followed by dropwise addition of diethyl (bromodifluoromethyl)phosphonate (3.13 g, 11.7 mmol), and the reaction mixture was stirred at −20° C. for 30 minutes. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO and concentrated under vacuum. The crude compound was purified by flash column chromatography to give compound methyl 2-(difluoromethoxy)-3-fluorobenzoate as a yellow syrup (520 mg, 40.31%). 1H NMR (400 MHz, DMSO): δ 7.69-7.64 (m, 2H), 7.47-7.43 (m, 1H), 7.12 (t, J = 73.6 Hz, 1H), 3.98 (s, 3H).

[0239] Step 2: 2-(Difluoromethoxy)-3-fluorobenzoic acid

[0240] [ka]

[0241] To a stirred solution of methyl 2-(difluoromethoxy)-6-fluorobenzoate (500 mg, 2.27 mmol) in THF:HO (2:1) at 0°C, LiOH (954.5 mg, 22.7 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was acidified with 1N HCl and then extracted with 10% methanol in CHCl, and the organic layer was dried over MgSO and concentrated in vacuo to give 2-(difluoromethoxy)-3-fluorobenzoic acid as an off-white solid (210 mg, 44.8%). 1 H NMR (400 MHz, DMSO): δ 13.53 (s, 1H), 7.70 - 7.57 (m, 2H), 7.44 (dt, J = 13.2, 6.6 Hz, 1H), 7.10 (t, J = 73.8 Hz, 1H).

[0242] Step 3: 2-(difluoromethoxy)-3-fluoro-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 135):

[0243] [ka]

[0244] To a stirred solution of 2-(difluoromethoxy)-3-fluorobenzoic acid (100 mg, 0.48 mmol) in CHCl (10 mL) at 0 °C, EDC.HCl (139.07 mg, 0.72 mmol), HOBt (111.50 mg, 0.72 mmol), and triethylamine (147 mg, 1.45 mmol) were added. The resulting mixture was stirred for 10 minutes, and (5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (125 mg, 0.48 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with aqueous NHCl and extracted with CHCl. ​​The organic layer was then washed successively with 1N HCl, aqueous NHCO, and brine. The organic layer was then dried over MgSO and concentrated in vacuo to give the crude product. This was then purified by flash column chromatography to give the product 2-(difluoromethoxy)-3-fluoro-N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as an off-white solid (70 mg, 35.17). 1 H NMR (400 MHz, DMSO): δ 13.71 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.04-8.01 (m, 1H), 7.89 (dd, J = 9.2, 3.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.35-7.29 (m, 2H), 7.23-7.20 (m, 1H), 7.37 (t, J = 73.2 Hz, 1H), 4.53 (d, J = 5.2 Hz, 2H), 3.94 (s, 3H)

[0245] Step 4: 2-(difluoromethoxy)-6-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 36):

[0246] To a stirred solution of 2-(difluoromethoxy)-3-fluorobenzoic acid (100 mg, 0.48 mmol) in dichloromethane (10 mL) at 0 °C, EDC.HCl (139.07 mg, 0.72 mmol), HOBt (111.50 mg, 0.72 mmol), and triethylamine (147 mg, 1.45 mmol) were added. The resulting mixture was stirred for 10 minutes, and (5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (116.53 mg, 0.48 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with aqueous NH4Cl and extracted with CHCl2. The organic layer was then washed successively with 1 N HCl, aqueous NH4CO3, and brine. The organic layer was then dried over MgSO4 and concentrated to give the crude product. The crude compound was purified by flash column chromatography to give the product 2-(difluoromethoxy)-6-fluoro-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as a white solid (70 mg, 36.75%). 1 H NMR (400 MHz, DMSO): δ 13.55 (s, 1H), 8.97 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.56 - 7.38 (m, 4H), 7.12 (ddd, J = 67.7, 53.3, 45.4 Hz, 3H), 4.52 (d, J = 5.6 Hz, 2H), 3.95 (s, 3H). LC-MS (ESI): m / z 393.29 (M+H)

[0247] Example of N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (compound 127):

[0248] [ka]

[0249] To a stirred solution of 2-(trifluoromethoxy)benzoic acid (250 mg, 1.21 mmol) in CHCl (10 mL) at 0 °C, EDC.HCl (348.93 mg, 1.82 mmol), HOBt (278.72 mg, 1.82 mmol), and triethylamine (367.68 mg, 3.63 mmol) were added. The resulting mixture was stirred for 10 minutes, and (5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methanamine hydrochloride (313.12 mg, 1.21 mmol) was added and further stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with aqueous NHCl and extracted with CHCl. ​​The organic layer was then washed successively with 1 N HCl, aqueous NHCO, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the crude compound, which was purified by flash column chromatography to give the product N-((5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide as an off-white solid (300 mg, 60%). 1 H NMR (400 MHz, DMSO): δ 13.68 (s, 1H), 8.92 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 16.6, 7.6 Hz, 2H), 7.45 (dd, J = 21.1, 7.7 Hz, 2H), 7.32 (s, 1H), 7.22 (s, 1H), 4.52 (d, J = 5.3 Hz, 2H), 3.94 (s, 3H). LC-MS (ESI): m / z 411.24 (M+H)

[0250] Synthesis of 2-(difluoromethoxy)-N-((5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 60):

[0251] [ka]

[0252] Step 1: Methyl 2-hydroxybenzoate

[0253] [ka]

[0254] To a stirred solution of 2-hydroxybenzoic acid (1 g, 6.57 mmol) in methanol was added H2SO4 (0.8 mL) at 0 °C. The reaction mixture was then heated to 75 °C and stirred for 8 hours. After completion of the reaction, the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give methyl 2-hydroxybenzoate (1.8 g, yield: 81%) as a colorless liquid. 1 H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 7.83 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.54 - 7.50 (m, 1H), 6.90-6.91 (m, 2H), 3.88 (s, 3H).

[0255] Step 2: 2-Hydroxybenzohydrazide

[0256] [ka]

[0257] To a stirred solution of methyl 2-hydroxybenzoate (1 g, 6.57 mmol) in ethanol was added hydrazine hydrate (1 mL) at room temperature. The reaction mixture was heated to reflux for 3 hours. After completion of the reaction, the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-hydroxybenzohydrazide (480 mg, yield: 48%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.50 (brs, 1H), 10.05 (brs, 1H), 15.60 (dd, J = 8.0 Hz, 1.2 Hz,1H), 7.38 - 7.34 (m, 1H), 6.89 - 8.82 (m, 2H), 4.64 (brs, 2H). LC-MS (m / z): 153.1 (M+H)+

[0258] Step 3: 2-(difluoromethoxy)-N-((5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 60):

[0259] [ka]

[0260] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)benzamide (200 mg, 0.88 mmol) and 2-hydroxybenzohydrazide (202 mg, 1.32 mmol) in n-BuOH, KCO (61 mg, 0.44 mmol) was added at room temperature. The resulting reaction mixture was irradiated in a microwave oven at 165 °C for 50 minutes. After completion of the reaction, the mixture was concentrated in vacuo to give the crude product, which was purified by flash column chromatography to give 2-(difluoromethoxy)-N-((5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (110 mg, yield: 35%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 14.18 (brs, 1H), 11.42 (brs, 1H), 8.85 (brs, 1H), 7.92 (brs, 1H), 7.64 - 7.53 (m, 2H), 7.33 - 6.96 (m, 6H), 4.61 (d, J = 2.8 Hz, 2H). LC-MS (m / z): 361.1 (M+H)+

[0261] Synthesis of 2-(difluoromethoxy)-N-((5-(2,3-dihydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 61):

[0262] [ka]

[0263] Step 1: Methyl 3-(benzyloxy)-2-hydroxybenzoate

[0264] [ka]

[0265] To a stirred solution of methyl 2,3-dihydroxybenzoate (1 g, 5.95 mmol) in a mixture of chloroform and methanol, KCO (3.3 g, 23.8 mmol) and benzyl bromide (0.85 mL, 7.14 mmol) were added. The reaction mixture was stirred at 60 °C for 8 hours. After completion of the reaction, the mixture was concentrated in vacuo, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by flash column chromatography to give methyl 5-(benzyloxy)-2-hydroxybenzoate (600 mg, yield: 38%) as a colorless liquid. 1 H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.33 - 7.29 (m, 2H), 7.24 - 7.21 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 3.88 (s, 3H). LC-MS (m / z): 259.07 (M+H) +

[0266] Step 2: 3-(benzyloxy)-2-hydroxybenzohydrazide

[0267] [ka]

[0268] To a stirred solution of methyl 5-(benzyloxy)-2-hydroxybenzoate (600 mg, 2.32 mmol) in ethanol, hydrazine hydrate (1 mL) was added at room temperature. The reaction mixture was then refluxed for 3 hours. After completion of the reaction, the mixture was concentrated in vacuo, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 3-(benzyloxy)-2-hydroxybenzohydrazide (430 mg, yield: 43%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 6.8 Hz, 2H), 7.32 - 7.30 (m, 2H), 7.09 (dd, J = 9.2 Hz, 3.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.07 (s, 2H), 4.51 (brs, 2H), 3.79 (s, 1H). LC-MS (m / z): 273.17 (M+H) +

[0269] Step 3: N-((5-(3-(benzyloxy)-2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide

[0270] [ka]

[0271] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)benzamide (200 mg, 0.88 mmol) and 3-(benzyloxy)-2-hydroxybenzohydrazide (300 mg, 1.16 mmol) in n-BuOH was added KCO (61 mg, 0.44 mmol) at room temperature. The reaction mixture was irradiated with microwaves at 165 °C for 50 minutes. After completion of the reaction, the mixture was concentrated in vacuo to give the crude product, which was then purified by flash column chromatography to give N-((5-(3-(benzyloxy)-2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide (120 mg, yield: 29%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 14.37 (s, 1H), 11.53 (brs, 1H), 11.25 (brs, 1H), 8.90 (brs, 1H), 7.53 - 7.52 (m, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.40 - 7.30 (m, 5H), 7.25 (d, J = 7.6 Hz, 1H), 7.14 (s, 1H), 6.83 (brs, 1H), 5.15 (S, 2H), 4.65 (brs, 2H). LC-MS (m / z): 467.2 (M+H) +

[0272] Step 4: 2-(difluoromethoxy)-N-((5-(2,3-dihydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 61):

[0273] [ka]

[0274] To a stirred solution of N-((5-(3-(benzyloxy)-2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide (120 mg, 0.25 mmol) in ethanol was added Pd / C (100 mg) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere of 50 Psi for 12 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 2-(difluoromethoxy)-N-((5-(2,3-dihydroxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (30 mg, yield: 18%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.27 (brs, 1H), 9.20 (brs, 1H), 9.17 (s, 1H), 7.60 (d, J = 7.2 Hz,1H), 7.55 (t, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.26 (d, J =8.4 Hz, 1H), 7.15 (s, 1H), 6.75 (t, J = 8 Hz, 1H), 4.60 (brs 2H), 3.15 (s, 1H). LC-MS (m / z): 377.10 (M+H) +

[0275] Synthesis of 2-(difluoromethoxy)-N-((5-(5-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 63):

[0276] [ka]

[0277] Step 1: Methyl 5-(benzyloxy)-2-hydroxybenzoate

[0278] [ka]

[0279] To a stirred solution of methyl 2,5-dihydroxybenzoate (1 g, 5.95 mmol) in chloroform and methanol, KCO (3.3 g, 23.8 mmol) and benzyl bromide (0.85 mL, 7.14 mmol) were added. The reaction mixture was then stirred at 60 °C for 8 h. Upon completion of the reaction, the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product thus obtained was purified by flash column chromatography to give methyl 5-(benzyloxy)-2-hydroxybenzoate (470 mg, yield: 30%) as a colorless liquid. 1 H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.33 - 7.29 (m, 2H), 7.24 - 7.21 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 3.88 (s, 3H). LC-MS (m / z): 259.07 (M+H) +

[0280] Step 2: Methyl 5-(benzyloxy)-2-methoxybenzoate

[0281] [ka]

[0282] To a stirred solution of methyl 5-(benzyloxy)-2-hydroxybenzoate (1.2 g, 4.65 mmol) in DMF was added K2CO3 (1.29 g, 9.3 mmol) and methyl iodide (0.44 mL, 6.9 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give methyl 5-(benzyloxy)-2-methoxybenzoate (1.0 g) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.42 (d, J = 6.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 4.8 Hz, 1H), 7.25 (d, J =3.2 Hz, 1H), 7.15 (dd, J = 7.07 (d, J = 8.0 Hz, 1H), 5.07 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H). LC-MS (m / z): 273.10 (M+H) +

[0283] Step 3: 5-(benzyloxy)-2-methoxybenzohydrazide

[0284] [ka]

[0285] To a stirred solution of methyl 5-(benzyloxy)-2-methoxybenzoate (1 g, 3.6 mmol) in ethanol was added hydrazine hydrate (1 mL) at room temperature. The resulting reaction mixture was refluxed for 3 hours. After completion of the reaction, the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 5-(benzyloxy)-2-methoxybenzohydrazide (430 mg, yield: 43%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 6.8 Hz, 2H), 7.32 - 7.30 (m, 2H), 7.09 (dd, J = 9.2 Hz, 3.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.07 (s, 2H), 4.51 (brs, 2H), 3.79 (s, 1H). LC-MS (m / z): 273.17 (M+H) +

[0286] Step 4: N-((5-(5-(benzyloxy)-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide

[0287] [ka]

[0288] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)benzamide (200 mg, 0.88 mmol) and 5-(benzyloxy)-2-methoxybenzohydrazide (360 mg, 1.32 mmol) in n-BuOH was added KCO (61 mg, 0.44 mmol) at room temperature. The reaction mixture was irradiated in a microwave oven at 165 °C for 50 minutes. The resulting reaction mixture was then concentrated in vacuo to give the crude product (200 mg), which was used in the next step without further purification.

[0289] Step 5: 2-(difluoromethoxy)-N-((5-(5-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 63):

[0290] [ka]

[0291] To a stirred solution of N-((5-(5-(benzyloxy)-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide (200 mg, 0.42 mmol) in ethanol was added Pd / C (160 mg) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (50 Psi) at room temperature for 12 hours. The resulting reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give the crude product, which was further purified by preparative HPLC to give 2-(difluoromethoxy)-N-((5-(5-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (30 mg, yield: 18%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.45 (s, 1H), 9.20 (s, 1H), 8.75 (brs, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.35 - 7.33 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.01 - 6.98 (m, 1H), 6.82 (d, J = 3.2 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H). LC-MS (m / z): 391.10 (M+H) +

[0292] Synthesis of 2-(difluoromethoxy)-N-((5-(3-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (compound 62):

[0293] [ka]

[0294] Step-1: Synthesis of methyl 3-(benzyloxy)-2-hydroxybenzoate

[0295] [ka]

[0296] To a stirred solution of methyl 2,3-dihydroxybenzoate (1) (500 mg, 2.973 mmol) in acetone (10 mL) at 0 °C, K2CO3 (410 mg, 2.973 mmol) was added, followed by (bromomethyl)benzene (423.8 mg, 3.568 mmol) and tetrabutylammonium bromide (191.7 mg, 0.594 mmol). The reaction mixture was stirred at room temperature for 12 h. The resulting reaction mixture was concentrated under reduced pressure, and the crude product thus obtained was diluted with cold water and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using 2% EtOAc in n-hexane to give a white solid as methyl 3-(benzyloxy)-2-hydroxybenzoate (100 mg, 13%). 1 H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.40 - 7.29 (m, 4H), 7.27 (d, J = 8 Hz, 1H), 6.84 (t, J = 8 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 3H).LC-MS (m / z): 259.30 (M+H) +

[0297] Step-2: Synthesis of methyl 3-(benzyloxy)-2-methoxybenzoate

[0298] [ka]

[0299] To a stirred solution of methyl 3-(benzyloxy)-2-hydroxybenzoate (500 mg, 1.937 mmol) in DMF (20 mL) at 0 °C, K2CO3 (410 mg, 2.973 mmol) was added, followed by iodomethane (412.4 mg, 2.905 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether and dried under vacuum to give methyl 3-(benzyloxy)-2-methoxybenzoate (450 mg, 85.3%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 17.45 (d, J = 7.2 Hz, 2H), 7.39 (t, J =7.2 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.09 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 5.14 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H).

[0300] Step-3: Synthesis of 3-(benzyloxy)-2-methoxybenzohydrazide

[0301] [ka]

[0302] To a stirred solution of methyl 3-(benzyloxy)-2-methoxybenzoate (450 mg, 1.65 mmol) in EtOH (20 mL) at 0 °C was added hydrazine hydrate (0.5 mL). The resulting reaction mixture was stirred at 90 °C for 12 hours and concentrated. The resulting residue was diluted with ice-cold water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether and dried under vacuum to give 3-(benzyloxy)-2-methoxybenzohydrazide (250 mg, 55.5%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.40 (t, J =7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.21 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.09 - 7.01 (m, 2H), 5.15 (s, 2H), 4.47 (brs, 2H), 2.93 (s, 3H).

[0303] Step-4: Synthesis of N-((5-(3-(benzyloxy)-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide

[0304] [ka]

[0305] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)benzamide (250 mg, 1.105 mmol) in n-BuOH (10 mL) at 0 °C, K2CO3 (76.2 mg, 0.552 mmol) was added, followed by 3-(benzyloxy)-2-methoxybenzohydrazide (331 mg, 1.215 mmol). The resulting reaction mixture was stirred at 165 °C for 50 minutes under microwave irradiation. Upon completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using 60% EtOAc in n-hexane to give N-((5-(3-(benzyloxy)-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide (170 mg, 32%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.63 (s, 1H), 8.54 (t, J = 5.6 Hz, 1H), 7.60 (t, J = 8.4 Hz, 2H), 7.54 - 7.49 (m, 3H), 7.42 (t, J = 7.2 Hz, 2H), 7.36 - 7.30 (m, 2H), 7.26 (t, J = 8.8 Hz, 2H), 7.17 (t, J = 7.6 Hz, 2H), 5.19 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 3.84 (s, 3H).LC-MS (m / z): 481.20 (M+H) +

[0306] Step-5: Synthesis of 2-(difluoromethoxy)-N-((5-(3-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (Compound 62):

[0307] [ka]

[0308] To a stirred solution of N-((5-(3-(benzyloxy)-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2-(difluoromethoxy)benzamide (170 mg, 0.354 mmol) in methanol (20 mL) was added Pd / C (170 mg). The reaction mixture was stirred at room temperature under a hydrogen balloon for 12 hours. Upon completion of the reaction, the mixture was filtered through a short Celite bed, washed with methanol, dried over anhydrous NaSO, and concentrated. The crude product thus obtained was purified by column chromatography using 50% EtOAc in n-hexane to give 2-(difluoromethoxy)-N-((5-(3-hydroxy-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide (45 mg, 32.6%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.71 (brs, 1H), 8.79 (t, J = 5.2 Hz, 1H), 7.62 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.39 - 7.31 LC-MS (m / z): 391.1 (M+H) +

[0309] Synthesis of N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(trifluoromethoxy)benzamide (compound 123) and 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)benzamide (compound 124):

[0310] [ka]

[0311] Step-1: 5-(2-methoxyphenyl)-4H-1,2,4-triazole-3-thiol:

[0312] [ka]

[0313] To a stirred solution of 2-methoxybenzhydrazide (2.5 g, 15.04 mmol) in ethanol (25 mL) at 0 °C, trimethylsilyl isothiocyanate (1.97 g, 15.04 mmol) was added, and the reaction was heated at 90 °C for 4 h. The resulting reaction mixture was then added to 4 M NaOH solution (25 mL) and further heated at 90 °C for 4 h. The reaction mixture was then concentrated, diluted with HO (10 mL), and acidified with HCl (40 mL, 4 M). The resulting precipitate was filtered and dried under vacuum to give 5-(2-methoxyphenyl)-4H-1,2,4-triazole-3-thiol as an off-white solid (2.1 g mg, 67.37%). 1 H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 13.11(s, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 3.83 (s, 3H). LC-MS (ESI): m / z 208.1 (M+H)

[0314] Step-2: 5-(2-methoxyphenyl)-1H-1,2,4-triazole-3-sulfonamide:

[0315] [ka]

[0316] To a stirred solution of 5-(2-methoxyphenyl)-4H-1,2,4-triazole-3-thiol (500 mg, 15.04 mmol) in dichloromethane (10 mL) at 0 °C, 4 M HCl (10 mL) and 4% NaOCl (10 mL) were added dropwise while maintaining the temperature below 5 °C, followed by further stirring at the same temperature for 15 min. The organic layer was separated from the resulting mixture, and aqueous NH4OH was added and stirred for 12 h. After completion of the reaction, the organic layer was collected, concentrated under reduced pressure, and coevaporated with toluene to remove water to give 5-(2-methoxyphenyl)-1H-1,2,4-triazole-3-sulfonamide as an off-white solid (2.1 g, 67.37%). LC-MS (ESI): m / z 255.1 (M+H)

[0317] Step-3: N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(trifluoromethoxy)benzamide (Compound 123):

[0318] [ka]

[0319] To a stirred solution of 5-(2-methoxyphenyl)-1H-1,2,4-triazole-3-sulfonamide (100 mg, 0.393 mmol) and 2-(trifluoromethoxy)benzoic acid (81.06 mg, 0.393 mmol) in dichloromethane (20 mL) at 0 °C, EDC.HCl (113.09 mg, 0.589 mmol), HOBt (79.58 mg, 0.588 mmol), DMAP (5 mg), and triethylamine (98.98 mg, 0.98 mmol) were added. The resulting reaction mixture was stirred at room temperature for 12 h and concentrated. The resulting residue was diluted with HO (10 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The combined organic layers were dried over NaSO and concentrated to give the crude compound. The crude compound was purified by preparative HPLC to give N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(trifluoromethoxy)benzamide as an off-white solid (14 mg, 8%). 1 H NMR (400 MHz, DMSO) δ 13.75 (s, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H ), 7.20 (t, J = 9.6 Hz, 2H ), 7.09 (t, J = 8.0 Hz, 1H ), 3.95 (s, 3H). LC-MS (ESI): m / z 443.1 (M+H)

[0320] Step-4: 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)benzamide (Compound 124):

[0321] [ka]

[0322] To a stirred solution of 5-(2-methoxyphenyl)-1H-1,2,4-triazole-3-sulfonamide (261.20 mg, 1.065 mmol) in dichloromethane (20 mL) at 0 °C, pyridine (168.48 mg, 2.130 mmol) was added, followed by freshly prepared 2-(difluoromethoxy)benzoyl chloride (220 mg, 1.065 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The combined organic layers were dried over NaSO and concentrated to give the crude compound. This was purified by preparative HPLC to give 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)sulfonyl)benzamide as an off-white solid (22 mg, 4.86%). 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 8.0 Hz, 1H), 7.67 (m, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 6.88-7.21 (m, 6H), 3.94 (s, 3H). LC-MS (ESI): m / z 425.1 (M+H)

[0323] Synthesis of 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-pyrazol-3-yl)sulfonyl)benzamide (compound 121):

[0324] [ka]

[0325] Step 1: 5-(2-Methoxyphenyl)-1H-pyrazol-3-amine

[0326] [ka]

[0327] To a stirred solution of methyl 3-(2-methoxyphenyl)-3-oxopropanenitrile (2.5 g, 14.27 mmol) in ethanol (10 mL) was added hydrazine hydrate (10 mL), followed by a catalytic amount of acetic acid. The resulting mixture was stirred at 80° C. for 24 hours and concentrated. The residue was washed twice with toluene (10 mL) and dried under vacuum to give 5-(2-methoxyphenyl)-1H-pyrazol-3-amine as a yellow viscous liquid (2 g, 74%). 1 H NMR (400 MHz, DMSO) δ 11.56 (bs, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.26 (dd, J = 1.6, 8.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 4.58 (bs, 2H), 3.84 (s, 3H). LC-MS m / z (M+H): 190.1.

[0328] Step 2: 5-(2-Methoxyphenyl)-1H-pyrazole-3-sulfonamide

[0329] [ka]

[0330] To a suspension of CuCl (0.204 g, 2.1 mmol) in water (265 mL) was added thionyl chloride (44.85 mL, 0.618 mmol) dropwise with vigorous stirring at 0° C. The resulting solution was stirred at room temperature overnight to give a pale yellow solution. Separately, to a solution of 5-(2-methoxyphenyl)-1H-pyrazol-3-amine (0.62 g, 4.1 mmol) in concentrated HCl (4 mL) was added dropwise a solution of NaNO (0.33 g, 4.8 mmol) in water (4 mL) at −10° C. The resulting dark orange solution was stirred at −10° C. for 30 minutes and then added to the solution of copper(I) chloride (10.6 mL) from the first step at −5° C. over 5 minutes. The resulting reaction mixture was stirred at −5° C. for 1 hour and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated in vacuo to give a yellow solid. This solid was dissolved in THF (20 mL) and cooled to 0° C., followed by the dropwise addition of ammonia (10 mL, 28 wt%). The resulting reaction mixture was stirred at 0° C. for 2 hours and then concentrated in vacuo. The crude product thus obtained was purified by flash chromatography using dichloromethane and methanol as eluting solvents to give 5-(2-methoxyphenyl)-1H-pyrazole-3-sulfonamide as an off-white solid (85 mg, 10%). 1 H NMR (400 MHz, DMSO) δ 13.53 (s, 1H), 7.71 (dd, J = 1.2, 7.6 Hz, 1H), 7.40-7.37 (m, 3H), 7.18 - 7.16 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H). LC-MS m / z (M+H): 254.09.

[0331] Step 3: 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-pyrazol-3-yl)sulfonyl)benzamide (compound 121):

[0332] [ka]

[0333] To a stirred solution of 2-(difluoromethoxy)benzoic acid (44 mg, 0.2371 mmol) in DMF (1 mL) at 0 °C, HATU (72.13 mg, 0.1897 mmol), 5-(2-methoxyphenyl)-1H-pyrazole-3-sulfonamide (40 mg, 0.1581 mmol), and DIPEA were added, and the resulting mixture was stirred at room temperature for 16 hours. It was then quenched with ice-cold water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was further purified by preparative HPLC to give 2-(difluoromethoxy)-N-((5-(2-methoxyphenyl)-1H-pyrazol-3-yl)sulfonyl)benzamide as an off-white solid (28 mg, 41.87%). 1 H NMR (400 MHz, DMSO) δ 13.84 (s, 1H), 12.61 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 6.8 Hz, 1H), 7.24 - 6.95 (m, 5H), 3.91 (s, 3H). LC-MS m / z (MH): 423.39.

[0334] N-[[5-(2-methoxyphenyl)-1H-pyrazol-3-yl]sulfonyl]-2-(trifluoromethoxy)benzamide (compound 122):

[0335] [ka]

[0336] Compound 122 was synthesized using the protocol described for compound 121. Yield: 25%. LC-MS m / z (M−H): 442.1.

[0337] Biochemical and cellular assays Biochemical modulation of UBE2K polyubiquitination activity by small molecule modulators. In vitro polyubiquitination activity assays were performed using 3 μM UBE2K, 300 nM UBE1, and 200 μM Ub in 50 mM Tris (pH 8.0), 1 mM TCEP buffer containing 0.05% Tween 20, 4 mM ATP, and 10 mM MgCl2. Reactions were performed with various compound concentrations, incubated at 37°C for 3 hours, and quenched with non-reducing sample loading dye. Samples were analyzed using 4-20% Criterion™ TGX Stain-Free™ Protein Gels and 4-20% Criterion Stained Gels, and imaged using a BioRad imager without staining and after Coomassie staining. Compound titrations were performed in 1X PBS-P+ (GE) buffer containing 3% DMSO. Freshly opened DMSO was used to prepare the running buffer immediately before the experiment. Compound stock solutions (in DMSO, provided by Berg) were first diluted in 1X PBS-P+ without DMSO to match 3% DMSO. The final concentration of this 3% DMSO matched solution was determined by the concentration of the original stock solution (i.e., for a 100mM DMSO stock solution, the 3% matched stock solution is 3mM). The matched stock solution was then diluted to 100uM using 1X PBS-P+ (GE) buffer containing 3% DMSO, and serially diluted.

[0338] Compounds were observed to stabilize monoubiquitinated UBE2K in polyubiquitination assays in unstained gels, resulting in a decrease in poly-Ub production. The reverse was observed in stained gels, where less ubiquitin was used in polyubiquitination polymerization upon compound treatment. Both effects were dose-dependent. Figure 1 shows analyses performed from five independent experiments (N = 5). Unstained gels utilize in-gel compounds that enhance the fluorescence of tryptophan amino acids when exposed to UV light. Native ubiquitin lacks tryptophan residues, whereas UBE2K and UBE1 contain tryptophan. Therefore, it is easier to detect the mono-Ub UBE2K band in unstained gels.

[0339] UBE2K selectivity assay The selectivity of the compounds of the present invention for UbE2K versus other E2s was tested in an in vitro polyubiquitination assay as previously described. E2-ubiquitin conjugating enzymes from the E2 family of enzymes, namely UBE2D4, UBE2E1, UBE2Q2, UBE2S, and UBE2W, were selected. The ability of the compounds of the present invention at 500 μM to stabilize monoubiquitinated E2s and polyUb products was observed. The compounds of the present invention stabilized mono-Ub UBE2K and reduced polyUb chains, which was not observed in assays with representative E2s from other classes. E2s have highly conserved active sites, and the observation that the compounds of the present invention did not affect or modulate other E2s supports the allosteric site involved in these molecules. The results are shown in Figure 2.

[0340] Praja 1 assay This assay utilizes UBE2K thioester-linked ubiquitin and the ability of small molecule modulators to affect the release of ubiquitin to the Praja1 RING domain and polyubiquitinate Praja1. Polyubiquitination levels were measured using an ELISA format using an anti-Ub A5 primary antibody (AF594) in combination with an alkaline phosphatase-conjugated secondary antibody (goat polyclonal anti-mouse AP) and the Attophos AP fluorescent substrate system. Fluorescence was read using a Teacan Spark 10M plate reader at an excitation wavelength of 435 and an emission wavelength of 555.

[0341] The compounds of the present invention were observed to modulate the release of ubiquitin from UBE2K and the degree of polyubiquitination of the Praja1 RING protein in a concentration-dependent manner. A decrease in the ELISA signal indicates a decrease in the release of ubiquitin to form polyUb Praja1 RING. The compounds of the present invention were observed to reduce polyUb Praja1. See Figure 3.

[0342] Cell viability assay Cell viability assays were performed using Cell Titer Fluor™ Assays (Promega G6080). MIA PaCa-2 cells were grown in DMEM medium containing 10% FBS and 1% Pen / Strep / Amphotericin B. Cells were trypsinized and counted using a Nexcelom cellometer. 5,000 cells / 100 μl were seeded per well in a Greiner black / clear 96-well plate. Cells should be within 10 passages from the stock vial for use in the workflow. Three different lines of these cells were cultured in parallel for multiple passages, with each line seeding five complete plates per run. Small molecule compounds were provided as 100 mM stock solutions in DMSO. A dilution series was prepared using a 1:3 dilution to achieve seven concentrations on a semi-logarithmic scale. After compound addition, cells were incubated at 37°C and 5% CO2 for 72 hours.

[0343] Three technical replicates are used for each test compound condition. Two technical replicates are used for each reference compound. At the end of the 72-hour incubation, the spent medium is discarded. 100 μl of GF-AFC diluted in DMEM (serum- and phenol red-free) is then added at a 1:2000 concentration (5 μl / 10 ml). The cells are incubated with the reaction buffer at 37°C for 1 hour. Fluorescence is then read on a plate reader at an excitation wavelength of 390 nm and an emission wavelength of 505 nm. All raw data is analyzed in Microsoft Excel 2010 and normalized to the DMSO vehicle control. Relative results are copied to GraphPad Prism for nonlinear regression analysis to determine IC50 and other dose curve parameters (minimum, maximum, Hill slope, etc.) using the log(inhibitor) vs. response equation. The results are shown in Table 11. The values ​​are as follows: A represents an IC50 of less than 1.0 mM, B represents an IC50 of 1 mM to 10 mM, and C represents an IC50 of greater than 10 mM.

[0344] [Table 11]

[0345] Tumor growth inhibition – in vivo PoC study in mouse xenograft model Materials and Methods material supplier IMDM medium Sigma Fetal Bovine Serum (FBS) Invitrogen Phosphate Buffered Saline (PBS) Invitrogen Trypsin-EDTA Invitrogen Penicillin-Streptomycin Invitrogen Matrigel (Cat. No. 354234) Corning Individually ventilated animal cages Tecniplast, UK Rodent Feed Nutrilab Rodent Feed, India 1ml syringe BD-Biosciences

[0346] Cell lines and tumor models: The K-562 cancer cell line was supplied by the American Type Culture Collection (ATCC), USA. Cells were grown in IMDM medium (Sigma, Cat. No. 30-2005) supplemented with 10% FBS (Invitrogen, Cat. No. 10438-026) and 1% penicillin-streptomycin (Invitrogen, Cat. No. 15140-122). To establish xenografts, cells were harvested by trypsinization when they reached approximately 70–80% confluence. Five million K-562 cells were suspended in 200 μL of serum-free medium, mixed with Matrigel at a 1:1 ratio, and then implanted subcutaneously into the right dorsal flank of SCID Bg mice using a 1 mL BD syringe fitted with a 24-gauge needle.

[0347] Randomization After 10 days of cell inoculation, K-562 tumor implants were measured when they became palpable, with a mean tumor volume of approximately 85 mm. 3 Once this was reached, the animals were dosed after randomization into the different treatment groups, maintaining tumor volume and animal numbers such that the mean tumor volume in each group remained the same between groups. Species: Mouse (Mus musculus) Strain: SCID Bg mouse Gender: Female Source: Taconic Total number of animals in the study: 30 Number of study groups: 5 Number of animals per group: 6 Weight at the start of treatment: 16-18g Age of animals at the start of treatment: 7-8 weeks old

[0348] Study design Compounds were formulated in 0.5% CMC + 0.1% Tween 80 and given BID at 8 hour intervals for 12 consecutive days. The results for tumor growth inhibition are shown in Table 11 below.

[0349] [Table 12]

[0350] Antitumor efficacy of compound 131 in an MV.4.11 cell (B myelomonocytic leukemia) line-induced xenograft model in nude mice 5 × 10 6 MV.4.11 cells were implanted subcutaneously. Twelve days after cell implantation, mice were randomized into three groups (8 mice each). Vehicle controls received a formulation of the test compound, while treatment groups received Compound 131 orally twice daily (bid) for 24 days at doses of 75 mg / kg and 150 mg / kg as a suspension in 0.1% Tween-80 + 0.5% CMC (carboxymethylcellulose). Tumor measurements and body weights were recorded three times weekly throughout the study period until study completion (day 24). Tumor growth inhibition in the treatment groups (75 mg / kg and 150 mg / kg) was 73.6% and 86.3%, respectively. See Figure 4.

[0351] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are to be given the meaning commonly known to those of ordinary skill in the art. The following are examples of embodiments of the present invention. [Embodiment 1] Formula I: [ka] (In the formula, Z 1 and Z 2 are each independently N or CH; X is N or CH; Ring A is phenyl or 5- to 9-membered heteroaryl, each of which is R 5 optionally substituted with 1 to 3 groups selected from; Y is CH 2 , -CHR a , -CR a R b , or SO; R a and R b are independently halo, (C 1 ~C 6 ) alkyl or halo(C 1 ~C 6 ) alkyl; or R a and R b together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which is selected from halo, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl OH, (C 1 ~C 6 ) alkylO(C 1 ~C 6 ) optionally substituted with 1 to 3 groups selected from alkyl, and OH; R 1 Halo (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkoxy, or -NR c R d and the halo(C 1 ~C 6 ) alkyl and halo(C 1 ~C 6 The two available hydrogen atoms on an alkoxy, together with the carbon atom to which they are attached, form a halo, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, and halo(C 1 ~C 6 ) alkoxy; R c and R d are each independently hydrogen, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkylO(C 1 ~C 6 ) alkyl, halo(C1 ~C 6 ) alkylO(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )Alkyl-O-halo(C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 )Alkyl-O-halo(C 1 ~C 6 ) alkyl, or (C 1 ~C 6 ) alkylOH; or R c and R d together with the nitrogen atom to which they are attached form halo, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 ) forming a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from alkoxy, and oxo; R 2 CN, halo, OH, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy or halo(C 1 ~C 6 ) alkoxy; or R 1 and R 2 are on adjacent carbon atoms, together with the carbon atoms to which they are attached, form halo, (C 1 ~C 6 ) alkyl, and halo(C 1 ~C 6 ) alkyl, optionally substituted with 1 to 3 groups selected from 5- or 6-membered oxygen-containing heterocyclyl; R 3 is hydrogen, (C 1 ~C 6 ) alkyl, or halo(C 1 ~C 6 ) alkyl; R 4 CN, halo, OH, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 )alkoxy, -NH(C 1 ~C 6 ) alkyl, -N[(C 1 ~C 6 ) alkyl] 2 or 5-6 membered heterocyclyl; and p is 0 or 1, or a pharmaceutically acceptable salt thereof. [Embodiment 2] formula:

change

change

change

Claims

1. Formula I: 【Chemistry 1】 (In the formula, Z 1 and Z 2 are each independently N or CH; X is N or CH; Ring A is phenyl and R 4 optionally substituted with 1 to 3 groups selected from: Y is CH 2 , -CHR a , -CR a R b , or SO; R a and R b are independently halo, (C 1 ~C 6 ) alkyl or halo(C 1 ~C 6 ) alkyl; or R a and R b together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which may be selected from halo, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl OH, (C 1 ~C 6 ) alkylO(C 1 ~C 6 ) optionally substituted with 1 to 3 groups selected from alkyl, and OH; R 1 is halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, or —NR c R d ; R c is hydrogen and R d is halo(C 1 -C 4 )alkyl; or R c and R d together form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, and oxo; R c and R d are each independently hydrogen, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkylO(C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkylO(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )Alkyl-O-halo(C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 )Alkyl-O-halo(C 1 ~C 6 ) alkyl, or (C 1 ~C 6 ) alkylOH; or R c and R d together with the nitrogen atom to which they are attached form halo, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 ) forming a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from alkoxy, and oxo; R 2 CN, halo, OH, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy or halo(C 1 ~C 6 ) alkoxy; or R 1 and R 2 are on adjacent carbon atoms, together with the carbon atoms to which they are attached, form halo, (C 1 ~C 6 ) alkyl, and halo(C 1 ~C 6 ) alkyl, forming a 5- or 6-membered oxygen-containing heterocyclyl optionally substituted with 1 to 3 groups selected from; R 3 is hydrogen, (C 1 ~C 6 ) alkyl, or halo(C 1 ~C 6 ) alkyl; R 4 CN, halo, OH, (C 1 ~C 6 ) alkyl, halo(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, halo(C 1 ~C 6 )alkoxy, -NH(C 1 ~C 6 ) alkyl, -N[(C 1 ~C 6 ) alkyl] 2 or 5- to 6-membered heterocyclyl; p is 0), or a pharmaceutically acceptable salt thereof.

2. Formula IV: 【Chemistry 2】 2. The compound of claim 1, wherein the compound is:

3. R 3 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

4. Y is CH 2 4. The compound of claim 1, wherein:

5. Z 1 is N and Z 2 is CH;Z 1 is CH and Z 2 is N; or Z 1 and Z 2 or a pharmaceutically acceptable salt thereof.

6. Z 1 and Z 2 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is CH.

7. R 1 But, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , -CH 2 CF 3 , -CHF 2 , piperidinyl, pyrrolidinyl, azepanyl, morpholinyl, thiomorpholinyl, piperazinyl, or azetidinyl, wherein each of the piperidinyl, pyrrolidinyl, azepanyl, morpholinyl, thiomorpholinyl, piperazinyl, and azetidinyl is selected from the group consisting of halo, (C 1 ~C 4 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 groups selected from alkyl, and oxo.

8. R 2 However, CN, Halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, or (C 1 ~C 4 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

9. R 2 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is CN or halo.

10. R 2 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

11. R 4 But, Halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )alkoxy, -N[(C 1 ~C 4 ) alkyl] 2 or 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

12. R 4 are F, Br, Cl, -OCH 3 , -OCH 2 CH 3 , OH, -O(CH 2 ) 2 CH 3 , -NMe 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH(CH 3 ) 2 , morpholinyl, -CH 3 , or -CF 3 12. The compound of any one of claims 1 to 11, wherein: 【Request Item 13】 【Chemistry 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharmaceutically acceptable salt of any of the above. 【Request Item 14】 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

16. 16. The pharmaceutical composition of claim 15 for treating cancer in a subject.

17. 17. The pharmaceutical composition of claim 16, wherein the cancer is selected from solid and liquid tumors.

Images