HDAC-6 inhibiting compounds and treatment of diseases with the same

Abstract

The present invention provides histone deacetylase 6 (HDAC6) inhibitors. The compounds provided in the present invention may be useful for methods of treating or preventing diseases or conditions associated with HDAC6,

Description

[0001] HDAC-6 INHIBITING COMPOUNDS AND TREATMENT OF DISEASES WITH THE SAME FIELD OF THE INVENTION The present invention provides histone deacetylase 6 (HDAC6) inhibitors. The compounds provided in the present invention may be useful for methods of treating or preventing diseases or conditions associated with HDAC6. BACKGROUND Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. Post-translational modification of proteins through acetylation and deacetylation of lysine residues plays a critical role in regulating their cellular functions. HDACs are zinc hydrolases that modulate gene expression through deacetylation of the N-acetyl-lysine residues of histone proteins and other transcriptional regulators (Hassig et al Curr. Opin. Chem. Biol. 1997, 1, 300-308). HDACs participate in cellular pathways that control cell shape and differentiation, and an HDAC inhibitor has been shown effective in treating an otherwise recalcitrant cancer (Warrell et al J. Natl. Cancer Inst.1998, 90, 1621-1625). At this time, eleven human HDACs, which use Zn as a cofactor, have been identified (Taunton et al. Science 1996, 272, 408-411; Yang et al. J. Biol. Chem.1997, 272, 28001-28007. Grozinger et al. Proc. Natl. Acad. Sci. U.S.A.1999, 96, 4868-4873; Kao et al. Genes Dev. 2000, 14, 55-66. Hu et al J. Biol. Chem. 2000, 275, 15254-15264; Zhou et al. Proc. Natl. Acad. Sci. U.S.A.2001, 98, 10572-10577; Venter et al. Science 2001, 291, 1304-1351), and these members fall into three classes (class I, II, and IV). An additional seven HDACs have been identified which use NAD as a cofactor. HDAC6 affects transcription and translation by regulating heat-shock protein 90 (Hsp90). Recently, HDAC6 was identified as necessary for aggresome formation and for survival of cells following ubiquitinated misfolded protein stress. The aggresome is an integral component of survival in cancer cells. The mechanism of HDAC6-mediated aggresome formation is a consequence of the catalytic activity of the carboxy-terminal deacetylase domain, targeting an uncharacterized non-histone target. HDAC inhibition results in hyperacetylation of chromatin, alterations in transcription, growth arrest, and apoptosis in cancer cell lines. Early phase clinical trials with available nonselective HDAC inhibitors demonstrate responses in hematologic malignancies including multiple myeloma, although with significant toxicity. SUMMARY HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders. There remains a need for the development of inhibitors of histone deacetylases and tubulin histone deacetylases. In certain aspects, the invention provides inhibitors of HDAC6. In certain embodiments, these compounds are potent and selective inhibitors of HDAC6. The present invention provides compounds, pharmaceutical compositions thereof, and methods of using these compounds to treat disorders related to HDAC6 including cancers, inflammatory disorders, autoimmune disorders, neurological disorders, and neurodegenerative disorders. In certain aspects, the invention provides compounds of Formula (Ia): (Ia) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6 alkyl group substituted with 4-6 membered aryl; Y1and Y2are independently N or CR2, wherein R2is H, alkyl, or halogen; X1, X2, X3, X4, and X5 are independently N or CR3, wherein each R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In certain aspects, the invention provides compounds of Formula (Ib): (Ib) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6 alkyl group substituted with 4-6 membered aryl; Y1and Y2are independently N, S, O, or CR2, wherein R2is H, C1-C6alkyl, or halo; Z1, Z2, and Z3are independently selected from C, CH, N and O; R4 is -CHF2 or -CF3; R5 is H, C1-C4 alkyl, or C3-C4 cycloalkyl; and X1, X2, X3, X4, and X5are independently N or CR3, wherein each R3 is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In certain embodiments, the compound is a compound of Formula (Ic): (Ic) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1, R4, Z1, Z2, Z3, X1, X2, X3, X4, and X5 are!as defined and described herein. In certain embodiments, the compound is a compound of Formula (Id): (Id) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1, R4, Z1, Z2, Z3, X1, X2, X3, X4, and X5 are as defined and described herein. In certain aspects, the invention provides compounds of Formula (II):

[0002] (II) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R2and R3 are H or halogen; and A is an optionally substituted 4-8 membered heterocycle having N or O as heteroatoms, wherein said one or more substitutions on the Ring A are selected from the group consisting of H, optionally substituted C1-C6 alkyl, and halogen. In certain aspects, the invention provides compounds of Formula (III): (III) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is C1-C6alkyl, 6-membered aryl, alkyl substituted aryl; and R2’ is optionally substituted C1-C6 alkyl, optionally substituted saturated or partially unsaturated 4-10 membered cycloalkyl or heterocycloalkyl having N as heteroatom, wherein cycloalkyl or heterocycloalkyl is optionally bridged or spiro, or an optionally substituted 6-10 membered heteroaryl having N as heteroatom. In certain aspects, the invention provides compounds of Formula (IV): (IV) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1is C1-C6alkyl, 6-membered aryl, alkyl substituted aryl; Y1 and Y2 are independently N or CR2, wherein R2is H, C1-C6 alkyl, or halogen; R2’’ is H, optionally substituted C1-C6 alkyl, -N(R)2 optionally substituted phenyl, 3-6- membered cycloalkyl, 3-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, with N or O as heteroatoms in said heterocycloalkyl or N as heteroatom in said heteroaryl ; A’ is H, optionally substituted C1-C6 alkyl, optionally substituted 4-10 membered cycloalkyl wherein said cycloalkyl is optionally bridged; 6-membered heterocycloalkyl having N, O as heteroatoms, phenyl, or 6-membered heteroaryl having N as heteroatom; and R is H or C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (V):

[0003] ĨV) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: is a single or double bond; Y1 is N or CR2; wherein R2is H or halogen; R1 is optionally substituted C1-C6 alkyl; X1, X2, X3, and X4are independently N, O, S, CR3, or NR3, wherein each R3is independently H, -OR, optionally substituted C1-C6 alkyl wherein substitutions are one or more halogen; and R is H, C1-C6alkyl. Optionally substituted 3-6-membered cycloalkyl, or optionally substituted 3-6-membered heterocycloalkyl. As defined above and described herein, n is 1 or 2, In some embodiments, n is 0. In some embodiments, n is 1. As defined above and described herein, each R1is H, C1-C6alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or alkyl group substituted with 4-6 membered aryl. In some embodiments, R1 is H. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is a 3- 6 membered cycloalkyl. In some embodiments, R1is an 4-6 membered aryl ring. In some embodiments, R1 is an alkyl group substituted with 4-6 membered aryl. In some embodiments, R1is -CH3. In some embodiments, R1is -CH2CH3. In some embodiments, R1 is -CH2CH2CH3. In some embodiments, R1 is -CH2CH2CH2CH3. In some embodiments, R1is isopropyl. In some embodiments, R1is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1is . In some embodiments, R1is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is selected from those groups depicted in Table 1. As defined above and described herein, R2is H or halogen. In some embodiments, R2is H. In some embodiments, R2is halogen. In some embodiments, R2is F. In some embodiments, R2is selected from those groups depicted in Table 1. As defined above and described herein, each R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom. In some embodiments, R3is H. In some embodiments, R3is halo. In some embodiments, R3 is CN. In some embodiments, R3 is -OR. In some embodiments, R3 is -N(R)2. In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms. In some embodiments, two R3taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom. In some embodiments, R3is -CH3. In some embodiments, R3is isopropyl. In some embodiments, R3 is -CF3. In some embodiments, R3 is -CHF2. In some embodiments, R3 is - CH2CH2CF3. In some embodiments, R3 is . In some embodiments, R3 is -CN. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCF3. In some embodiments, R3is -OCH2CH3. In some embodiments, R3is -OCH2CF3. In some embodiments, R3 is -OCH2CH2CH3. In some embodiments, R3 is . In some embodiments, R3 is . In some embodiments, R3is -NH2. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3is . In some embodiments, R3 is optionally substituted piperazine. In some embodiments, R3 is . In some embodiments, R3is . In some embodiments, R3is . In some embodiments, R3 is . In some embodiments, R3is optionally substituted morpholine. In some embodiments, R3is . In some embodiments, R3 is optionally substituted azetidine. In some embodiments, R3 is . In some embodiments, R3is . In some embodiments, R3is . In some embodiments, two R3taken together with their intervening atoms form . In some embodiments, R3 is selected from those groups depicted in Table 1. As defined above and described herein, R4is -CHF2or -CF3.In some embodiments, R4is - CHF2. In some embodiments, R4is -CF3.In some embodiments, R4 is selected from those groups depicted in Table 1. As defined above and described herein, R5 is H, C1-C4 alkyl, or C3-C4 cycloalkyl. In some embodiments, R5is -CH3. In some embodiments, R5is -CH2CH2CH3. In some embodiments, R5is . In some embodiments, R5is selected from those groups depicted in Table 1. As defined above and described herein, A is an optionally substituted 4-8 membered heterocycle with N or O as the heteroatoms, wherein said one or more substitutions on the Ring A are selected from the group consisting of H, C1-C6alkyl, and halogen. In some embodiments, A is optionally substituted piperazine. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is optionally substituted diazepane. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is optionally substituted morpholine. In some embodiments, A is . In some embodiments, A is optionally substituted azetidine. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is selected from those groups depicted in Table 1. As defined above and described herein, R2’ is optionally substituted C1-C6alkyl, optionally substituted saturated or partially unsaturated 4-10 membered cycloalkyl or heterocycloalkyl having N as heteroatom, wherein cycloalkyl or heterocycloalkyl is optionally bridged or spiro, or an optionally substituted 6-10 membered heteroaryl having N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is an optionally substituted saturated or partially unsaturated 6- membered heterocyclic ring including N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is an optionally substituted substituted 6-10 membered heteroaryl having N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is -CH3. In some embodiments, R2’ is -CH2CH3. In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is selected from those groups depicted in Table 1. As defined above and described herein, A’ is H, optionally substituted C1-C6 alkyl, optionally substituted 4-10 membered cycloalkyl wherein said cycloalkyl is optionally bridged; 6- membered heterocycloalkyl having N, O as heteroatoms, 6-membered aryl or heteroaryl wherein said heteroaryl includes N as heteroatom. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted piperazine. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted tetrahydropyran. In some embodiments, A’ is . In some embodiments, A’ is optionally substituted oxetane. In some embodiments, A’ is . In some embodiments, A’ is optionally substituted morpholine. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted phenyl. In some embodiments, A’ is optionally phenyl. In some embodiments, A’ is optionally substituted pyridine. In some embodiments, A’ is optionally pyridine. In some embodiments, A’ is optionally substituted bicyclo[1.1.1]pentane. In some embodiments, A is In some embodiments, A’ is selected from those groups depicted in Table 1. As defined above and described herein, R2’’ is H, optionally substituted C1-C6alkyl, -N(R)2optionally substituted phenyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, or 5-6- membered heteroaryl, with N or O as heteroatoms in said heterocycloalkyl or N as heteroatom in said heteroaryl. In some embodiments, R2’’ is -CH3. In some embodiments, R2’’ is optionally substituted phenyl. In some embodiments, R2’’ is phenyl. In some embodiments, R2’’ is optionally substituted pyridine. In some embodiments, R2’’ is pyridine. In some embodiments, R2’’ is optionally substituted morpholine. In some embodiments, R2’’ is . In some embodiments, R2’’ is -NH2. In some embodiments, R2is -NH(CH3). In some embodiments, R2is -N(CH3)2. In some embodiments, R2’’ is optionally substituted pyridine. In some embodiments, R2’’ is optionally substituted tetrahydrofuran. In some embodiments, R2’’ is optionally substituted piperazine. In some embodiments, R2’’ is.In some embodiments, R2’’ is . In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted piperazine. In some embodiments, R2’’ is . In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted tetrahydropyran. In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted morpholine. In some embodiments, A’ is . In some embodiments, R2’’ is optionally substituted oxetane. In some embodiments, R2’’ is . In some embodiments, R2’’ is selected from those groups depicted in Table 1. As defined above and described herein, X1, X2, X3, and X4 are independently N, O, S, CR3, or NR3, wherein each R3 is independently H, -OR, optionally substituted C1-C6 alkyl wherein substitutions are one or more halogen; oxy- C1-C6alkyl, and C3-C6cycloalkyl. As defined above and described herein, in some embodiments, X1, X2, X3, and X4are independently N, O, S, CR3, or NR3, wherein each R3 is independently H, substituted or unsubstituted C1-C6 alkyl wherein substitutions are one or more halogen; oxy- C1-C6 alkyl, and C3-C6cycloalkyl. In some embodiments, X1 is N. In some embodiments, X1 is -NR3. In some embodiments, X1 is -CR3. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1is selected from those groups depicted in Table 1. In some embodiments, X2 is N. In some embodiments, X2 is NR3. In some embodiments, X2 is -CR3.In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2is selected from those groups depicted in Table 1. In some embodiments, X3 is N. In some embodiments, X3 is NR3. In some embodiments, X3 is -CR3. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3is selected from those groups depicted in Table 1. In some embodiments, X4is N. In some embodiments, X4is NR3. In some embodiments, X4 is -CR3. In some embodiments, X4 is O. In some embodiments, X4 is S. In some embodiments, X4is selected from those groups depicted in Table 1. In some embodiments, X5is N. In some embodiments, X5is -CR3. In some embodiments, X45 is O. In some embodiments, X5 is S. In some embodiments, X5 is selected from those groups depicted in Table 1. As defined above and described herein, R is H, optionally substituted C1-C6alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In some embodiments, R is H. In some embodiments, R is an optionally substituted C1-C6 alkyl. In some embodiments, R is optionally substituted 4-6 membered cycloalkyl. In some embodiments, R is optionally substituted 4-6 membered heterocycloalkyl having N or S as heteroatom. In some embodiments, R is an optionally substituted 3-6-membered cycloalkyl. In some embodiments, R is an optionally substituted 3-6-membered heterocycloalkyl In some embodiments, R is selected from those groups depicted in Table 1. Exemplary compounds of the invention are set forth in Table 1, below. In some embodiments, the present disclosure provides a compound set forth in Table 1, above, or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, in the compounds of Formula (Ia), R1 is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclobutyl, or CH2-phenyl. In certain embodiments, in the compounds of Formula (Ia), R1 is methyl. In certain embodiments, in the compounds of Formula (Ia), Y1 and Y2 are both CR2, and wherein R2is H, alkyl, or halogen. In certain embodiments, in the compounds of Formula (Ia), each R2is H. In certain embodiments, in the compounds of Formula (Ia), Y1 and Y2 are both CR2each R2is F. In certain embodiments, in the compounds of Formula (Ia), Y1orY2as CR2and R2is F. In certain embodiments, in the compounds of Formula (Ia), Y1 is N and Y2 is CR2, and wherein R2is hydrogen or fluoro. In certain embodiments, in the compounds of Formula (Ia), R2is fluoro. In certain embodiments, in the compounds of Formula (Ia), X1, X2, X3, X4, and X5 are each CR3, wherein each R3 is independently selected from H, alkyl, 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms, oxyalkyl, oxy-cycloalkyl or heterocycloalkyl, halo, amine, or halo substituted alkyl. In certain embodiments, in the compounds of Formula (Ia), each R3 is independently selected from the group consisting of H, -CF3, -NH2, -Cl, -O-azetidine, -OCH3, -cyclopropyl, -F, -CH3, and -CHF2. In certain embodiments, in the compounds of Formula (Ia), X5 is CR3, wherein R3 is -CF3. In certain embodiments, in the compounds of Formula (Ia), one and only one of X1, X2, X3, X4, or X5is N. In certain embodiments, in the compounds of Formula (Ia), two and only two of X1, X2, X3, X4, or X5 are N. In certain embodiments, in the compounds of Formula (Ia), three and only three of X1, X2, X3, X4, or X5are N. In certain embodiments, in the compound of Formula (Ia), when X1, X2, X3, X4, or X5 are CR3; each R3 is independently selected from the group consisting of H, -CF3, -NH2, fluoro, chloro, -O-azetidine, -OCH3, -cyclopropyl, -CH3, and -CHF2. In certain embodiments, each R3is H, F, or -CF3. In certain embodiments, each R3is H, -CH3, or cyclopropyl. In certain embodiments, R3is H, -OCH3, or CHF2. In certain embodiments, R3is cyclopropyl. In certain embodiments, in the compounds of Formula (Ia), the compound selected from the group consisting of:

[0004] In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R1is selected from the group consisting of -CH3, ethyl, propyl, butyl, -CH2-isopropyl, -CH2-phenyl, -cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R1is methyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1and Y2are independently N or CR2, wherein R2is H, C1-C6 alkyl, or halogen. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R2is H, -CH3, or F. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1 and Y2 are CH. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1 is N and Y2 is CR2. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), X1, X2, X3, X4, and X5 are CR3. In certain embodiments, each R3 is independently selected from H, C1-C6 alkyl, 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms, oxy-C1-C6 alkyl, oxy-cycloalkyl or heterocycloalkyl, halo, amine, halo substituted C1-C6alkyl, or two R3form an optionally substituted fused heterocycle with N as the heteroatom. In certain embodiments, each R3 is independently selected from the group consisting of: H, -CF3, -NH2, -F, -Cl, -O-azetidine, O- oxetane, -OCH3, -cyclopropyl, -CH3, -CHF2, -OCF3, -CH2-CF3, - CH2-CH2-CF3, -OCHF2, -OCH3, -CH(phenyl)2, isopropyl, and optionally two R3may form an optionally substituted fused heterocycle with N as the heteroatom. In certain embodiments, R3 is H. In certain embodiments, each R3is selected from the group consisting of -H, CHF2, and CF3. In certain embodiments, at least one R3is -OCF3or -OCHF2. In certain embodiments, at least one R3is -CH3, -OCH3or cyclopropyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), one of X1, X2, X3, X4, and X5is N. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), one of X2 and X3 is N. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R4is -CHF2. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R4is -CF3. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), selected from the group consisting of: Example 38 Example 35

[0005] Example 36 Example 39 Example 42 Example 37 Example 40 Example 41 Example 43 Example 44 Example 45 Example 8 Example 46 Example 47 Example 48 Example 10 Example 49 Example 54 Example 50 Example 51 Example 52 Example 53 Example 95 Example 55 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 23 Example 24 Example 29 Example 25

[0006] Example 30 Example 69 Example 70 Example 71 Example 72 Example 67 Example 68 Example 78

[0007] Example 80 Example 81 Example 82 Example 85 Example 88 Example 91 Example 92 Example 93 Example 98 Example 94 Example 99 Example 96 Example 97 Example 100 Example 102 Example 101 Example 103 Example 112 Example 114 Example 116 Example 126 Example 121 Example 127 Example 128 Example 129 Example 130 Example 131 Example 132 Example 135 In certain embodiments, in the compounds of Formula (II), R1 is H. In certain embodiments, in the compounds of Formula (II), R1 is F. In certain embodiments, in the compounds of Formula (II), R2is H. In certain embodiments, in the compounds of Formula (II), R2is F. In certain embodiments, in the compounds of Formula (II), A is piperazine. In certain embodiments, the piperazine is substituted with one, two, or three methyl groups. In certain embodiments, in the compounds of Formula (II), A is diazepane. In certain embodiments, the diazepane is substituted with one, two, or three methyl groups. In certain embodiments, in the compounds of Formula (II), A is difluoro azetidine or methyl-azetidine. In certain embodiments, in the compounds of Formula (II), A is morpholine. In certain embodiments, in the compounds of Formula (II), the compound is selected from the group consisting of: Example 137 Example 138 Example 139 Example 140 Example 141 Example 142 Example 143 Example 144 Example 145 Example 146 Example 147 Example 148 Example 149 Example 150 Example 151 In certain embodiments, in the compounds of Formula (III), R1 is methyl. In certain embodiments, in the compounds of Formula (III), R1 is phenyl. In certain embodiments, in the compounds of Formula (III), R1is -CH2-phenyl. In certain embodiments, in the compounds of Formula (III), R2is methyl. In certain embodiments, in the compounds of Formula (III), R2is ethyl. In certain embodiments, in the compounds of Formula (III), R2is selected from the group consisting of: and . In certain embodiments, in the compounds of Formula (III), R2is: . In certain embodiments, in the compounds of Formula (III), R2is . In certain embodiments, in the compounds of Formula (III), the compound is selected from the group consisting of: Example 152 Example 155 Example 153 Example 154 Example 157 Example 156

[0008] Example 158 Example 159 In certain embodiments, in the compounds of Formula (IV), R1 is selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, phenyl, and -CH2-phenyl. In certain embodiments, in the compounds of Formula (IV), R1 is methyl. In certain embodiments, in the compounds of Formula (IV), R1 is phenyl or -CH2-phenyl. In certain embodiments, in the compounds of Formula (IV), R2is selected from the group consisting of H, methyl, morpholine, -NH-CH3, -N-(CH3)2, oxetane, tetrahydropyran, optionally substituted piperazine, piperidine, pyridine, bicyclo[1.1.1]pentane, oxetane, and phenyl. In certain embodiments, in the compounds of Formula (IV), R2is morpholine. In certain embodiments, in the compounds of Formula (IV), R2is piperazine or methyl- piperazine. In certain embodiments, in the compounds of Formula (IV), A is phenyl or pyridine. In certain embodiments, in the compounds of Formula (IV), A is adamantane. In certain embodiments, in the compounds of Formula (IV), A is optionally substituted bicyclo[1.1.1]pentane. In certain embodiments, in the compounds of Formula (IV), the compound is a compound selected from the group consisting of: Example 161 Example 163

[0009] Example 164 Example 166 Example 167 Example 168 Example 170 Example 173 Example 187 Example 175

[0010] Example 190 Example 189 Example 191 Example 192 Example 194 Example 196 Example 197 Example 198

[0011] Example 201 In certain embodiments, in the compounds of Formula (IV), the compound is a compound selected from the group consisting of: Example 160 Example 162 Example 169 Example 165 Example 171 Example 172 Example 174 Example 176 Example 179 Example 177

[0012] Example 180 Example 181 Example 182 Example 183 Example 184 Example 185

[0013] Example 186 Example 188 Example 193 Example 195 Example 199 Example 200

[0014] Example 188a In certain embodiments, in the compounds of Formula (V), R3 is selected from H, -OR, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl; wherein R is H or optionally substituted C1-C6 alkyl. In certain embodiments, in the compounds of Formula (V), R1 is methyl. In certain embodiments, in the compounds of Formula (V), Y1is N. In certain embodiments, in the compounds of Formula (V), Y1is CH. In certain embodiments, in the compounds of Formula (V), X1 and X3 are N and S, respectively. In certain embodiments, in the compounds of Formula (V), when any one of X1, X2, X3, and X4 are CR3, or NR3, each of R3 is independently H or CH3.In certain embodiments, in the compounds of Formula (V), each R3 is independently H, -CH3, -CF3, -CHF2, -OCH3, -CH2CF3, or cyclopropyl. In certain embodiments, in the compounds of Formula (V), R3 is -CF3 or -CHF2. In certain embodiments, in the compounds of Formula (V), the compound is a compound selected from the group consisting of: Example 233 Example 221 Example 256 Example 257 Example 258 Example 262 In certain embodiments, in the compounds of Formula (V), the compound is a compound selected from the group consisting of: Example 202 Example 203 Example 204 Example 205 Example 206 Example 207 Example 208 Example 209 Example 210 Example 211 Example 212 Example 213 Example 214 Example 215 Example 216 Example 217 Example 218 Example 219 Example 220 Example 222 Example 223 Example 224 Example 225 Example 226 Example 227 Example 228 Example 229 Example 230 Example 231 Example 232 Example 234 Example 235 Example 236 Example 237 Example 238 Example 239 Example 240 Example 241 Example 242 Example 243 Example 244 Example 245 Example 246 Example 247 Example 248 Example 249 Example 250 Example 251Example 252 Example 253 Example 254 Example 255 Example 259 Example 260 Example 261 Example 263 Example 264 In another aspect, the invention provides inhibitors of HDAC6. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above. In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above. In one aspect, provided herein is a method of inhibiting the activity of HDAC6 in a subject in need thereof comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of selectively inhibiting the activity of HDAC6 over other HDACs in a subject in need thereof comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of the invention has a selectivity for HDAC6 when tested in a HDAC enzyme assay of about 5 to 1000 fold greater than for other HDACs. In another aspect, provided herein is a method of treating a disease mediated by HDAC6 in a subject in need thereof comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention. In one embodiment, the disease to be treated by the methods of the invention is a cancer or a proliferation disease. In a further embodiment, the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, and myelomas. In another embodiment, the cancer is a solid tumor. In a further embodiment, the solid tumor is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma. In a preferred embodiment, the cancer is multiple myeloma. DETAILED DESCRIPTION Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs. The definitions provided below are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure. Unless otherwise stated, the moieties described below are optionally substituted, i.e., they may be substituted at one or more positions. The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability to change one or more functional groups for another functional group or groups on a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions). When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R1 and R2can be substituted alkyls, or R1 can be hydrogen and R2can be a substituted alkyl, and the like. The terms “a,” “an,” or “a(n),” when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below. Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein. The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in the art, all valences must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like. The term “alkyl” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic saturated hydrocarbon group, or combination thereof, and can include di- and multivalent groups, having the number of carbon atoms designated (e.g., C1-C10means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to C1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., “straight-chain”), branched, or cyclic saturated hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers thereof. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-C8alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl. Thus, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon group having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom, such as O, N, P, Si or S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, - CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, - CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR’, -NR’R”, -OR’, -SR, -S(O)R, and / or -S(O2)R’. “Cycloalkyl” refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyeiohexenyl, cycloheptyl, and the like. The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The term “carbocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which all ring members are carbon atoms. Unless otherwise specified, a carbocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which at least one ring member is a heteroatom, such as N, O, or S. Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiozolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the aforementioned groups. The terms “cycloheteroalkyl” and “heterocycloalkyl” refer to a saturated ring system, such as a 3- to 10-member cycloalkyl ring system, that include one or more heteroatoms. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocycloalkyl include, but are not limited to, 1-(l, 2,5,6-tetrahydropyridyi), 1- piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms, such as oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6- membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like. An unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double bonds or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkenyl” as used herein refers to a monovalent group derived from a C2-C20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl. The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-C20hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), l- propynyl, pentynyl, hexynyl, and heptynyl groups, and the like. The term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched, or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (- CH2-CH2-); propylene (CH2)3, cyclohexylene (-C6H10-, -CH=CH-CH=CH-, -CH=CH-CH2-, - CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-N(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S- CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR’- represents both -C(O)OR’- and -R’OC(O)-. The term “spirocyclyl” refers to a polycyclic compound in which two rings have a single atom, e.g., carbon, as the only common member of two rings. Thus, a “spirocycloalkyl” refers to a cycloalkyl group with two rings having a single carbon in common, and a “spiroheterocycloalkyl” or “spiroheterocycloalkyl” refers to a cycloheteroalkyl group with two rings having a single carbon or other atom, e.g., nitrogen, in common. The term “aryl” means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to and groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzoihiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-qumolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively. Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., “3 to 7 membered”), the term “member” refers to a carbon atom or heteroatom. Each of the above terms is meant to include both substituted and unsubstituted forms of the indicated group. In some instances, the groups are explicitly defined as substituted, for example, “substituted aryl.” The optional substituents are provided below. Substituents can be one or more of a variety of groups selected from, but not limited to: - OR’, =O, =NR’, =N-OR’, -NR’R” -SR’, -halogen, -SiR’R”R”, -OC(O)R, -C(O)R, -CO2R - C(O)NR’R”, -OC(O)NR’R”, -NR”C(O)R, -NR’-C(O)NR”R’”, -NR”C(O)OR’, -NR- C(NR’R”)=NR”’, -S(O)R, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -CN, CF3, fluorinated C1-C4alkyl, and -NO2in a number ranging from zero to (2m’ +1), where m’ is the total number of carbon atoms in such groups. R’, R”, R’” and R”” each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Other non- limiting examples of substituents include (C1-C6)alkyl, (C2-C8)alkenyl, (C3-C8)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -O(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C8)cycloalkyl, (C6-C10)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1- C6)alkyl(C6-C10)aryl, -C(O)(C1-C6)alkyl, -C(O)NR’R”, -S(O)(C1-C6)alkyl, -S(O)NR’R”, - S(O)2(C1-C6)alkyl, -S(O)2NR’R”, -O(C1-C6)alkyl-S(O)(C1-C6)alkyl, -O(C1-C6)alkyl-S(O)NR’R”, -O(C1-C6)alkyl-S(O)2(C1-C6)alkyl, and -O(C1-C6)alkyl-S(O)2NR’R”. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen. When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of ordinary skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e. g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2)r-B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, - S(O)2NR’- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X’-(C”R’”)d-, where s and d are independently integers of from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR’-. The substituents R, R’, R” and R” may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. As used herein, the term “acyl” refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR, esters, - RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H. The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-C20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like. The term “alkoxy alkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group. “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl. “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplar)' aralkyloxyl group is benzyloxyl, i.e., C6H5CH2-O-. An aralkyloxyl group can optionally be substituted. “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl. “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl. “Aralkoxycarbonyl” refers to an aralkyl -O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. “Carbamoyl” refers to an amide group of the formula -C(=O)NH2. “Alkylcarbamoyl” refers to a R’RN -C(=O) group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and / or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R'RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described. The term “carbonyldioxyl,” as used herein, refers to a carbonate group of the formula - OC(=O)-OR. “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described. The term “amino” refers to the -NH2group and refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic groups. For example, the terms “acyl amino” and “alkylamino” refer to specific N- substituted organic groups with acyl and alkyl substituent groups respectively. An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be –(CH2)k where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine. The amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like. “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described. The term “carbonyl” refers to the -C(=O)- group, and can include an aldehyde group represented by the general formula R-C(=O)H. The term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety. The term “cyano” refers to the -CN group. The terms “halo,” “halide,” and “halogen” refer to fluoro, chloro, bromo, and iodo groups. The term “haloalkyl” refers to an alkyl group substituted with one or more halogens. Additionally, the term “haloalkyl,” includes monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. The terms “halocycloalky” and “cyclohaloalkyl” refer to a cycloalkly group with one or more halogens. The term “hydroxyl” refers to the -OH group. The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group. The term “mercapto” refers to the -SH group. The term “oxo” refers to an oxygen atom that is double bonded to a carbon atom or to another element. The term “nitro” refers to the -NO2group. The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom. The term “sulfate” refers to the - SO4group. The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH. More particularly, the term “sulfide” refers to compound having a group of the formula - SR. The term “sulfone” refers to compound having a sulfonyl group -S(O2)R’. The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R The term ureido refers to a urea group of the formula -NH-CO-NH2. Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, m terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one isomeric form to another. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. The compounds of the present disclosure may exist as salts, and particularly as pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or m a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow' the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. In addition to salt forms, the present disclosure provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. The term “protecting group” refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4- dimethoxybenzyl, while co existing amino groups may be blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Compounds In certain aspects, the invention provides compounds of Formula (Ia): (Ia) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1is H, C1-C6alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6alkyl group substituted with 4-6 membered aryl; Y1 and Y2 are independently N or CR2, wherein R2is H, alkyl, or halogen; X1, X2, X3, X4, and X5 are independently N or CR3, wherein each R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In certain aspects, the invention provides compounds of Formula (Ib): (Ib) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6 alkyl group substituted with 4-6 membered aryl; Y1 and Y2 are independently N, S, O, or CR2, wherein R2is H, C1-C6 alkyl, or halo; Z1, Z2, and Z3 are independently selected from C, CH, N and O; R4is -CHF2or -CF3; R5is H, C1-C4alkyl, or C3-C4cycloalkyl; and X1, X2, X3, X4, and X5 are independently N or CR3, wherein each R3 is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In certain embodiments, the compound is a compound of Formula (Ic): (Ic) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1, R4, Z1, Z2, Z3, X1, X2, X3, X4, and X5are!as defined and described herein. In certain embodiments, the compound is a compound of Formula (Id): (Id) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1, R4, Z1, Z2, Z3, X1, X2, X3, X4, and X5are as defined and described herein. In certain aspects, the invention provides compounds of Formula (II):

[0015] (II) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R2and R3are H or halogen; and A is an optionally substituted 4-8 membered heterocycle having N or O as heteroatoms, wherein said one or more substitutions on the Ring A are selected from the group consisting of H, C1-C6alkyl, and halogen. In certain aspects, the invention provides compounds of Formula (III): (III) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is C1-C6 alkyl, 6-membered aryl, alkyl substituted aryl; and R2’ is optionally substituted C1-C6alkyl, optionally substituted saturated or partially unsaturated 4-10 membered cycloalkyl or heterocycloalkyl having N as heteroatom, wherein cycloalkyl or heterocycloalkyl is optionally bridged or spiro, or an optionally substituted 6-10 membered heteroaryl having N as heteroatom In certain aspects, the invention provides compounds of Formula (IV): (IV) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1 is C1-C6 alkyl, 6-membered aryl, alkyl substituted aryl; Y1and Y2are independently N or CR2, wherein R2is H, C1-C6alkyl, or halogen; R2’’ is H, optionally substituted C1-C6 alkyl, -N(R)2 optionally substituted phenyl, 3-6- membered cycloalkyl, 3-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, with N or O as heteroatoms in said heterocycloalkyl or N as heteroatom in said heteroaryl; A’ is H, optionally substituted C1-C6alkyl, optionally substituted 4-10 membered cycloalkyl wherein said cycloalkyl is optionally bridged; 6-membered heterocycloalkyl having N, O as heteroatoms, phenyl, or 6-membered heteroaryl having N as heteroatom; and R is H or C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (V):

[0016] ĨV) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: is a single or double bond; Y1is N or CR2; wherein R2is H or halogen; R1 is optionally substituted C1-C6 alkyl; X1, X2, X3, and X4 are independently N, O, S, CR3, or NR3, wherein each R3 is independently H, -OR, optionally substituted C1-C6alkyl wherein substitutions are one or more halogen; and R is H, C1-C6 alkyl. Optionally substituted 3-6-membered cycloalkyl, or optionally substituted 3-6-membered heterocycloalkyl, As defined above and described herein, n is 1 or 2, In some embodiments, n is 0. In some embodiments, n is 1. As defined above and described herein, each R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or alkyl group substituted with 4-6 membered aryl. In some embodiments, R1 is H. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is a 3- 6 membered cycloalkyl. In some embodiments, R1 is an 4-6 membered aryl ring. In some embodiments, R1is an alkyl group substituted with 4-6 membered aryl. In some embodiments, R1is -CH3. In some embodiments, R1is -CH2CH3. In some embodiments, R1 is -CH2CH2CH3. In some embodiments, R1 is -CH2CH2CH2CH3. In some embodiments, R1is isopropyl. In some embodiments, R1is . In some embodiments, R1is . In some embodiments, R1is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1is . In some embodiments, R1is . In some embodiments, R1is selected from those groups depicted in Table 1. As defined above and described herein, R2is H or halogen. In some embodiments, R2is H. In some embodiments, R2is halogen. In some embodiments, R2is F. In some embodiments, R2is selected from those groups depicted in Table 1. As defined above and described herein, each R3 is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3taken together with their intervening atoms form an optionally substituted fused heterocycle with N as the heteroatom. In some embodiments, R3 is H. In some embodiments, R3 is halo. In some embodiments, R3 is CN. In some embodiments, R3is -OR. In some embodiments, R3is -N(R)2. In some embodiments, R3is optionally substituted C1-C6alkyl. In some embodiments, R3is optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms. In some embodiments, two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle with N as the heteroatom. In some embodiments, R3is -CH3. In some embodiments, R3is isopropyl. In some embodiments, R3 is -CF3. In some embodiments, R3 is -CHF2. In some embodiments, R3 is - CH2CH2CF3. In some embodiments, R3 is . In some embodiments, R3 is -CN. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCF3. In some embodiments, R3is -OCH2CH3. In some embodiments, R3is -OCH2CF3. In some embodiments, R3 is -OCH2CH2CH3. In some embodiments, R3 is . In some embodiments, R3 is . In some embodiments, R3is -NH2. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3is . In some embodiments, R3 is optionally substituted piperazine. In some embodiments, R3 is . In some embodiments, R3is . In some embodiments, R3is . In some embodiments, R3 is . In some embodiments, R3is optionally substituted morpholine. In some embodiments, R3is . In some embodiments, R3 is optionally substituted azetidine. In some embodiments, R3 is . In some embodiments, R3is . In some embodiments, R3is . In some embodiments, two R3taken together with their intervening atoms form . In some embodiments, R3 is selected from those groups depicted in Table 1. As defined above and described herein, R4is -CHF2or -CF3.In some embodiments, R4is - CHF2. In some embodiments, R4is -CF3.In some embodiments, R4 is selected from those groups depicted in Table 1. As defined above and described herein, R5 is H, C1-C4 alkyl, or C3-C4 cycloalkyl. In some embodiments, R5is -CH3. In some embodiments, R5is -CH2CH2CH3. In some embodiments, R5is . In some embodiments, R5is selected from those groups depicted in Table 1. As defined above and described herein, A is an optionally substituted 4-8 membered heterocycle with N or O as the heteroatoms, wherein said one or more substitutions on the Ring A are selected from the group consisting of H, C1-C6alkyl, and halogen. In some embodiments, A is optionally substituted piperazine. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is optionally substituted diazepane. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is optionally substituted morpholine. In some embodiments, A is . In some embodiments, A is optionally substituted azetidine. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is selected from those groups depicted in Table 1. As defined above and described herein, R2’ is optionally substituted C1-C6alkyl, optionally substituted saturated or partially unsaturated 4-10 membered cycloalkyl or heterocycloalkyl having N as heteroatom, wherein cycloalkyl or heterocycloalkyl is optionally bridged or spiro, or an optionally substituted 6-10 membered heteroaryl having N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is an optionally substituted partially unsaturated 6-membered heterocyclic ring including N as heteroatom. In some embodiments, R2’ is an optionally substituted saturated or partially unsaturated 6- membered heterocyclic ring including N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is an optionally substituted substituted 6-10 membered heteroaryl having N as heteroatom. In some embodiments, R2’ is . In some embodiments, R2’ is -CH3. In some embodiments, R2’ is -CH2CH3.

[0017] In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In someembodiments, R2’ is .In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is.In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is . In some embodiments, R2’ is.In some embodiments, R2’ is selected from those groups depicted in Table 1. As defined above and described herein, A’ is H, optionally substituted C1-C6 alkyl, optionally substituted 4-10 membered cycloalkyl wherein said cycloalkyl is optionally bridged; 6- membered heterocycloalkyl having N, O as heteroatoms, 6-membered aryl or heteroaryl wherein said heteroaryl includes N as heteroatom. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted piperazine. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted tetrahydropyran. In some embodiments, A’ is . In some embodiments, A’ is optionally substituted oxetane. In some embodiments, A’ is . In some embodiments, A’ is optionally substituted morpholine. In some embodiments, A’ is . In some embodiments, A’ is . In some embodiments, A’ is optionally substituted phenyl. In some embodiments, A’ is optionally phenyl. In some embodiments, A’ is optionally substituted pyridine. In some embodiments, A’ is optionally pyridine. In some embodiments, A’ is optionally substituted bicyclo[1.1.1]pentane. In some embodiments, A is In some embodiments, A’ is selected from those groups depicted in Table 1. As defined above and described herein, R2’’ is H, optionally substituted C1-C6alkyl, -N(R)2optionally substituted phenyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, or 5-6- membered heteroaryl, with N or O as heteroatoms in said heterocycloalkyl or N as heteroatom in said heteroaryl. In some embodiments, R2’’ is -CH3. In some embodiments, R2’’ is optionally substituted phenyl. In some embodiments, R2’’ is phenyl. In some embodiments, R2’’ is optionally substituted pyridine. In some embodiments, R2’’ is pyridine. In some embodiments, R2’’ is optionally substituted morpholine. In some embodiments, R2’’ is . In some embodiments, R2’’ is -NH2. In some embodiments, R2is -NH(CH3). In some embodiments, R2is -N(CH3)2. In some embodiments, R2’’ is optionally substituted pyridine. In some embodiments, R2’’ is optionally substituted tetrahydrofuran. In some embodiments, R2’’ is optionally substituted piperazine. In some embodiments, R2’’ is . In some embodiments, R2’’ is . In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted piperazine. In some embodiments, R2’’ is . In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted tetrahydropyran. In some embodiments, R2’’ is . In some embodiments, R2’’ is optionally substituted morpholine. In some embodiments, A’ is . In some embodiments, R2’’ is optionally substituted oxetane. In some embodiments, R2’’ is . In some embodiments, R2’’ is selected from those groups depicted in Table 1. As defined above and described herein, X1, X2, X3, and X4 are independently N, O, S, CR3, or NR3, wherein each R3is independently H, -OR, optionally substituted C1-C6alkyl wherein substitutions are one or more halogen; oxy- C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, X1 is N. In some embodiments, X1 is -NR3. In some embodiments, X1is -CR3. In some embodiments, X1is O. In some embodiments, X1is S. In some embodiments, X1 is selected from those groups depicted in Table 1. In some embodiments, X2is N. In some embodiments, X2is NR3. In some embodiments, X2 is -CR3.In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is selected from those groups depicted in Table 1. In some embodiments, X3is N. In some embodiments, X3is NR3. In some embodiments, X3 is -CR3. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is selected from those groups depicted in Table 1. In some embodiments, X4is N. In some embodiments, X4is NR3. In some embodiments, X4is -CR3. In some embodiments, X4is O. In some embodiments, X4is S. In some embodiments, X4 is selected from those groups depicted in Table 1. In some embodiments, X5is N. In some embodiments, X5is -CR3. In some embodiments, X45is O. In some embodiments, X5is S. In some embodiments, X5 is selected from those groups depicted in Table 1. As defined above and described herein, R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms. In some embodiments, R is H. In some embodiments, R is an optionally substituted C1-C6 alkyl. In some embodiments, R is optionally substituted 4-6 membered cycloalkyl. In some embodiments, R is optionally substituted 4-6 membered heterocycloalkyl having N or S as heteroatom. In some embodiments, R is an optionally substituted 3-6-membered cycloalkyl. In some embodiments, R is an optionally substituted 3-6-membered heterocycloalkyl In some embodiments, R is selected from those groups depicted in Table 1. Exemplary compounds of the invention are set forth in Table 1, below. Compound Compound Example 1 Example 2 Example 4 Example 3 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Compound Compound Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Compound Compound Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Compound Compound Example 31 Example 32 Example 33 Example 34 Example 36 Example 35 Example 38 Example 37Example 39Example 40 Compound Compound Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Compound Compound Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Compound Compound Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70 Example 71 Example 72 Compound Compound Example 73 Example 74 Example 75 Example 76 Example 77 Example 78Example 79Example 80 Example 82 Example 81 Compound Compound Example 83 Example 84 Example 85 Example 86 Example 87 Example 88 Example 89 Example 90 Example 91 Example 92 Compound Compound Example 94 Example 93 Example 95 Example 96 Example 98 Example 97 Example 99 Example 100 Example 102 Example 101 Compound Compound Example 103 Example 104 Example 105 Example 106 Example 107 Example 108 Example 109 Example 110 Example 111 Example 112 Compound Compound Example 113 Example 114 Example 115 Example 116 Example 117 Example 118Example 119Example 120 Example 122 Example 121 Compound Compound Example 124 Example 123 Example 125 Example 126 Example 127 Example 128 Example 129 Example 130 Example 131 Example 132 Compound Compound Example 134 Example 133 Example 135 Example 136 Example 137 Example 138 Example 139 Example 140 Example 141 Example 142 Example 143 Example 144 Compound Compound Example 145 Example 146 Example 147 Example 148 Example 149 Example 150 Example 151 Example 152 Example 153 Example 154 Compound Compound Example 155 Example 156 Example 157 Example 158 Example 159 Example 160 Example 161 Example 162 Compound Compound Example 163 Example 164 Example 166 Example 165 Example 167 Example 168 Example 169 Example 170 Compound Compound Example 171 Example 172 Example 173 Example 174 Example 175 Example 176 Example 177 Example 178 Compound Compound Example 179 Example 180 Example 181 Example 182 Example 183 Example 184 Example 185 Example 186 Compound Compound Example 187 Example 188 Example 188a Example 189 Example 190 Example 191 Example 192 Example 193 Example 194 Example 195 Compound Compound Example 196 Example 197 Example 198 Example 199 Example 200 Example 201 Example 202 Example 203 Example 204 Compound Compound Example 205 Example 206 Example 207 Example 208 Example 209 Example 210 Example 211 Example 212 Example 213 Example 214 Example 215 Compound Compound Example 216 Example 217 Example 218 Example 219 Example 220 Example 221 Example 223 Example 222 Example 224 Example 225 Example 226 Example 227 Compound Compound Example 228 Example 229 Example 231 Example 230 Example 232 Example 233 Example 234 Example 235 Example 236 Example 237 Example 238 Example 239 Example 240 Example 241 Compound Compound Example 242 Example 243 Example 244 Example 245 Example 246 Example 247 Example 248 Example 249 Example 250 Example 251 Example 252 Example 253 Compound Compound Example 254 Example 255 Example 256 Example 257 Example 258 Example 259 Example 260 Example 261 Example 262 Example 263 Example 264 Example 265 Compound Compound Example 266 Example 267 Example 268 Example 269Example 270Example 271 Example 272 Example 273 Example 274 Example 275 Compound Compound Example 276 Example 277 Example 278 Example 279 Example 280 Example 281 Example 282 Example 283 Example 284 Example 285 Compound Compound Example 286 Example 287 Example 288 Example289 Example 290 Example 291 Example 292 Example 293 Example 294 Example 295 Compound Compound Example 296 Example 297 Example 298 Example 299

[0018] Compound Compound

[0019] Compound Compound

[0020] Compound Compound

[0021] In some embodiments, the present disclosure provides a compound set forth in Table 1, above, or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, in the compounds of Formula (Ia), R1 is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclobutyl, or CH2-phenyl. In certain embodiments, in the compounds of Formula (Ia), R1 is methyl. In certain embodiments, in the compounds of Formula (Ia), Y1 and Y2 are both CR2, and wherein R2is H, alkyl, or halogen. In certain embodiments, in the compounds of Formula (Ia), each R2is H. In certain embodiments, in the compounds of Formula (Ia), each R2is F. In certain embodiments, in the compounds of Formula (Ia), Y1is N and Y2is CR2, and wherein R2is hydrogen or fluoro. In certain embodiments, in the compounds of Formula (Ia), R2is fluoro. In certain embodiments, in the compounds of Formula (Ia), X1, X2, X3, X4, and X5 are each CR3, wherein each R3is independently selected from H, alkyl, 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms, oxyalkyl, oxy-cycloalkyl or heterocycloalkyl, halo, amine, or halo substituted alkyl. In certain embodiments, in the compounds of Formula (Ia), each R3is independently selected from the group consisting of H, -CF3, -NH2, -Cl, -O-azetidine, -OCH3, -cyclopropyl, -F, -CH3, and -CHF2. In certain embodiments, in the compounds of Formula (Ia), X5 is CR3, wherein R3 is -CF3. In certain embodiments, in the compounds of Formula (Ia), one and only one of X1, X2, X3, X4, or X5 is N. In certain embodiments, in the compounds of Formula (Ia), two and only two of X1, X2, X3, X4, or X5are N. In certain embodiments, in the compounds of Formula (Ia), three and only three of X1, X2, X3, X4, or X5 are N. In certain embodiments, in the compound of Formula (Ia), when X1, X2, X3, X4, or X5 are CR3; each R3 is independently selected from the group consisting of H, -CF3, -NH2, fluoro, chloro, -O-azetidine, -OCH3, -cyclopropyl, -CH3, and -CHF2. In certain embodiments, each R3 is H, F, or -CF3. In certain embodiments, each R3 is H, -CH3, or cyclopropyl. In certain embodiments, R3 is H, -OCH3, or CHF2. In certain embodiments, R3 is cyclopropyl. In certain embodiments, in the compounds of Formula (Ia), the compound selected from the group consisting of: Example 1 Example 2 Example 4 Example 3 Example 5 Example 6 Example 7 Example 9 Example 11 Example 12 Example 13 Example 14 Example 15 Example 17 Example 18 Example 19

[0022] Example 20 Example 56 Example 21 Example 22 Example 27 Example 26 Example 28 Example 31 Example 32 Example 33 Example 16 Example 34 Example 73 Example 74 Example 75 Example 76 Example 77 Example 79 Example 83 Example 84 Example 86 Example 87Example 89Example 90 Example 104 Example 105 Example 106 Example 107 Example 108 Example 109 Example 110 Example 111 Example 113 Example 115 Example 117 Example 118 Example 119 Example 120 Example 122 Example 123 Example 125 Example 124 Example 133 Example 134 Example 136 In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R1 is selected from the group consisting of -CH3, ethyl, propyl, butyl, -CH2-isopropyl, -CH2-phenyl, -cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R1 is methyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1and Y2are independently N or CR2, wherein R2is H, C1-C6 alkyl, or halogen. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R2is H, -CH3, or F. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1and Y2are CH. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), Y1 is N and Y2 is CR2. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), X1, X2, X3, X4, and X5 are CR3. In certain embodiments, each R3 is independently selected from H, C1-C6 alkyl, 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms, oxy-C1-C6 alkyl, oxy-cycloalkyl or heterocycloalkyl, halo, amine, halo substituted C1-C6alkyl, or two R3may form an optionally substituted fused heterocycle with N as the heteroatom. In certain embodiments, each R3 is independently selected from the group consisting of: H, -CF3, -NH2, -F, -Cl, -O-azetidine, O- oxetane, -OCH3, -cyclopropyl, -CH3, -CHF2, -OCF3, -CH2-CF3, - CH2-CH2-CF3, -OCHF2, -OCH3, -CH(phenyl)2, isopropyl, and optionally two R3may form an optionally substituted fused heterocycle with N as the heteroatom. In certain embodiments, R3 is H. In certain embodiments, each R3is selected from the group consisting of -H, CHF2, and CF3. In certain embodiments, at least one R3is -OCF3or -OCHF2. In certain embodiments, at least one R3is -CH3, -OCH3or cyclopropyl. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), one of X1, X2, X3, X4, and X5is N. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), one of X2 and X3 is N. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R4is -CHF2. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), R4is -CF3. In certain embodiments, in the compounds of Formula (Ib), (Ic), or (Id), selected from the group consisting of: Example 38 Example 35

[0023] Example 36 Example 39 Example 42 Example 37 Example 40 Example 41 Example 43 Example 44 Example 45 Example 8 Example 46 Example 47 Example 48 Example 10 Example 49 Example 54 Example 50 Example 51 Example 52 Example 53 Example 95 Example 55 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 23 Example 24 Example 29 Example 25

[0024] Example 30 Example 69 Example 70 Example 71 Example 72 Example 67 Example 68 Example 78

[0025] Example 80 Example 81 Example 82 Example 85 Example 88 Example 91 Example 92 Example 93 Example 98 Example 94 Example 99 Example 96 Example 97 Example 100 Example 102 Example 101 Example 103 Example 112 Example 114 Example 116 Example 126 Example 121 Example 127 Example 128 Example 129 Example 130 Example 131 Example 132 Example 135 In certain embodiments, in the compounds of Formula (II), R1 is H. In certain embodiments, in the compounds of Formula (II), R1 is F. In certain embodiments, in the compounds of Formula (II), R2is H. In certain embodiments, in the compounds of Formula (II), R2is F. In certain embodiments, in the compounds of Formula (II), A is piperazine. In certain embodiments, the piperazine is substituted with one, two, or three methyl groups. In certain embodiments, in the compounds of Formula (II), A is diazepane. In certain embodiments, the diazepane is substituted with one, two, or three methyl groups. In certain embodiments, in the compounds of Formula (II), A is difluoro azetidine or methyl-azetidine. In certain embodiments, in the compounds of Formula (II), A is difluoro azetidine. In certain embodiments, in the compounds of Formula (II), A is morpholine. In certain embodiments, in the compounds of Formula (II), the compound is selected from the group consisting of: Example 137 Example 138 Example 139 Example 140 Example 141 Example 142 Example 143 Example 144 Example 145 Example 146 Example 147 Example 148 Example 149 Example 150 Example 151 In certain embodiments, in the compounds of Formula (III), R1is methyl. In certain embodiments, in the compounds of Formula (III), R1 is phenyl. In certain embodiments, in the compounds of Formula (III), R1 is -CH2-phenyl. In certain embodiments, in the compounds of Formula (III), R2is methyl. In certain embodiments, in the compounds of Formula (III), R2is ethyl. In certain embodiments, in the compounds of Formula (III), R2is selected from the group consisting of: and . In certain embodiments, in the compounds of Formula (III), R2is: . In certain embodiments, in the compounds of Formula (III), R2is . In certain embodiments, in the compounds of Formula (III), the compound is selected from the group consisting of: Example 152 Example 155 Example 153 Example 154 Example 157 Example 156

[0026] Example 158 Example 159 I In certain embodiments, in the compounds of Formula (IV), R1 is selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, phenyl, and -CH2-phenyl. In certain embodiments, in the compounds of Formula (IV), R1 is methyl. In certain embodiments, in the compounds of Formula (IV), R1 is phenyl or -CH2-phenyl. In certain embodiments, in the compounds of Formula (IV), R2is selected from the group consisting of H, methyl, morpholine, -NH-CH3, -N-(CH3)2, oxetane, tetrahydropyran, optionally substituted piperazine, piperidine, pyridine, bicyclo[1.1.1]pentane, oxetane, and phenyl. In certain embodiments, in the compounds of Formula (IV), R2is morpholine. In certain embodiments, in the compounds of Formula (IV), R2is piperazine or methyl- piperazine. In certain embodiments, in the compounds of Formula (IV), A is phenyl or pyridine. In certain embodiments, in the compounds of Formula (IV), A is adamantane. In certain embodiments, in the compounds of Formula (IV), A is optionally substituted bicyclo[1.1.1]pentane. In certain embodiments, in the compounds of Formula (IV), the compound is a compound selected from the group consisting of:

[0027] Example 161 Example 163 Example 164 Example 166 Example 167 Example 168 Example 170 Example 173

[0028] Example 187 Example 175 Example 190 Example 189 Example 191 Example 192 Example 194 Example 196

[0029] Example 197 Example 198 Example 201 In certain embodiments, in the compounds of Formula (IV), the compound is a compound selected from the group consisting of: Example 160 Example 162

[0030] Example 169 Example 165 Example 171 Example 172 Example 174 Example 176

[0031] Example 177 Example 179 Example 181 Example 180 Example 182 Example 183 Example 184 Example 185 Example 188 Example 186 Example 193Example 195 Example 199 Example 200 Example 188a In certain embodiments, in the compounds of Formula (V), R3is selected from H, -OR,optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl; wherein R is H or optionally substituted C1-C6 alkyl. In certain embodiments, in the compounds of Formula (V), R1 is methyl. In certain embodiments, in the compounds of Formula (V), Y1is N. In certain embodiments, in the compounds of Formula (V), Y1 is CH. In certain embodiments, in the compounds of Formula (V), X1and X3are N and S, respectively. In certain embodiments, in the compounds of Formula (V), when any one of X1, X2, X3, and X4are CR3, or NR3, each of R3is independently H or CH3.In certain embodiments, in the compounds of Formula (V), each R3 is independently H, -CH3, -CF3, -CHF2, -OCH3, -CH2CF3, or cyclopropyl. In certain embodiments, in the compounds of Formula (V), R3is -CF3or -CHF2. In certain embodiments, in the compounds of Formula (V), the compound is a compound selected from the group consisting of: Example 233 Example 221 Example 256 Example 257 Example 262 Example 258 In certain embodiments, in the compounds of Formula (V), the compound is a compound selected from the group consisting of: Example 202 Example 203 Example 204 Example 205 Example 206 Example 207 Example 208 Example 209 Example 210 Example 211 Example 212 Example 213 Example 214 Example 215 Example 216 Example 217 Example 218 Example 219 Example 220 Example 222 Example 223 Example 224 Example 225 Example 226 Example 227 Example 228 Example 229 Example 230 Example 231 Example 232 Example 234 Example 235 Example 236 Example 237 Example 238 Example 239 Example 240 Example 241 Example 242 Example 243 Example 244 Example 245 Example 246 Example 247 Example 248 Example 249 Example 250 Example 251 Example 252 Example 253 Example 254 Example 255 Example 259 Example 260 Example 261 Example 263 Example 264 In another aspect, the invention provides inhibitors of HDAC6. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above. In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above. In one aspect, provided herein is a method of inhibiting the activity of HDAC6 in a subject in need thereof comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease is cancer or a proliferation disease. In a further embodiment, the disease is a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, and myelomas. In another embodiment, the cancer is a solid tumor. In a further embodiment, the solid tumor is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma. In a further embodiment, the cancer is multiple myeloma. In other embodiments, the disease is Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's Disease, spinal muscular dystrophy, Lewy body dementia or chemotherapy-induced cognitive dysfunction. In other embodiments, the disease is an inflammatory, immune or autoimmune diseases including, but not limited to, arthritic conditions, such as, rheumatoid arthritis, osteoarthritis, juvenile arthritis, or rheumatoid spondylitis; psoriasis; post ischemic perfusion injury; inflammatory bowel disease; chronic inflammatory pulmonary disease; eczema; asthma; psoriasis; ischemia / reperfusion injury; ulcerative colitis; acute respiratory distress syndrome; psoriatic arthritis; infectious arthritis; progressive chronic arthritis; deforming arthritis; osteoarthritis; traumatic arthritis; gouty arthritis; Reiter's syndrome; polychondritis; acute synovitis and spondylitis; glomerulonephritis (with or without nephrotic syndrome); autoimmune hematologic disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia and neutropenia); ulcerative colitis; Crohn's disease; host versus graft disease; graft versus host disease; allograft rejection; chronic thyroiditis; Graves' disease; schleroderma; diabetes (type I and type II); active hepatitis (acute and chronic); primary binary cirrhosis; myasthenia gravis; multiple sclerosis (MS); systemic lupus erythematosus; atopic dermatitis; contact dermatitis; skin sunburns; chronic renal insufficiency; Stevens-Johnson syndrome; idiopathic sprue; sarcoidosis; Guillain-Barre syndrome; uveitis; conjunctivitis; keratoconjunctivitis; otitis media; periodontal disease; pulmonary interstitial fibrosis; asthma; bronchitis; rhinitis; sinusitis; pneumoconiosis; pulmonary insufficiency syndrome; pulmonary emphysema; pulmonary fibrosis; silicosis; chronic inflammatory pulmonary disease (e.g. chronic obstructive pulmonary disease); and other inflammatory or obstructive diseases of the airways. In another embodiment, the HDAC6 inhibitors of the invention are useful for treating diseases of or related to the kidney, including but not limited to, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Alstrom syndrome, Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, nephronophthisis, orofaciodigital syndrome 1, Senior-Loken syndrome, or primary ciliary dyskinesia (Kartagener Syndrome). In one embodiment, the HDAC6 inhibitors of the invention are useful for treating any one or more of the following autoimmune diseases or disorders: systemic lupus erythematosis, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, including keratoconjunctivitis sicca secondary to Sjögren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, aphthous ulcer, iritis, conjunctivitis, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, lichen planus, sarcoidosis, primary biliary cirrhosis, uveitis posterior, and interstitial lung fibrosis. Additionally, the methods of the invention may also be useful in the treatment of protozoal infections. The methods of the invention are also useful in the treatment of diseases associated with aberrant protein catabolism, for example, protein degradation disorders, disorders associated with misfolded proteins, and protein deposition disorders. In certain embodiments, the HDAC6 inhibitors of the invention are useful in the treatment of the protein deposition disorders, Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, amyloidosis, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, Lewy body dementia and chemotherapy-induced cognitive dysfunction. Neurodegenerative diseases that can be treated or prevented include Alzheimer's disease, Parkinson's disease, cerebral ischaemia, traumatic neurodegenerative disease, Huntington's disease or chorea, senile dementia, memory disorder, vascular dementia, lesions associated with cerebral ischemia (stroke), and with cranial and medullary trauma, among others. Preferably, the HDAC6 inhibitors are selective inhibitors of HDAC6 and, as such, are useful in the treatment of disorders modulated by histone deacetylases. In one embodiment, the HDAC6 inhibitors of the invention are selective inhibitors of tubulin deacetylases and, as such, are useful in the treatment of disorders modulated by tubulin deacetylases. Thus, in another aspect of the invention, methods for the treatment of cancer are provided comprising administering a therapeutically effective amount of an HDAC6 inhibitor, as described herein, to a subject in need thereof. In certain embodiments, the subject is identified as in need of such treatment. In certain embodiments, a method for the treatment of a diseases is provided comprising administering a therapeutically effective amount of an HDAC6 inhibitor, or a pharmaceutical composition comprising an HDAC6 inhibitor to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. In certain embodiments, the method involves the administration of a therapeutically effective amount of an HDAC6 inhibitor or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it (including a subject identified as in need). In certain embodiments, the HDAC6 inhibitors are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia (e.g., CML, AML, CLL, ALL), lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non- Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer, melanoma and multiple melanoma). In certain embodiments, the HDAC6 inhibitors of the invention are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas. In still other embodiments, the inventive anticancer agents are active against solid tumors (e.g., lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma). Accordingly, in yet another aspect, according to the methods of treatment of the present invention, tumor cells are killed, or their growth is inhibited by contacting said tumor cells with an HDAC6 inhibitor, as described herein. In another aspect, provided herein are methods of treating or preventing a peripheral neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compounds of the invention, or a pharmaceutical composition comprising a compound of the invention, to thereby treat or prevent the peripheral neuropathy. In an embodiment, the peripheral neuropathy is Charcot-Marie Tooth Disease. In another embodiment, the peripheral neuropathy is a medication induced neuropathy. In a further embodiment, the peripheral neuropathy is chemotherapy induced peripheral neuropathy. In yet a further embodiment, the chemotherapy induced peripheral neuropathy is taxol induced peripheral neuropathy or vincristine induced peripheral neuropathy. The chemotherapy induced peripheral neuropathy may be associated with various classes of chemotherapeutics including, but not limited to, thalidomide and thalidomide derivatives, epithilones, vinca alkaloids, taxanes, proteasome inhibitors, and platinum-based chemotherapeutics. Specific chemotherapies associated with peripheral neuropathy include, but are not limited to, cisplatin, carboplatin, oxaliplatin, bortezomib, dicarbazine, procarbazine, thalidomide, lenalidomide, pomalidomide, misonidazole, etoposide, altretamine, docetaxel, ixabepilone, streptozocin, syclophosphamide, carmustine, lomustine, procarbazine, mitomyocin, cytarabine, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel, asparaginase, busulfan, dacarbazine, fludarabine, hydroxyurea, ifosfamide, mercaptopurine, mitotane, streptozocin, taxol or a mixture of two or more agents thereof. In certain embodiments, the invention provides a method of treatment of any of the disorders described herein, wherein the subject is a human. In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of an HDAC6 inhibitor of the invention or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In other embodiments of the methods as described herein, the subject is a human. As discussed above, the present invention provides compounds useful for the treatment of various diseases. In certain embodiments, the compounds of the present invention are useful as inhibitors of histone or tubulin deacetylases and thus are useful as anti-cancer agents, and thus may be useful in the treatment of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells. In certain exemplary embodiments, the inventive anticancer agents are useful in the treatment of cancers and other proliferative disorders, as described above. In certain embodiments, the inventive anticancer agents are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas. In certain embodiments, the compounds are useful in the treatment of multiple myeloma. The compounds of the invention are also effective to treat or prevent autoimmune hematologic disorders (e.g. hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia and neutropenia), chronic inflammatory pulmonary disease (e.g. chronic obstructive pulmonary disease) and other inflammatory or obstructive diseases of the airways. In exemplary embodiments, the compounds of the invention are useful for disorders associated with histone deacetylation activity. In certain exemplary embodiments, the compounds of the invention are useful for disorders associated with tubulin deacetylation activity. Methods of treating a condition in a subject may include providing a composition of the invention to a subject. The composition may be provided to a subject by any suitable route or mode of administration. For example and without limitation, the composition may be provided buccally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device. The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration. Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week. The dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in a divided dosage, i.e., the dose may be provided as multiple tablets, capsules, pills, etc. The dosing may continue for a defined period. For example and without limitation, doses may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months or more. Compositions The invention provides pharmaceutical compositions containing compounds of the inventions, such as those described above. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003 / 0232877, the contents of which are incorporated herein by reference. Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating. Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and / or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In certain embodiments, the formulation is a sustained release formulation. In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension. The composition may be formulated for administration by a particular mechanism. The composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents). The composition may be formulated a single daily dosage. The composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages. EXAMPLES The exemplary compounds of the invention and their methods of preparation are provided below. A skilled artisan would be able to rely on the disclosure provided herein to prepare the compounds of the invention in their entire scope. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven / desiccator dried. Solvents were ACS grade unless otherwise noted. All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. Abbreviations and Acronyms The following list provides definitions of certain abbreviations as used herein. It will be appreciated that the list is not exhaustive, but the meaning of those abbreviations not herein below defined will be readily apparent to those skilled in the art: Ac2O acetic anhydride anhy Anhydrous n-BuOH n-butanol t-BuOH t-butanol CD3OD methanol-d4 Celite ® diatomaceous earth filter agent,  ® Celite Corp. CH2Cl2methylene chloride DCM dichloromethane CI-MS chemical ionization mass spectroscopy conc concentrated dec decomposition bs broad singlet br broad DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide DMSO-d6dimethylsulfoxide-d6ELSD evaporative light scattering device EtOAc ethyl acetate EtOH ethanol (100%) Et2O diethyl ether Et3N triethylamine HPLC ESI-MS high performance liquid chromatography-electrospray mass spectroscopy MPLC medium pressure liquid chromatography NMR nuclear magnetic resonance spectroscopy TOF-MS time-of-flight-mass spectroscopy NMM 4-methylmorpholine Ph3P triphenylphosphine Pd(dppf)Cl2[1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2 palladium(II) acetate P(O)Cl3phosphorous oxychloride Rf TLC retention factor Rt retention time (HPLC) rt room temperature MS Mass spectra THF tetrahydrofuran TFA trifluoroacetic acid TLC thin layer chromatography LC-MS (ESI) liquid chromatography-mass spectroscopy (electrospray ionization) DIEA diisopropylethylamine Et3N triethylamine MsCl Methanesulfonylchloride HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride AcOH acetic acid HCl hydrochloric acid H2SO4 sulfuric acid HNO3 nitric acid HBr hydrobromic acid CDCl3 chloroform-d CHCl3 chloroform H2O water NaOAc sodium acetate KOH potassium hydroxide NaOH sodium hydroxide NaCl sodium chloride NaHCO3 sodium bicarbonate Na2CO3 sodium carbonate K2CO3potassium carbonate Na2SO4 sodium sulfate MgSO4 magnesium sulfate MeOH methanol SiO2 silica gel K3PO4 potassium phosphate NH4Cl ammonium chloride AIBN 2,2′-axo bisisobutyronitrile DMAP N,N-dimethylpyridin-4-amine PIDA (Diacetoxyiodo)benzene TsCl p-toluenesulfonyl chloride PG protecting group NBS N-Bromosuccinimide NIS N-Iodosuccinimide NCS N-Chlorosuccinimide PE Petroleum ether FA Formic acid ee Enantiomeric excess atm Atmosphere Example 1: Synthesis of (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-2,6-bis(trifluoromethyl)benzohydrazide: Step-1: tert-Butyl 2-(2,6-bis(trifluoromethyl)benzoyl)-2-methylhydrazine-1-carboxylate (2): To the stirred solution of 2,6-bis(trifluoromethyl)benzoic acid 1 (3.0 g, 11.622 mmol) in DCM (30.00 mL) was added thionyl chloride (2.0 mL) at 25oC. The reaction mixture was stirred for 2 hours at 70oC and directly evaporated under N2 atmosphere to get the crude acid chloride. The crude acid chloride was dissolved in DCM (20.00 mL) and tert-butyl 2-methylhydrazine-1- carboxylate (2.02 g, 13.948 mmol) was added to the reaction mixture. Then DIPEA (8.12 mL, 46.490 mmol) was added into the reaction mixture and stirred for 12 hours at 70oC. Progress of the reaction was monitored by LCMS. After complete consumption of starting material, the reaction was quenched with cold water (150 mL), extracted with EtOAc (250 mL × 2). The organic layer was washed with brine solution (150 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude compound. The crude compound was purified using silica gel (230-400 mesh) and eluted 0-40% ethyl acetate in pet ether to get tert-butyl 2-(2,6- bis(trifluoromethyl)benzoyl)-2-methylhydrazine-1-carboxylate 2 (0.640 g, 12%) as off-white solid. LC-MS: 87.22 %, m / z [M+H]+= 387.25. Step-2: N-methyl-2,6-bis(trifluoromethyl)benzohydrazide (3): To a stirred solution of tert-butyl 2-(2,6-bis(trifluoromethyl)benzoyl)-2-methylhydrazine-1- carboxylate 2 (0.640 g, 1.657 mmol) in DCM (6.4 mL) was added HCl (4 M in 1,4-dioxane) (3.34 mL) at 0 °C and stirred for 2 hours at 25 °C. Progress of the reaction was monitored by LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get N-methyl-2,6-bis(trifluoromethyl)benzohydrazide 3 (0.450 g, 94.91%) which was used for the next step without further purification. LC-MS: 67.24%, m / z [M+H]+= 287.20. Step-3: (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-2,6- bis(trifluoromethyl)benzohydrazide: To a stirred solution of N-methyl-2,6-bis(trifluoromethyl)benzohydrazide 3 (0.475 g, 1.660 mmol) in ethanol (4.5 mL) was added 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde 4 (0.409 g, 1.826 mmol) at 25oC and stirred for 1 h. The reaction mixture was monitored by LCMS and after complete consumption of starting material, the reaction mixture was directly evaporated under reduced pressure to get the crude compound. The crude compound was purified by reverse phase prep HPLC to afford (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-2,6-bis(trifluoromethyl)benzohydrazide (0.405 g, 49.32%) as off-white solid. LC-MS: 98.85%, m / z [M+H]+= 493.22; HPLC purity: 99.45%;1H NMR (400 MHz, DMSO-d6) δ: 8.22 (d, J = 8.0 Hz, 2H), 8.17 (s, 1H), 8.01-7.96 (m, 3H), 7.66-7.40 (m, 3H), 3.53 (s, 3H). Prep HPLC method: Column: X-BRIDGE (19x150 mm) 5U; Mobile Phase A: 10 MM- Ammonium-bi-carbonate in water; Mobile Phase B: Acetonitrile; Gradient: METHOD (T / %B): 0 / 30, 10 / 40, 13 / 40, 13.01 / 98, 17.5 / 98, 17.51 / 30, 21 / 30; FLOW: 15 mL / minute. Example 2: Synthesis of (E)-2-chloro-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzylidene)-N-methyl-4-(trifluoromethyl) nicotinohydrazide: Step-1: tert-butyl (E)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-1- methylhydrazine-1-carboxylate (2): To a stirred solution of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzaldehyde 1 (0.500 g, 2.23 mmol) and tert-butyl 1-methylhydrazine-1-carboxylate (0.359 g, 2.45 mmol) in ethanol (2.0 mL) was added hydrochloric acid, 1N standard solution (0.211 mL) and stirred the reaction mixture at room temperature for 10 min. Progress of reaction was monitored by and LCMS. After completion of starting material, the reaction mixture was evaporated under reduced pressure to get crude mass of tert-butyl (E)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-1-methylhydrazine- 1-carboxylate 2 (0.700 g, 89.07%) as off-white solid which was used for the next step without further purification. LC-MS: 95.65%, m / z [M+H-56]+= 297.04. Step-2: (E)-2-(difluoromethyl)-5-(4-((2-methylhydrazineylidene)methyl)phenyl)-1,3,4- oxadiazole (3): To a stirred solution of tert-butyl (E)-2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzylidene)-1-methylhydrazine-1-carboxylate 2 (0.770 g, 2.185 mmol) in DCM (7.70 mL) was added 4N HCl in dioxane (7.70 mL) at room temperature and stirred for 1 h. Progress of reaction was monitored by LCMS. After completion of starting material, the reaction mixture was concentrated under reduced pressure to get (E)-2-(difluoromethyl)-5-(4-((2- methylhydrazineylidene)methyl)phenyl)-1,3,4-oxadiazole 3 (0.500 g, 90.71%) as of white -solid which was used for the next step without further purification. LC-MS: 95.04%, m / z [M+H]+= 253.02. Step-3: (E)-2-chloro-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzylidene)-N-methyl- 4-(trifluoromethyl) nicotinohydrazide: Thionyl chloride (10.0 mL, 0.406 mmol) was added to 2-chloro-4-(trifluoromethyl) nicotinic acid 4 (1.0 g, 4.434 mmol) in at 0oC under nitrogen and then stirred for 1 h at 60 °C. The reaction mixture was evaporated under reduced pressure. Then the residue was dissolved in DCM (10 mL). Then DIPEA (3.85 mL, 22.16 mmol), followed by (E)-2-(difluoromethyl)-5-(4-((2- methylhydrazineylidene)methyl)phenyl)-1,3,4-oxadiazole 3 (2.237 g, 8.867 mmol) in DCM (5 mL) was added to the reaction mixture at 0oC under nitrogen and stirred for 1 h at rt. Progress of reaction was monitored by LCMS. After complete consumption of starting material, the reaction mixture was diluted with DCM, then washed with cold water 20 mL, DCM layer was separated and dried over on anhydrous sodium sulphate, concentrated under reduced pressure to get crude compound. The crude compound was purified by normal phase silica-gel (100-200 mesh) column chromatography and eluted with 50% ethyl acetate in pet ether to afford (E)-2-chloro-N'-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-4-(trifluoromethyl) nicotinohydrazide (0.600 g, 29.44%) as off-white solid. LC-MS: 99.64%, m / z [M+H]+= 460.15; HPLC purity: 99.46%;1H NMR (400 MHz, DMSO-d6) δ: 8.84 (dd, J = 5.2 Hz, 0.4 Hz, 1H), 8.26 (s, 1H), 8.05-8.01 (m, 3H), 7.66-7.41 (m, 3H), 3.57 (s, 3H). Example 3: Synthesis of (E)-3-amino-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methyl-5-(trifluoromethyl)-1,2,4-triazine-6-carbohydrazide: To a stirred solution of 3-amino-N-methyl-5-(trifluoromethyl)-1,2,4-triazine-6-carbohydrazide 1 (0.06 g, 0.25 mmol) in ethanol (2.0 mL) and water (0.2 mL) were added acetic acid (0.1 mL) and 4- (5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzaldehyde 2 (0.063 g, 0.27 mmol) at room temperature. The resulting reaction mixture was stirred at 50 °C for 48 h. Progress of the reaction was monitored by LCMS. After complete consumption of starting material, reaction mixture was evaporated under reduced pressure to get crude (120 mg) compound. Crude compound was purified by reverse phase prep HPLC to afford (E)-3-amino-N'-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)benzylidene)-N-methyl-5-(trifluoromethyl)-1,2,4-triazine-6-carbohydrazide (0.020 g, 17 %) as an off white solid. LC-MS: 98.01%, m / z [M+H]+= 443.14; HPLC Purity: 98.67%;1H NMR (400 MHz, DMSO-d6) δ: 8.35 (br s, 2H), 8.22 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.67-7.42 (m, 3H), 3.57 (s, 3H). Prep HPLC method: Column: XSELECT-CSH-C18 (19 x 150 mm, 5µ), Mobile phase A: CO2in water, Mobile phase B: Acetonitrile, Flow: 15 ml / min, Method (T / % of B): 0 / 30, 2 / 35, 10 / 55, 11 / 55, 11.1 / 99, 13 / 99, 13.1 / 30, 17 / 30, Solubility: THF+ACN+H2O. Example 4: Synthesis of (E)-2-(Azetidin-3-yloxy)-6-chloro-N'-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)benzylidene)-N-methylbenzohydrazide: Step-1: tert-Butyl 3-(3-chloro-2-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate (2): To stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.02 g, 11.66 mmol) in DMF (20 mL) was added sodium hydride (0.38 g, 15.9 mmol) at 0 °C and stirred for 30 min. Then methyl 2-chloro-6-fluorobenzoate 1 (2.0 g, 10.6 mmol) was added into the reaction mixture and stirred for 2 h at rt. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with ice cold water (50 mL), extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to give crude tert-butyl 3-(3- chloro-2-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate 2 (2 g, 55%) as a colorless oil which was used in the next step without further purification. LC-MS: 32%, m / z [M+H]+= 342.03. Step-2: 2-((1-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)-6-chlorobenzoic acid (3): To a stirred solution of tert-butyl 3-(3-chloro-2-(methoxycarbonyl)phenoxy)azetidine-1- carboxylate 2 (2.0 g, 5.85 mmol) in methanol (20 mL) and water (4 mL) was added lithium hydroxide (0.7 g, 17.55 mmol) and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated to get crude compound, which was dissolved in water adjusted pH~1 with citric acid and the solid precipitated out was filtered and dried to get 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-chlorobenzoic acid 3 (1 g, 52%) as an off white solid. LCMS: 90%, m / z [M+H]+= 328.04. Step-3: tert-Butyl 3-(2-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-3- chlorophenoxy)azetidine-1-carboxylate (5): To a stirred solution of 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-chlorobenzoic acid 3 (1 g, 3.05 mmol) and tert-butyl 2-methylhydrazine-1-carboxylate 4 (0.44 g, 3.05 mmol) in DMF (10 mL) were added 1-hydroxybenzotriazole (0.41 g, 3.05 mmol) and HBTU (1.15 g, 3.05 mmol) and DIPEA (1.06 mL, 6.1 mmol) at 0oC. The resulting reaction mixture was stirred for 16 h at rt. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water (50 mL) and the solid precipitated was filtered and dried to get tert- butyl 3-(2-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-3-chlorophenoxy)azetidine- 1-carboxylate 5 (0.8 g, crude) as an off white solid. LCMS: 57.15%, m / z 456.11 [M+H]+. Step-4: 2-(Azetidin-3-yloxy)-6-chloro-N-methylbenzohydrazide (6): To a stirred solution of tert-butyl 3-(2-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-3- chlorophenoxy)azetidine-1-carboxylate 5 (1.0 g, 2.19 mmol) in DCM (10 mL) was added 4M HCl in dioxane (10 mL) at 0 °C and stirred for 2 h at rt. The progress of the reaction was monitored by TLC. The reaction mixture was directly concentrated under reduced pressure to afford 2-(azetidin- 3-yloxy)-6-chloro-N-methylbenzohydrazide 6 (0.5 g, crude) as a red color oil, which was used in the next step without purification. LCMS: 14%, m / z 256.17 [M+H]+Step-5: (E)-2-(Azetidin-3-yloxy)-6-chloro-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methylbenzohydrazide (Example 4):

[0032] A solution of 2-(azetidin-3-yloxy)-6-chloro-N-methylbenzohydrazide (0.3 g, 1.17 mmol) in EtOH (3 mL) was added 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde (0.26 g, 1.17 mmol) at rt. The resulting reaction mixture was stirred at rt for 1 h. After complete consumption of starting material, ethanol was evaporated under reduced pressure to afford crude compound, which was purified by reverse phase prep-HPLC to afford (E)-2-(azetidin-3-yloxy)-6-chloro-N'-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methylbenzohydrazide (105 mg, 19.6%) as an off-white solid. LC-MS: 97.18%, m / z 462.40 [M+H]+: HPLC: 96.06%:1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.66–7.37 (m, 4H), 7.13 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.99–4.96 (m, 1H), 3.66–3.56 (m, 1H), 3.52 (s, 3H), 3.39–3.72 (m, 1H), 3.240–3.20 (m, 2H). Examples 5, 6, 7, and 8: Synthesis of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) picolinaldehyde (Intermediate-7):

[0033] Step-1: 6-Bromonicotinohydrazide (2): To a stirred solution of methyl 6-bromonicotinate 1 (20 g, 92.58 mmol) in methanol (200 mL), was added hydrazine hydrate (5.96 g, 181.15 mmol) at rt. The resulting reaction mixture was stirred for 16 h at 25 °C. After complete consumption of starting material. The reaction mixture was cooled to 0 °C, solid was precipitated and was filtered to give 6-bromonicotinohydrazide 2 (11 g, 55.0%) as an off white solid. LCMS: 76.09%, m / z 216.03 [M+H]+. Step-2: 2-(6-Bromopyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (4): To a stirred solution of 6-bromonicotinohydrazide 2 (4 g, 18.52 mmol) in DMF (30 mL) was added 2,2-difluoroacetic anhydride 3 (3.87 g, 22.22 mmol) at 25 °C. The resulting reaction mixture was heated for 16 h at 110 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was quenched with ice cold water (100 mL), extracted with ethyl acetate (2 x 150 mL), combined organic layer was dried over Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by column chromatography, product was eluted at 15-20% ethyl acetate in pet ether to afford 2- (6-bromopyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (2.5 g, 48.91%) as an off white solid. LC-MS: 80.14%, m / z [M+H]+=278.02. Step-3: 2-(Difluoromethyl)-5-(6-vinylpyridin-3-yl)-1,3,4-oxadiazole (6): To a stirred solution of 2-(6-bromopyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (2.5 g, 9.05 mmol) in 1, 4-dioxane (30 mL), were added tributyl(vinyl)stannane 5 (4.83 g, 15.22 mmol) at rt. The reaction mixture was degassed with N2under stirring for 10 minutes. Later bis(triphenylphosphine)palladium chloride (0.71 g, 1.01 mmol) was added to the reaction mixture at rt. The resulting reaction mixture was again degassed with N2for an additional 5 mints and heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was cooled to rt and filtered over celite pad, filtrated was diluted with EtOAc (100 mL), washed with ice cold water (2 x 100 mL), organic layer dried over anhydrous Na2SO4,and concentrated under reduced pressure to give crude compound, which was purified by silica gel column chromatography, eluted using 30% ethyl acetate in hexane to afford 2-(difluoromethyl)-5-(6-vinylpyridin-3-yl)-1,3,4-oxadiazole 6 (1.1 g, 54.42%) as a color less liquid. LCMS: 79.41%, m / z 224.02 [M+H]+. Step-4: 5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl) picolinaldehyde (Int-7): To a stirred solution of 2-(difluoromethyl)-5-(6-vinylpyridin-3-yl)-1,3,4-oxadiazole 6 (1.1 g, 4.93 mmol) in dioxane (20 mL) and water (6 mL), were added osmium tetroxide (4% in water) (0.627 g, 2.46 mmol) and 2,6 lutidine (2.12 g, 19.72 mmol) at rt. The reaction mixture was stirred 30 mints, then sodium periodate (3.16 g, 14.48 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was quenched with water (100 mL), extracted with EtOAc (2 x 250 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get the 5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)picolinaldehyde (Intermediate) (0.41 g, 36.57%) as a brown color solid. LCMS: 88.47%, m / z 225.97 [M+H]+;1H NMR (400 MHz, CDCl3) δ: 10.17 (d, J = 0.8 Hz, 1H), 9.52 (dd, J = 2.0 Hz, 0.8 Hz, 1H), 8.61-8.59 (m, 1H), 8.15 (dd, J= 8.4 Hz, 0.8 Hz, 1H), 6.97 (t, J = 51.6 Hz, 1H). Example 5: Synthesis of (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methylene)-2-methoxy-N-methylbenzohydrazide:

[0034] Step-1: tert-Butyl 2-(2-methoxybenzoyl)-2-methylhydrazine-1-carboxylate (3): To a stirred solution of 2-methoxybenzoic acid 1 (2 g, 13.14 mmol) in DCM (30 mL) was added thionyl chloride (5 mL) in 0 °C. The resulting reaction mixture was heated at 70 °C for 1 h. After complete consumption of starting material, the reaction was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in DCM (5 mL) were added DIPEA (5.10 g, 39.43 mmol) and tert-butyl 2-methylhydrazine-1-carboxylate 2 (2.30 g, 15.77 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 25 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold water (50 mL), extracted with DCM (2 x 50 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound, which was purified by silica gel column chromatography (eluent: 0 - 40% ethyl acetate in petroleum ether) to give tert-butyl 2-(2- methoxybenzoyl)-2-methylhydrazine-1-carboxylate 3 (2 g, 54.28%) as a pale-yellow liquid. LCMS: 85.22%, m / z 281.40 [M+H]+. Step-2: 2-Methoxy-N-methylbenzohydrazide (4): To a stirred solution of tert-butyl 2-(2-methoxybenzoyl)-2-methylhydrazine-1-carboxylate 3 (1.0 g, 3.57 mmol) in DCM (20 mL) was added 4.0 M HCl in dioxane (10 mL) at 0 °C. The resulting reaction mixture was stirred for 2 h at rt. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the 2-methoxy-N-methylbenzohydrazide 4 (0.6 g, crude) as an off white solid. The crude compound was directly used in the next step without purification. LCMS: 70.59%, m / z 181.03 [M+H]+. Step-3: (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methylene)-2- methoxy-N-methylbenzohydrazide (Example 5): To a stirred solution of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)picolinaldehyde 4 (0.35 g, 1.55 mmol) in Ethanol (10 mL), was added 2-methoxy-N-methylbenzohydrazide (0.42 g, 2.33 mmol) at RT. The resulting reaction mixture was stirred at room temperature for 1h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the crude compound, which was purified by using PrepHPLC to give (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin- 2-yl) methylene)-2-methoxy-N-methylbenzohydrazide(0.205 g, 33.22%) as an off white solid. LCMS: 98.20%, m / z 388.18 [M+H]+; HPLC: 99.13%;1H NMR (400 MHz, DMSO-d6) δ: 9.19 (t, J = 2.0 Hz, 1H), 8.35 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.96 (s, 1H), 7.69-7.43 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.05-7.01 (m, 1H), 3.72 (s, 3H), 3.52 (s, 3H). Example 6: Synthesis of (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methylene)-4-methoxy-N-methylnicotinohydrazide (Example 6):

[0035] Step-1: tert-Butyl 2-(4-methoxynicotinoyl)-2-methylhydrazine-1-carboxylate (3): To a stirred solution of 4-methoxynicotinic acid 1 (2 g, 13.06 mmol) in DCM (30 mL) was added thionyl chloride (10 mL) at 0 °C. The resulting reaction mixture was heated for 1 h at 75 °C. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to give crude acid chloride. The resulting crude acid chloride was dissolved in DCM (5 mL), were added DIPEA (5.067 g, 39.18 mmol) and tert-butyl 2-methylhydrazine-1- carboxylate 2 (2.291 g, 15.67 mmol) at 0 °C and stirred for 1 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL), extracted with DCM (2 x 250 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound, which was purified by silica gel column chromatography (eluent: 0 - 40% ethyl acetate in petroleum ether) to get tert-butyl 2-(4- methoxynicotinoyl)-2-methylhydrazine-1-carboxylate 3 (1.2 g, 32.66%) as a pale-yellow liquid. LCMS: 72.41%, m / z 282.32 [M+H]+. Step-2: 4-Methoxy-N-methylnicotinohydrazide (4): To a stirred solution of tert-butyl 2-(4-methoxynicotinoyl)-2-methylhydrazine-1-carboxylate 3 (1.2 g, 4.27 mmol) in DCM (20 mL) was added 4.0 M HCl in dioxane (12 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the 4-methoxy-N- methylnicotinohydrazide (0.7 g, crude) as an off white solid. The crude compound was directly used in the next step without purification. LCMS: 59.96%, m / z 182.03 [M+H]+. Step-3: (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methylene)-4- methoxy-N-methylnicotinohydrazide (Example 6): To a stirred solution of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)picolinaldehyde 4 (0.35 g, 1.55 mmol) in ethanol (10 mL), was added 2-methoxy-N-methylbenzohydrazide (0.42 g, 2.33 mmol) at rt. The resulting reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the crude compound, which was purified by using reverse phase prep HPLC to obtain (E)-N'-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methylene)-4-methoxy-N-methylnicotinohydrazide (Example 6) (0.220 g, 31.9%) as an off white solid. LCMS: 98.20%, m / z 387.34 [M+H]+; HPLC: 97.70%;1H NMR (400 MHz, DMSO-d6) δ: 9.20 (dd, J = 2.0 Hz, 0.8 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.40-8.37 (m, 2H), 8.01 (s, 1H), 7.59 (t, J=51.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 3H). Example 7: Synthesis of (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methylene)-N-methyl-5-(trifluoromethyl)nicotinohydrazide: Step-1 tert-Butyl 2-methyl-2-(5-(trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate (3): To a stirred solution of 5-(trifluoromethyl)nicotinic acid 1 (2 g, 10.46 mmol) in DCM (30 mL) was added thionyl chloride (10 mL) in 0 °C. The resulting reaction mixture was heated for 1h at 75 °C. After complete consumption of starting material, the reaction was concentrated under reduced pressure to give crude acid chloride. The crude acid chloride was dissolved in DCM (5 mL), were added DIPEA (4.06 g, 31.39 mmol) and tert-butyl 2-methylhydrazine-1-carboxylate 2 (1.83 g, 12.56 mmol) at 0 °C. The resulting mixture was stirred for 1h at 25 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL), extracted with DCM (3 x 50 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound, which was purified by silica column chromatography (eluent: 0-40% ethyl acetate in petroleum ether) to get tert-butyl 2-methyl-2-(5- (trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate 3 (2g, 59.86%) as a pale yellow liquid. LCMS: 84.0%, m / z 320.38 [M+H]+. Step-2: N-methyl-5-(trifluoromethyl)nicotinohydrazide (4): To a stirred solution of tert-butyl 2-methyl-2-(5-(trifluoromethyl)nicotinoyl)hydrazine-1- carboxylate 3 (1.0 g, 3.13 mmol) in DCM (20 mL) was added 4.0 M HCl in dioxane (10 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the 5-(difluoromethyl)- N-methyl- 5-(trifluoromethyl)nicotinohydrazide 4 (0.65 g, crude) as an off white solid. The crude compound was directly used in the next step without purification. LCMS: 59.20%, m / z 220.01 [M+H]+. Step-3: (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methylene)-N- methyl-5-(trifluoromethyl)nicotinohydrazide (Example 7):

[0036] To a stirred solution of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)picolinaldehyde 5 (0.33 g, 1.46 mmol) in ethanol (10 mL), was added N-methyl-6-(trifluoromethyl)nicotinohydrazide 4 (0.64 g, 2.93 mmol) at rt. The resulting reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the crude compound, which was purified by reverse phase prep HPLC to obtain (E)-N'-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methylene)-N-methyl-5-(trifluoromethyl)nicotinohydrazide (Example 7) (0.220g, 34.4%) as an off white solid. LCMS: 98.25%, m / z 426.307 [M+H]+; HPLC: 99.09%;1H NMR (400 MHz, DMSO-d6) δ: 9.24 (dd, J = 0.8 Hz, 2.4 Hz, 1H), 9.15 (dd, J = 4.4 Hz,1.6 Hz, 2H), 8.52 (s, 1H), 8.40 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.12 (s, 1H), 7.70-7.45 (m, 2H), 3.60 (s, 3H). Example 8: Synthesis of (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methylene)-N-methyl-6-(trifluoromethyl)nicotinohydrazide (Example 8):

[0037] Step-1: tert-Butyl 2-methyl-2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate (3): To a stirred solution of 6-(trifluoromethyl)nicotinic acid 1 (2 g, 10.46 mmol) in DCM (30 mL) was added thionyl chloride (10 mL) in 0 °C. The resulting reaction mixture was heated for 1 h at 70 °C. After complete consumption of starting material, the reaction was concentrated under reduced pressure to give crude acid chloride. The crude acid chloride was dissolved in DCM (5 mL), were added DIPEA (4.06 g, 31.39 mmol) and tert-butyl 2-methylhydrazine-1-carboxylate 2 (1.83 g, 12.56 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 25 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was quenched with ice cold water (100 mL), extracted with DCM (2 x 50 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound, which was purified by silica column chromatography (eluent: 0-40% ethyl acetate in petroleum ether) to get tert-butyl 2-methyl-2-(6- (trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate 3 (1.8 g, 76.21%) as a ash color solid. LCMS: 76.21%, m / z 320.34 [M+H]+. Step-2: N-methyl-6-(trifluoromethyl)nicotinohydrazide (4): To a stirred solution of tert-butyl 2-methyl-2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1- carboxylate 3 (1.0 g, 3.13 mmol) in DCM (20 mL), was added 4.0 M HCl in dioxane (10 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the N-methyl-6-(trifluoromethyl) nicotinohydrazide 4 (0.65 g, crude) as a light-yellow solid. The crude compound was directly used in the next step without further purification. LCMS: 75.23%, m / z 220.12 [M+H]+. Step-3: (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methylene)-N- methyl-6-(trifluoromethyl)nicotinohydrazide (Example 8): To a stirred solution of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)picolinaldehyde 5 (0.4 g, 1.78 mmol) in ethanol (10 mL), was added 4-formyl-N-hydroxybenzamide 5 (0.78 g, 3.55 mmol) at rt. The resulting reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get the crude compound, which was purified by reverse phase prep HPLC to obtain (E)-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methylene)-N-methyl-6-(trifluoromethyl)nicotinohydrazide (Example 8) (0.287 g, 38.29%) as an off white solid. LCMS: 99.43%, m / z 427.20 [M+H]+; HPLC: 99.43%;1H NMR (400 MHz, DMSO-d6) δ: 9.24 (t, J = 1.2 Hz 1H), 9.02 (d, J = 1.2 Hz, 1H), 8.44 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.37 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.70-7.44 (m, 2H), 3.60 (s, 3H). Example 9: Synthetic Scheme of (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methyl-5-(trifluoromethyl)nicotinohydrazide (Example 9): Step-1: 2-(Difluoromethyl)-5-(p-tolyl)-1,3,4-oxadiazole (3): To a stirred solution of 4-methylbenzohydrazide 1 (20 g, 133.17 mmol) in DMF (200 mL) was added 2,2-difluoroacetic anhydride (47.94 mL, 399.52 mmol) at room temperature. The resulting reaction mixture was stirred for 12 h at 70 °C. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was allowed to cool to rt and quenched with ice water (100 mL) and extracted with diethyl ether (2 x 100 mL). The combined organic layer was washed ice cold water (2 x 200 mL) and dried over anhydrous Na2SO4, concentrated under reduced pressure to get the crude compound. The crude compound was purified by column chromatography (100-200 mesh silica gel, 10% EtOAc in pet ether as an eluent) to obtain 2-(difluoro methyl)-5-(p-tolyl)-1, 3,4-oxadiazole 3 (7.8 g, 34%) as an off white solid. LCMS purity: 99%; m / z [M+H]+= 211.07;1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.90 (t, J = 51.6 Hz, 1H), 2.45 (s, 3H). Step-2: 2-(4-(Bromomethyl) phenyl)-5-(difluoro methyl)-1,3,4-oxadiazole (4): To a stirred solution of 2-(difluoro methyl)-5-(p-tolyl)-1, 3, 4-oxadiazole 3 (6 g, 28.54 mmol) in CCl4(60 mL) were added N-bromo succinimide (6.60 g, 37.11 mmol) and AIBN (0.93 g, 0.571 mmol) at 0 °C. The resulting reaction mixture was stirred at 80 °C for 12 h. After complete consumption of starting material, the reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get crude. The crude was purified by column chromatography (230-400 mesh silica gel, ~0-20% ethyl acetate in pet ether as an eluent) to obtain 2-(4-(bromomethyl) phenyl)-5-(difluoro methyl)-1,3,4- oxadiazole 4 (6.5 g, 78%) as a white solid. LCMS purity: 98.36%; m / z [M+H]+= 289.11;1H NMR (500 MHz, CDCl3) δ: 8.10 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 6.92 (t, J = 52.0 Hz, 1H), 4.53 (s, 2H). Step-3: 4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl) benzaldehyde (5): To a stirred solution of 2-(4-(bromomethyl) phenyl)-5-(difluoro methyl)-1,3,4-oxadiazole 4 (6.5 g, 20.76 mmol) in DMSO (65 mL) was added 4-methylmorpholine N-oxide (12.14 g, 89.94 mmol) at room temperature. The resulting reaction mixture was stirred rt for 12 h. After complete consumption of starting material, the reaction mixture was quenched with water (100 mL) and extracted with diethyl ether (2 x 30 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude. The compound was purified by flash column chromatography (230-400 mesh silica gel, ~10-15 % ethyl acetate in pet ether as an eluent) to afford 4-(5-(difluoro methyl)-1,3,4-oxadiazol- 2-yl) benzaldehyde 5 (1.5 g, 29.76%) as a white solid. LC-MS purity: 93%, m / z [M+H]+= 225.02;1H NMR (400 MHz, CDCl3) δ: 10.13 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 51.6 Hz, 1H). Step-4: (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-5- (trifluoromethyl)nicotinohydrazide (Example 9): To a stirred solution of N-methyl-5-(trifluoromethyl)nicotinohydrazide 6 (400 mg, 1.82 mmol) in mixture of ethanol (4.0 mL) and water (1.0 mL), was added 4-(5-(difluoro methyl)-1,3,4- oxadiazol-2-yl) benzaldehyde 5 (409.12 mg, 1.82 mmol). The resulting reaction mixture was stirred for 1 h at room temperature (formation of white solid was observed). The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the resultant solid was filtered through the bucker funnel and washed with water (2 x 2 mL). The solid was dried under vacuum to obtain (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-5-(trifluoromethyl)nicotinohydrazide (Example 9) (391 mg, 45%) as a white solid. LC- MS purity: 99%; m / z [M+H]+= 426.18; HPLC purity: 98.86%;1H NMR (400 MHz, DMSO-d6) δ: 8.11 (dd, J = 1.6 Hz, J = 1.6 Hz, 2H), 8.48 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 51.6 Hz, 1H), 3.56 (s, 3H). Examples 10, 11, 12, and 13: General scheme:

[0038]

[0039] General Procedure for Preparation of Compound 2: To a solution of compound 1 (60.0 g, 365 mmol, 1.00 eq) in MeOH (300 mL) was added TsOH (6.29 g, 36.5 mmol, 0.10 eq) and 2,2-dimethoxypropane (76.1 g, 731 mmol, 89.6 mL, 2.00 eq). The mixture was stirred at 20 °C for 2 hrs. LCMS (ET84553-1-P1A1) and TLC (Petroleum ether / Ethyl acetate = 2 / 1) showed the mixture was completed. The reaction mixture was poured in 500 mL aq.NaHCO3. The residue was diluted with H2O 500 mL and extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine 500 mL, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. After concentration, the crude product was used directly for the next step without purification. Compound 2 (84.0 g, crude) was obtained as yellow oil. General procedure for Preparation of Compound 3: To a solution of compound 2 (78.0 g, 371 mmol, 1.00 eq) in MeOH (400 mL) was added NH2NH2.H2O (66.8 g, 1.31 mol, 64.7 mL, 98% purity, 3.53 eq) under N2. The mixture was stirred at 60 °C for 2 hrs. TLC (Petroleum ether / Ethyl acetate = 2 / 1) showed the mixture was completed. The mixture was concentrated 2 / 3 MeOH, The residue was diluted with EtOAc 500 mL. The combined organic layers were washed with brine 500 mL*2, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. After concentration, the crude product was used directly for the next step without purification. Compound 3 (75.0 g, 357 mmol, 96.1% yield) was obtained as a white solid. General procedure for Preparation of Compound 4: To a solution of compound 3 (20.0 g, 95.1 mmol, 1.00 eq) in THF (160 mL) was added Et3N (48.1 g, 476 mmol, 66.2 mL, 5.00 eq) and (2,2-difluoroacetyl) 2,2-difluoroacetate (49.7 g, 285 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 80 °C for 1 hr. LCMS and TLC (Petroleum ether / Ethyl acetate = 3 / 1) showed the mixture was completed. The reaction mixture was diluted with H2O 100 mL and extracted with EtOAc (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 0 / 1). Compound 4 (24.0 g, 88.8 mmol, 93.3% yield) was obtained as colorless oil. General procedure for preparation of compound 5: To a solution of compound 4 (24.0 g, 88.8 mmol, 1.00 eq) in THF (150 mL) was added HCl (3 M, 148 mL, 5.00 eq). The mixture was stirred at 20 °C for 1 hr. LCMS and TLC (Petroleum ether / Ethyl acetate = 2 / 1) showed the mixture was completed. The mixture was adjusted to pH = 8 by aq.NaHCO3, and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine 200 mL, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 0 / 1). Compound 5 (12.0 g, 53.5 mmol, 60.2% yield) was obtained as a white solid. General procedure for preparation of compound 6 To a solution of compound 5 (11.0 g, 49.0 mmol, 1.00 eq) in MeOH (60.0 mL) was added methylhydrazine (6.67 g, 57.9 mmol, 7.62 mL, 1.18 eq) under N2. The mixture was stirred at 20 °C for 2 hrs. TLC (Petroleum ether / Ethyl acetate = 2 / 1) showed the mixture was completed. The mixture was concentrated 2 / 3 of MeOH, filtered and washed with MeOH 10.0 mL * 3. After concentration, the crude product was used directly for the next step without purification. Compound 6 (9.00 g, 35.7 mmol, 72.7% yield) was obtained as a yellow solid. General procedure for preparation of the title compounds: To a solution of 4-(trifluoromethyl)pyridine-3-carboxylic acid (400 mg, 2.09 mmol, 1.00 eq) and compound 6 (422 mg, 1.67 mmol, 0.80 eq) in DCM (10.0 mL) was added NMI (361 mg, 4.40 mmol, 350 μL, 2.10 eq) and TCFH (881 mg, 3.14 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. TLC (Petroleum ether / Ethyl acetate = 2 / 1) and LCMS showed the mixture was completed. The reaction mixture was diluted with H2O 10.0 mL and extracted with DCM (10.0 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1, 0 / 1). The crude product was triturated with MeOH 5.00 mL at 20 °C for 30min. The analytical information for Examples 10, 11, 12, and 13 is provided in the table below: Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, METHANOL-d4) δ = 8.13 - 8.01 (m, 3H), 375.1 7.66 (d, J = 8.4 Hz, white solid [M+H]+ 2H), 7.62 - 7.45 (m, 100% 2H), 7.40 - 7.06 (m, RT = 2.630 3H), 3.61 (s, 3H) Example 10 1H NMR (400 MHz, METHANOL-d4) δ = 8.08 - 7.96 (m, 3H), 425.1 7.86 - 7.65 (m, 3H), yellow [M+H]+ 7.57 - 7.45 (m, 3H), solid 100% 7.22 (t, J = 51.7 Hz, RT = 2.738 1H), 3.61 (s, 3H) Example 11 1H NMR (400 MHz, METHANOL-d4) δ = 8.13 - 7.97 (m, 3H), 407.1 7.79 - 7.45 (m, 6H), white solid [M+H]+ 7.22 (t, J = 51.7 Hz, 97.61% 1H), 6.82 (t, J = 55.7 RT = 2.681 Hz, 1H), 3.62 (s, 3H) Example 12 1H NMR (400 MHz, METHANOL-d4) δ = 8.93 (d, J = 5.3 Hz, 1H), 8.78 (s, 1H), 8.12 Li 426.1 (s, 1H), 8.04 (d, J = 8.4 ght [M+ 2H), 7.87 (d, J = yel H]+ Hz, low 4 Hz, 1H), 7.56 (d, J s 100% 5. olid RT = 2.531 = 8.4 Hz, 2H), 7.22 (t, Example 13 J = 51.7 Hz, 1H), 3.64 (s, 3H) Example 14: Synthesis of (E)-5-cyclopropyl-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methylene)-N-methyl-1,2,4-triazine-6-carbohydrazide Step 1: To a solution of 1 (90.0 g, 576 mmol, 1 eq) in ACN (900 mL) was added TEA (175 g, 1.73 mol, 241 mL, 3 eq). TsN3(182 g, 692 mmol, 75.0% purity, 1.2 eq) was added dropwise into above mixture. The mixture was stirred at 25°C for 5 hrs. LC-MS showed 1 was consumed and one main peak with desired mass was detected. The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 5 / 1). The desired product 2 (78.0 g, 428 mmol, 74.3% yield) was obtained as yellow oil. Step 2: To a solution of 2 (20.0 g, 110 mmol, 1 eq) in THF (200 mL) was added PPh3 (30.2 g, 115 mmol, 1.05 eq). The mixture was stirred at 25°C for 16hrs. LC-MS showed 2 was consumed and one main peak with desired mass was detected. The organic layers were concentrated under reduced pressure to give a residue. The desired product 3 (48.0 g, crude) was obtained as yellow solid. Step 3: To a solution of 3 (48.0 g, 108 mmol, 1 eq) in EtOH (240 mL) and H2O (240 mL). The mixture was stirred at 80°C for 2 hrs. LC-MS showed 3 was consumed and one main peak with desired mass was detected. The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1). The desired product 4 (13.0 g, 70.6 mmol, 65.4% yield) was obtained as yellow solid. Step 4:

[0040] To a solution of 4 (13.0 g, 70.6 mmol, 1 eq) in THF (130 mL) DMFDMA (16.8 g, 141 mmol, 18.8 mL, 2 eq) was added. The mixture was stirred at 65°C for 3 hrs. LC-MS showed 4 was consumed and one main peak with desired mass was detected. The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1). The desired product 5 (13.0 g, 54.3 mmol, 77.0% yield) was obtained as yellow solid. Step 5: To a solution of 5 (8.00 g, 33.4 mmol, 1 eq) in AcOH (80.0 mL) CH3COONH4(5.15 g, 66.9 mmol, 2 eq) was added. The mixture was stirred at 80°C for 1 hrs. LC-MS showed 5 was consumed and one main peak with desired mass was detected. The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 5 / 1). The desired product 6 (13.0 g, 54.3 mmol, 77.0% yield) was obtained as yellow solid. Step 6:

[0041] 6 (600 mg, 3.11 mmol, 1.00 eq) and Cpd.A01 (786 mg, 3.11 mmol, 1.00 eq) were added into THF (4.20 mL). AlMe3 (2 M, 3.11 mL, 2.00 eq) was added. The mixture was stirred at 25 °C for 1 hr. LC-MS showed Cpd.6 was consumed and one main peak with desired mass was detected. The reaction was quenched by NH4Cl aqueous solution (10.0 mL) and extract with EtOAc (8.00 mL*3). The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*50mm*10µm; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 25%-65% B over 10.0 min). The tile compound (Example 14) was obtained (300 mg, 749 μmol, 24.1% yield) as a light yellow solid. LC-MS: 401.1, [M+H]+ 99.1% RT = 2.218.1H NMR: (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.23 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 2.1, 8.4 Hz, 1H), 8.16 (s, 1H), 7.57 (t, J = 51.2 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 3.67 (s, 3H), 2.03 - 1.89 (m, 1H), 1.29 - 1.05 (m, 4H) Example 15: Synthesis of (E)-6-cyclopropyl-N'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methylene)-N-methyl-1,2,4-triazine-5-carbohydrazide

[0042] Step 1: To a solution of 1 (200 g, 945 mmol, 1 eq) in EtOH (2000 mL) and Tol. (2000 mL) was added EtONa (326 g, 945 mmol, 20% purity, 1 eq) and stirred at 25 °C for 30 min. Concentrated the reaction mixture under reduced pressure to give a residue and added toluene (2000 mL). Added DMF-DMA (147 g, 1.23 mol, 163mL, 1.3 eq) to the mixture, then stirred at 110oC for 30 min and stirred at 25°C for 16 h. LC-MS showed Cpd.1 was consumed completely and desired mass was detected. Concentrated the reaction mixture under reduced pressure to give a residue. Obtained 2 (400 g, crude) was as a yellow solid. Step 2: To a solution of 2 (218 g, 947 mmol, 1 eq) in EtOH (2000 mL) was addedhydrazine hydrochloride (97.3 g, 1.42 mol, 1.5 eq). Stir the mixture at 60 °C for 2 hrs. Filter the reaction mixture and concentrated under reduced pressure to give a residue. Obtain 3 (500 g, crude) as a white solid. Step 3: To a solution of 3 (11.3 g, 66.0 mmol, 1eq) in EtOH (400 mL) was added PhI(OAc)2(23.4 g, 72.6 mmol, 1.1eq). Stir the mixture at 25 °C for 3hrs. Concentrate the reaction mixture under reduced pressure to give a residue. Purify the residue by column chromatography (SiO2, DCM: MeOH = 10:1). Obtain 4 (10.5 g, 62.1 mmol, 94.0% yield) as a yellow gum. Step 4: To a solution of 4 (7.42 g, 43.8 mmol, 1eq) in MeCN (140 mL) was added POBr3(25.2g, 87.7 mmol, 8.92 mL, 2 eq), then stirred at 85 °C for 5 hrs. Quench the reaction mixture by addition H2O 20 mL at 25°C, then add NaHCO3to the mixture till pH 7 and extract with EtOAC 3*10 mL, concentrate the combined organic layers under reduced pressure to give a residue. Obtain 5 (3.5 g, 15.1 mmol, 34.4% yield) was as a yellow oil. Step 5: A mixture of 5 (3.54 g, 15.3 mmol, 1 eq), potassium;cyclopropyl(trifluoro)boranuide (3.39 g, 22.9 mmol, 1.5 eq), tripotassium;phosphate (9.72 g, 45.8 mmol, 3 eq), Pd(dppf)Cl2(1.12 g, 1.53 mmol, 0.1 eq) and in Tol. (40 mL) was degassed and purged with N2for 3 times. Stir the mixture at 100 °C for 16 hrs under N2 atmosphere. Quench the reaction mixture by addition H2O 50 mL at 25°C, extract with EtOAc (30 mL * 2). Concentrate the combined organic layers under reduced pressure to give a residue. Purify the residue by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1to 3 / 1). Obtain 6 (0.8 g, 4.14 mmol, 27.1% yield) as a white solid. Step 6: To a solution of 6 (0.5 g, 2.59 mmol, 1 eq) andA01 (655 mg, 2.59 mmol, 1 eq) in THF (10 mL) was added AlMe3 (2 M, 2.59 mL, 2 eq) at 25°C. Stir the mixture at 50°C for16 hrs. Quench the reaction mixture by addition NH4Cl 3 mL at 25°C, and extract with DCM (5 mL * 3). Concentrate the combined organic layers under reduced pressure to give a residue. Purify the residue by prep- HPLC (neutral condition;column: Waters Xbridge BEH C18 250*50mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-55% B over 10.0 min). Obtain Example 15 (0.415 g, 1.04 mmol, 40.1% yield) as a white solid. LC-MS: 401.1, [M+H]+, 98.1%, RT = 2.1071H NMR (400 MHz, DMSO-d6); δ 1.01 - 1.16 (m, 2 H) 1.19 - 1.28 (m, 2 H) 1.94 - 2.06 (m, 1 H) 3.59 - 3.73 (m, 3 H) 7.21 - 7.36 (m, 1 H) 7.40 - 7.79 (m, 1 H) 8.13 - 8.26 (m, 1 H) 8.36 - 8.48 (m, 1 H) 9.15 - 9.34 (m, 1 H) 9.62 - 9.82 (m, 1 H). Example 16, Example 17, Example 18, and Example 19:

[0043] Step 1: To a solution of compound 1 (23.0 g, 98.2 mmol) in THF (90 mL), MeOH (90 mL) and H2O (50 mL) was added LiOH-H2O (12.3 g, 294 mmol). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 1 was consumed completely and desired mass was detected. The reaction was quenched with 1N HCl (100 mL) and extracted with EtOAc (150 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The crude product was used into the next step without further purification. Compound 2 (21.7 g, crude) was obtained as a white solid. LCMS: (product: RT = 0.254 mins) Step 2: To a solution of compound 2 (21.7 g, 98.6 mmol) in THF (220 mL) was added HATU (45.0 g, 118 mmol) and DIEA (25.5 g, 197 mmol) under N2. After stirring for 30 mins, BocNHNH2(15.6 g, 118 mmol) was added to the mixture. The mixture was stirred at 25 °C for 16 hr. LC-MS showed compound 2 was consumed completely and desired mass was detected. The reaction was quenched with H2O (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~31% THF / Petroleum ether @ 100 mL / min). Compound 3 (30.0 g, 91.0% yield) was obtained as a white solid. Step 3: To a solution of compound 3(30.0 g, 89.7 mmol) in DCM (320 mL) was added TFA (150 mL). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 3 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove TFA. The crude product was used into the next step without further purification. Compound 4 (32.0 g, crude, TFA salt) was obtained as a white solid. LCMS: (product: RT = 0.319 mins) Step 4: A solution of compound 4 (32.0 g, 91.9 mmol, TFA) in DCM (700 mL) was treated with Imidazole (31.3 g, 459 mmol), and then (2,2-difluoroacetyl) 2,2-difluoroacetate (64.0 g, 367 mmol) was added to the mixture. The mixture was stirred at 40 °C for 16 hr. LC-MS showed compound 4 was consumed completely and desired mass was detected. The reaction was quenched with aq NaHCO3 (150 mL) and extracted with DCM (200 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~26% THF / Petroleum ether @ 100 mL / min). Compound 5 (21.0 g, 77.6% yield) was obtained as a white solid. LCMS: (product: RT = 0.362 mins) Step 6: To a solution of compound 5 (20.3 g, 69.0 mmol) in dioxane (160 mL) and H2O (25 mL) was added vinyl-BF3K (13.8 g, 103 mmol), K2CO3 (23.8 g, 172 mmol) and Pd(dppf)Cl2 (5.05 g, 6.90 mmol) under N2. The mixture was stirred at 100 °C for 16 hr under N2atmosphere. LC-MS showed compound 5 was consumed completely and desired mass was detected. The reaction was quenched with H2O (200 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~15% THF / Petroleum ether @ 100 mL / min). Compound 6 (12.6 g, 75.6% yield) was obtained as a white solid. LCMS: (product: RT = 0.381 mins) Step 7: To a solution of compound 6 (2.60 g, 10.7 mmol) in THF (20 mL) and H2O (20 mL) was added NaIO4(11.5 g, 53.9 mmol, 2.99 mL) and K2OsO4-2H2O (198.0 mg, 539.0 μmol). The mixture was stirred at 25 °C for 1.5 hr. LC-MS showed compound 6 was consumed completely and desired mass was detected. The reaction was quenched with sat. NaCl (50 mL) and extracted with EtOAc (40 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~31% THF / Petroleum ether @ 60 mL / min). Compound 7 (1.40 g, 53.4% yield) was obtained as a white solid. LCMS: (product: RT = 0.348 mins) Step 8: To a solution of compound 7 (1.30 g, 5.35 mmol) in MeOH (13 mL) was added methylhydrazine (923.0 mg, 8.01 mmol, 1.05 mL). The mixture was stirred at 25 °C for 1 hr. LC-MS showed compound 7 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure. The crude product was used into the next step without further purification. Compound 8 (1.40 g, 96.5% yield) was obtained as a red solid. LCMS: (product: RT = 0.450 mins) Synthesis of Examples 16, 17, 18, and 19:

[0044] To a solution of 4-(trifluoromethyl) pyridine-3-carboxylic acid (916.0 mg, 4.79 mmol) in THF (8 mL) was added compound 8 (650.0 mg, 2.40 mmol), TCFH (1.21 g, 4.31 mmol) and NMI (491 mg, 5.99 mmol). The mixture was stirred at 25 °C for 4 hr. LC-MS showed compound 8 was consumed completely and desired mass was detected. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~17% THF / Petroleum ether @ 40 mL / min). Compound (Example 16) (481.0 mg, 45.1% yield) was obtained as a yellow solid. LCMS: (EC22276-48-P1J1, product: RT = 1.837 mins).1H NMR: (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.93 (d, J = 5.0 Hz, 1H), 8.83 (s, 1H), 8.30 (dd, J = 1.6, 10.9 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.57 (t, J = 51.2 Hz, 1H), 3.59 (s, 3H) Examples 17, 18, and 19 were prepared using the same process as described above for Example 16. The analytical information for Examples 16, 17, 18, and 19 is provided below:

[0045] Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.93 (d, J = 5.0 Hz, 1H), 8.83 (s, 1H), 8.30 445.1 (dd, J = 1.6, 10.9 Hz, yellow [M+H]+ 1H), 8.08 (s, 1H), 7.88 (d, solid 97.53% J = 5.3 Hz, 1H), 7.57 (t, J RT = 1.837 = 51.2 Hz, 1H), 3.59 (s, 3H) Example 16 1H NMR (400 MHz, DMSO-d6) δ = 9.08 - 9.03 (m, 1H), 8.84 (d, J = 445.1 4.8 Hz, 1H), 8.30 (dd, J = 1H), 8.10 - yell [M+H]+ 1.6, 10.9 Hz, ow , 2H), 7.81 (dd, J soli 97.88% 8.03 (m d RT = 1.843 = 4.7, 7.9 Hz, 1H), 7.57 (t, J = 51.2 Hz, 1H), 3.58 Example 17 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.87 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.0 Hz, 445.1 1H), 8.26 (dd, J = 1.3, yellow [M+H]+ 10.9 Hz, 1H), 8.06 (s, solid 96.14% 1H), 7.74 (dd, J = 4.9, 8.1 RT = 1.840 Hz, 1H), 7.57 (t, J = 51.2 Example 18 Hz, 1H), 3.58 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 445.1 2H), 8.94 (d, J = 5.0 Hz, , J = 1.5, yell [M+H]+ 1H), 8.30 (dd ow solid 99.33% 10.9 Hz, 1H), 8.09 (s, RT = 1.835 1H), 7.71 - 7.43 (m, 2H), 3.57 (s, 3H) Example 19 Examples 20, 21, and 22:

[0046] Synthesis of Examples 20, 21, and 22: To a solution of 2-(trifluoromethyl)pyridine-3-carboxylic acid (682.0 mg, 3.57 mmol) in DCM (5 mL) was added [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (1.00 g, 3.57 mmol), 1-methylimidazole (407.0 mg, 4.96 mmol) and compound 5 (500.0 mg, 1.98 mmol). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O (5 mL) and DCM (15 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase flash chromatography (0.1% NH3-H2O, Eluent of 0~50% H2O / MeCN @ 40 mL / min). Example 20 (316.97 mg, 47.44% yield) was obtained as a white solid. Example 21 and Example 22 were prepared using similar process to that provided above for Example 20. Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, CHLOROFORM-d) δ 8.85 (d, J = 4.5 Hz, 1H), 8.04 426 (d, J = 8.4 Hz, 2H), 7.84 - Off- [M+H]+ 7.74 (m, 2H), 7.61 (dd, J = white 99.11% 4.8, 7.8 Hz, 1H), 7.44 (d, J solid RT = = 8.4 Hz, 2H), 6.91 (t, J = 1.822 Example 20 51.7 Hz, 1H), 3.61 (s, 3H) 1H NMR (400 MHz, CHLOROFORM-d) δ 9.13 409.1 - 8.84 (m, 2H), 8.05 (br d, J Off- [M+H]+ = 7.8 Hz, 2H), 7.79 (s, 1H), white 100% 7.49 - 7.34 (m, 3H), 6.91 solid RT = (br t, J = 51.7 Hz, 1H), 3.60 1.823 (s, 3H) Example 21 1H NMR (400 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.38 (s, 1H), 9.23 (br s, 1H), 9.08 (s, 1H), 8.64 409.1 (s, 1H), 7.91 - 7.81 (m, Gray [M+H]+ 2H), 7.11 (d, J = 8.8 Hz, solid 97.42% 1H), 6.93 (d, J = 2.2 Hz, RT = 2H), 6.62 (t, J = 2.1 Hz, 1.814 Example 22 1H), 3.89 (s, 3H), 3.82 (s, 6H) Example 23, Example 24, Example 25, and Example 26:

[0047] Representative process of preparation Intermediate 2: Preparation of 2_A01: To a solution of compound 1 (900 mg, 4.01 mmol, 1.00 eq) in THF (9.00 mL) and DMF (1.80 mL) was added A01 (549 mg, 4.01 mmol, 1.00 eq). The mixture was stirred at 25 °C for 2 hr. LC- MS showed one main peak with desired mass was detected. The reaction mixture was filtered and the filter cake was dried in vacuo. The crude product was used into the next step without further purification. Compound 2_A01 (572 mg, 46.5% yield) was obtained as a yellow solid. The other intermediates 2_A02 and 2_A03 were prepared using similar compounds as those above. Preparation of Examples 23, 24, 25, and 26: To a solution of 4-(trifluoromethyl)pyridine-3-carboxylic acid (535 mg, 2.80 mmol, 1.50 eq) in DCM (6.00 mL) was added TCFH (943 mg, 3.36 mmol, 1.80 eq) and NMI (383 mg, 4.67 mmol, 2.50 eq). Then compound 2_A01 (572 mg, 1.87 mmol, 1.00 eq) was added. The mixture was stirred at 25 °C for 16 hr. LC-MS showed 62% of desired compound was detected. The reaction mixture was partitioned between water (20 mL) and DCM (30 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~15% THF / Petroleum ether gradient @ 60 mL / min). The compound of Example 23 (0.383 g, 80.0% yield, 99.8% purity) was obtained as a white solid. Examples 24, 25, and 26 were also prepared using similar processes as those provided above. The analytical data for Examples 23, 24, 25, and 26 are provided below. Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, DMSO-d6) δ = 8.93 (d, J = 5.0 Hz, 1H), 8.81 (s, 1H), 480.1 8.31 (s, 1H), 7.99 (br d, J =+(br d, J = whit [M+H] 8.1 Hz, 2H), 7.88 e 68 - 7.36 (m, so 99.83% 5.1 Hz, 1H), 7. lid RT = 3H), 5.07 - 4.94 (m, 1H), 2.444 2.17 (br s, 2H), 2.07 - 1.92 Example 23 (m, 4H), 1.66 (br s, 2H) 1H NMR (400 MHz, DMSO-d6) δ = 8.92 (br d, J = 5.1 Hz, 1H), 8.78 (s, 1H), 8.38 (s, 1H), 7.98 (br d, J = 8.1 Hz, 2H), 7.87 (br d, J = 494.1 .1 Hz, 1H), 7.68 - 7.38 (m, Off-white [M+5 +H] 3H), 4.48 (br t, J = 11.8 Hz, solid 99.84% 1H), 2.44 - 2.28 (m, 2H), RT = 1.84 (br t, J = 14.2 Hz, 4H), 2.533 1.69 (br d, J = 11.9 Hz, 1H), Example 24 1.55 - 1.39 (m, 2H), 1.27 (br d, J = 12.6 Hz, 1H) 1H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 1H), 488.1 (d, J = 5.1 Hz, 1H), yellow [M+9.03 +H] 8.01 - 7.93 (m, 3H), 7.76 - solid 98.92% 7.63 (m, 3H), 7.53 - 7.37 RT = (m, 6H) 2.316 Example 25 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.93 (d, J = 5.1 Hz, 1H), 502.1 8.83 (s, 1H), 7.98 (d, J = 8.5 [M+H]+Hz, 2H), 7.75 (s, 1H), 7.69 white 3 Hz, 1H), 7.46 - soli 98.65% (d, J = 5. d RT = 7.40 (m, 2H), 7.33 (dd, J = 2.409 8.0, 17.0 Hz, 5H), 6.89 (t, J Example 26 = 51.7 Hz, 1H), 5.48 (s, 2H) Examples 27, 28, 29, and 30:

[0048] General process for preparation of Example 30: To a solution of compound 185 (0.30 g, 1.84 mmol, 1.00 eq) in DMF (3.00 mL) was added compound a (372.43 mg, 1.47 mmol, 0.80 eq) and NMI (377.38 mg, 4.60 mmol, 366.39 μL, 2.50 eq) and TCFH (773.78 mg, 2.76 mmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0 / 1). Example 30 (0.32 g, 787.70 μmol, 42.84% yield, 98.06% purity) was obtained as an off white solid, which was confirmed by LCMS. Examples 27 and 29 were also prepared using a similar process described above for Example 30. General process for preparation of Example 28: To a mixture of 127799-54-6 (516 mg, 3.53 mmol, 1.20 eq) in DCM (5.0 mL) was added 183 (480 mg, 2.94 mmol, 1.00 eq), NMI (1.21 g, 14.7 mmol, 1.17 mL, 5.00 eq) and TCFH (1.24 g, 4.41 mmol, 1.50 eq) at 25 °C and stirred for 1 hr. LCMS showed show the desired MS was detected. The reaction mixture was quenched by addition H2O 10 mL at 25°C, and extracted with DCM 10 mL (5 mL * 2). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1). 183-2 (400 mg, 1.37 mmol, 46.67% yield) was a white solid. To a mixture of 183-2 (380 mg, 1.30 mmol, 1.00 eq) and 183-2a (264 mg, 1.17 mmol, 0.90 eq) in DCM (5.00 mL) was added TFA (1.00 mL) at 25°C and stirred for 12 hrs. LCMS shows that the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=10 / 1). Example 28 (310 mg, 778.18 μmol, 59.66% yield) was a yellow solid. Compound was confirmed by LCMS and HNMR. The analytical data for compounds of Examples 27, 28, 29, and 30 are provided below. Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 373.1 8.65 (s, 1H), 8.57 (s, 1H), 46 (br d, J = 8.2 Hz, 1H), of [M+H]+ 8. f white solid 96.0% 8.07 (s, 1H), 7.90 (s, 1H), RT = 7.75 - 7.40 (m, 2H), 3.58 1.856 (s, 3H), 2.40 (s, 3H) Example 27 1H NMR (400 MHz, METHANOL-d4) δ 9.26 (d, J = 1.4 Hz, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.40 (dd, J = 1.9, 8.4 Hz, 1H), 8.06 (s, 399.1 1H), 7.77 (t, J = 1.9 Hz, off white [M+H]+ 1H), 7.72 (d, J = 8.4 Hz, solid 99.225% 1H), 7.24 (t, J = 51.6 Hz, RT = 1H), 3.63 (s, 3H), 2.13 - 2.597 Example 28 2.04 (m, 1H), 1.16 - 1.07 (m, 2H), 0.86 - 0.79 (m, 2H) 1HNMR (400 MHz, DMSO-d6) δ = 9.24 (d, J = 1.7 Hz, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.47 (dd, J = 399.1 2.1, 8.3 Hz, 1H), 8.06 (s, .96 (dd, J = 2.3, 8.1 off wh [M+H]+ 1H), 7 ite 98.06% Hz, 1H), 7.72 - 7.40 (m, solid RT = 3H), 3.56 (s, 3H), 2.25 - 2.038 2.15 (m, 1H), 1.09 - 1.00 Example 30 (m, 4H) 1H NMR (400 MHz, DMSO-d6) δ = 9.26 - 9.21 (m, 1H), 8.75 (d, J = 2.0 373.1 Hz, 1H), 8.45 (dd, J = 2.1, Yellow [M+H]+ 8.4 Hz, 1H), 8.07 (s, 1H), solid 97.69% 8.00 (dd, J = 2.2, 8.1 Hz, RT = 1H), 7.73 - 7.38 (m, 3H), 1.662 Example 29 3.57 (s, 3H), 2.57 (s, 3H) Examples 31, 32, and 33:

[0049] Reactant: General Procedure for preparation of Example 33: To a solution of cpd 192 (90.1 mg, 473 μmol, 1.20 eq) in DCM (5 mL) was added TCFH (132 mg, 473 μmol, 1.20 eq) and NMI (81.1 mg, 987 μmol, 78.7 μL, 2.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed cpd 192 was consumed completely and one main peak with desired m / z was detected. TLC(P:E=1:1) indicated cpd 192 was consumed completely and one new spot formed. The reaction was clean according to TLC. The residue was diluted with H2O 10 mL and extracted with DCM 30 mL (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1to 0 / 1). Example 33 (0.310 g, 707 μmol, 51.2% yield, 97.0% purity) was obtained as a yellow solid. LCMS showed the purity is 97.0%.1H NMR and F NMR confirmed the obtained compound is the desired compound. The compounds provided in Examples 31 and 32 were prepared using similar methods as those provided above for Example 33. The analytical data for Examples 31, 32, and 33 are provided in the table below. Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, CHLOROFORM-d) δ 9.26 (d, J = 1.4 Hz, 1H), 8.22 (dd, J = 2.1, 8.4 426.0 Hz, 1H), 7.88 (s, 1H), white [M+H]+ 7.76 (d, J = 7.2 Hz, 1H), 95.11% 7.69 - 7.57 (m, 2H), solid RT = 7.43 (d, J = 7.0 Hz, 1H), 2.598 Example 31 7.31 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 51.6 Hz, 1H), 3.62 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 1H), 8.37 (br d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 426.0 8.02 (s, 1H), 7.98 (br d, white [M+H]+ J = 7.6 Hz, 1H), 7.94 (br solid 97.72% d, J = 7.9 Hz, 1H), 7.79 RT = - 7.72 (m, 1H), 7.71 - 2.555 Example 32 7.43 (m, 2H), 3.58 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (dd, 426.0 J = 0.7, 2.2 Hz, 1H), J = 2.1, 8.3 Hz, y [M+H]+ 8.43 (dd, ellow 97.08% 1H), 8.08 (s, 1H), 7.87 solid RT = (s, 4H), 7.74 - 7.41 (m, 2.567 2H), 3.59 (s, 3H) Example 33 Example 34:

[0050] Step 1: T4P (463.69 g, 643.55 mmol, 50% purity, 1.3 eq) was added to a mxiture of compound 1 (100 g, 495 mmol, 1,0 eq) and tert-butyl N-aminocarbamate (78.5 g, 594 mmol, 1.2 eq), TEA (150.28 g, 1.49 mol, 206.71 mL, 3.0 eq) in DCM (700 mL) at 0-10°C. The mixture was stirred at 0-10°C for 1 hr. TLC (Dichloromethane : Methanol = 10 : 1) showed that the reaction was complete. The mixture was quenched by water (1000 mL) and extracted with DCM (500 mL X 3) . The combine organic layer was concentrated to give the crude product. The crude product was triturated with PE / EA (1000 mL, 2 / 1) at 10-20oC for 30 min. Compound 2 (114 g, 360.59 mmol, 72.84% yield) was obtained as white solid. Step 2: HBr (425.47 g, 2.52 mol, 285.55 mL, 48% purity, 7 eq) was added to a mixture of tert-butyl N- [ (6-bromopyridine-3-carbonyl) amino]carbamate (114 g, 360.59 mmol, 1 eq) in MeOH (300 mL) at 10-20°C. The mixture was stirred at 30°C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 1:1) showed that the reaction was complete. The mixture was cooled to 0-10°C and filtered. The filtrate cake was washed by MeOH (30 mL). The filtered cake was dried under vacuum. Compound 3 (98 g, 330.03 mmol, 91.52% yield, HBr) was obtained as yellow solid. Step 3: (2,2-difluoroacetyl) 2,2-difluoroacetate (229 g, 1.32 mol, 4.0 eq) was added to a mixture of compound 3 (98.0 g, 330 mmol, 1.0 eq, HBr) and TEA (333 g, 3.30 mol, 459 mL, 10.0 eq) in anhydrous CHCl3 (700 mL) at -50--60°C under N2. The mixture was stirred at 10-20°C for 1 hr. The mixutre was stirred at 60°C for 1 hrs. TLC (Dichloromethane : Methanol = 10:1) showed that the reaction was complete. The mixture was cooled to 10-20°C and poured into water (1.5 L) . The mixture was extracted with DCM (800 mL X 2) . The combine organic layer was concentrated to give the crude product. The product was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1). Compound 4 (68.0 g, 246 mmol, 74.64% yield) was obtained as yellow solid. Step 4: Pd(dppf)Cl2 (6.0 g, 8.20 mmol, 3.33e-2 eq) was added to a mixture of 2- (6-bromo-3-pyridyl) -5- (difluoromethyl) -1,3,4-oxadiazole (68.0 g, 246 mmol, 1.0 eq) , potassium; trifluoro (vinyl) boranuide (66.00 g, 492.69 mmol, 2.0 eq) and K2CO3(68.1 g, 492 mmol, 2.0 eq) in dioxane (400 mL) and H2O (100 mL) at 10-20°C under N2. The mixture was stirred at 60°C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 2:1) showe that the reaction was complete. The mixture was diluted with water (700 mL) and extracted with EtOAc (1000 mL X 3). The combine organic layer was concentrated to give the crude product. The product was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1). Compound 5 (43.0 g, 192 mmol, 78.2% yield) was obtained as yellow solid. Step 5: NaIO4 (206 g, 963 mmol, 5.0 eq) was added to a mixture of compound 5 (43.0 g, 192 mmol, 1.0 eq) and K2OsO4.2H2O (3.55 g, 9.63 mmol, 0.05 eq) in THF (400 mL) and H2O (400 mL) in portions at 0-10°C. The mixture was stirred at 10-20°C for 16 hrs. TLC (Petroleum ether : Ethyl acetate = 2:1) showed that the reaction was complete. The mixture was diluted with water (1.5 L) extracted with EtOAc (700 mL X 5) . The combined organic layer was concentrated to give the crude product. The crude product was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1). Compound 6 (27.0 g, 119 mmol, 62.24% yield) was obtained as yellow solid. Step 6: Methylhydrazine (21.0 g, 182 mmol, 24.0 mL, 2.05 eq) was added to a mixture of compound 6 (20.0 g, 88.83 mmol, 1 eq) in MeOH (100 mL) at 10-20 °C under N2. The mixture was stirred at 30 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate= 2 : 1) showed that the reaction was completed. The mixture was cooled to 0-10 °C and filtered. The filtrate cake was washed by MeOH (30 mL). The filtrate cake was dried under vacuum. Compound 7 (18.1 g, 71.48 mmol, 80.47% yield) was obtained as yellow solid. Step 7: TCFH (23.05 g, 82.15 mmol, 1.6 eq) was added to a mixture of 2- (trifluoromethyl) pyridine-3- carboxylic acid (13.74 g, 71.88 mmol, 1.4 eq), compound 7 (13 g, 51.34 mmol, 1 eq) and NMI (16.86 g, 205.36 mmol, 16.37 mL, 4 eq) in DCM (100 mL) at 0-10°C. The mixture was stirred at 25°C for 16 hrs. TLC (Petroleum ether : Ethyl acetate = 0:1) showed that the reaction was completed. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 2). The combine organic layer was concentrated to give the crude product. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 100 / 1- 0 / 1) . Then the product was purified by trituration with Petroleum ether / Ethyl acetate (2 / 1, 90 mL) at 10-20°C for 1 hr. The product was filtered and the filtrate cake was dried under vacuum. The compound of Example 34 (16.5 g, 37.93 mmol, 73.87% yield, 97.99% purity) was obtained as white solid. The product was confirmed by LCMS and NMR.1H NMR: (400 MHz, DMSO-d6) δ 9.21 (d, J = 1.3 Hz, 1H), 8.91 (d, J = 4.2 Hz, 1H), 8.37 (dd, J = 2.0, 8.4 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.87 (dd, J = 4.8, 7.8 Hz, 1H), 7.74 - 7.35 (m, 1H), 7.25 (d, J = 8.3 Hz, 1H), 3.59 (s, 3H) LCMS 427.1, [M+H]+ 97.99%, RT = 2.703. Example 35: Synthesis of (E)-N'-(3-(3-(difluoromethyl)isoxazol-5-yl)benzylidene)-2-fluoro- N-methylbenzohydrazide: Step-1: 1-Bromo-3-(dimethoxymethyl)benzene (2): To a stirred solution of 3-bromobenzaldehyde 1 (5.0 g, 27.02 mmol) (3) in trimethyl orthoformate, (20 mL) were added formic acid (3.1 mL, 81.11 mmol) and sulfuric acid solution (0.05 mL, 1 N) at room temperature. The resulting reaction mixture was heated at 50 °C for 2 hr. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of starting material, reaction mixture was diluted with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude 3-bromobenzaldehyde (6 g, crude) as thick colorless liquid which was used for next step without further purification.1H NMR (400 MHz, CDCl3) δ: 7.62 (t, J = 1.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.26-7.22 (m, 1H), 5.36 (s, 1H), 3.32 (s, 6 H). Step-2: 1-Bromo-3-(dimethoxymethyl)benzene (3): To a stirred solution of 1-bromo-3-(dimethoxymethyl)benzene 2 (1.2 g, 5.19 mmol) in N, N- dimethylformamide (12.0 mL) were added copper (I) iodide (0.025 g, 0.130 mmol), triethylamine (0.788 g, 7.79 mmol), bis(triphenylphosphine)palladium(II) chloride (0.182 g, 0.260 mmol) and trimethylsilylacetylene (0.956 mL, 7.789 mmol) at room temperature under inert atmosphere. The resulting mixture was stirred for 16 hr at 90 °C. Progress of reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was diluted with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude 3-bromobenzaldehyde 3 (550 mg, 43%) as colorless liquid.1H NMR (400 MHz, CDCl3) δ: 7.57 (t, J = 1.6 Hz, 1H), 7.44-7.39 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 5.36 (s, 1H), 3.31 (s, 6H), 0.23 (s, 9H). Step-3: 1-Bromo-3-(dimethoxymethyl)benzene (4): To a stirred solution of 3-(dimethoxymethyl)phenyl)ethynyl)trimethylsilane 3 (0.5 g, 2.013 mmol) in methanol (7.5 mL) was added potassium carbonate (1.65 g, 5.03 mmol) at room temperature. The resulting mixture was stirred for 2 hr at room temperature. Progress of reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was diluted with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude compound which was purified silica gel column chromatography using 10% ethyl acetate in pet ether to afford 3-(dimethoxymethyl)phenyl)ethynyl)trimethylsilane 4 (300 mg, 84%) as colorless liquid.1H NMR (400 MHz, CDCl3) δ: 7.60 (s, 1H), 7.47-7.43 (m, 2H), 7.37 (s, 1H), 3.22 (s, 6 H), 3.07 (s, 1H). Step-4: 3-(3-(Difluoromethyl)isoxazol-5-yl)benzaldehyde (5): To a stirred solution of 1-(dimethoxymethyl)-3-ethynylbenzene 4 (1.6 g, 9.08 mmol) in chloroform (16.0 mL) were added 2,2-difluoroethan-1-amine (1.92 mL, 27.24 mmol), copper iodide (0.173 g, 0.91 mmol), zinc bromide (4.09 g, 18.69 mmol), acetic acid (218 mg, 3.63 mmol), tert-butyl nitrite (3.43 mL, 27.24 mmol) at room temperature under inert atmosphere. The resulting reaction mixture was stirred for 24 hr at room temperature. Progress of reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (75 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude compound which was purified by silica gel column chromatography using 40% ethyl acetate in pet ether to get compound 5 (610 mg, 31%) as thick liquid.1H NMR (400 MHz, CDCl3) δ:10.11 (s, 1H), 8.813 (t, J = 1.6 Hz, 1H), 8.09-8.07 (m,1H), 8.02-8.00 (m, 1H), 7.71 (t, J = 8.0 Hz, 1H), 6.96-6.69 (m, 2H). Step-5: (E)-N'-(3-(3-(difluoromethyl)isoxazol-5-yl)benzylidene)-2-fluoro-N methylbenzohydrazide (Example 35):

[0051] To a stirred solution of 3-(3-(difluoromethyl)isoxazol-5-yl)benzaldehyde 5 (0.5 g, 2.24 mmol) and 2-fluoro-N-methylbenzohydrazide 6 (0.37 g, 2.24 mmol) in ethanol (5 mL) was added sulfuric acid solution (0.500 mL, 1N) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hr. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of starting material, reaction mixture was diluted with water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude compound which was purified by reverse phase HPLC to afford (E)-N'-(3-(3- (difluoromethyl)isoxazol-5-yl)benzylidene)-2-fluoro-N-methylbenzohydrazide (Example 35) (220 mg, 26.3%) as an off white solid. LC-MS: 98.75%, m / z 374.16 [M+H]+; HPLC: 99.3%;1H NMR (400 MHz, DMSO-d6) δ: 8.14 (s, 1H), 7.97 (s, 1H), 7.93-7.91 (m, 1H), 7.60-7.21 (m, 8H), 3.52 (s, 3H). Example 36, Example 37, Example 38, and Example 39: Synthetic Schemes for Examples 36 and Example 37:

[0052] Step-1: 3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzoic acid (3): To a stirred solution of 3-(N-hydroxycarbamimidoyl) benzoic acid 1 (5 g, 27.75 mmol) in pyridine (83 mL) was added 2,2,2-trifluoroacetic anhydride 2 (11.6 mL, 83.25 mmol) at rt. The resulting reaction mixture was raised to reflux for 3h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with ice water and adjusted pH- 4 with 1N HCl and extracted with CH2Cl2 (100 mL x 2), separated organic layer, and concentrated under reduced pressure to get (3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzoic acid) 3 (6 g, 83.75%) as a white solid. LCMS: 84%, m / z: 257 [M-1]-. The crude compound was used in the next step without further purification. Step-2: N-methoxy-N-methyl-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzamide (4): To stirred solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzoic acid 3 (0.5 g, 1.93 mmol) in DMF (5 mL) were added N, O-dimethyl hydroxylamine. HCl (0.245 g, 2.518 mmol), 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.483 g, 2.518 mmol), 1-hydroxybenzotriazole hydrate (0.340 g, 2.518 mmol) and DIPEA (0.84 mL, 4.84 mmol) at rt and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice water and extracted with diethyl ether, separated from the organic layer, and concentrated under reduced pressure to get the crude product. The crude compound was purified using the GRACE FLASH column, product was eluted in 15-20% ethyl acetate in pet ether to get the N-methoxy-N-methyl-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzamide 4 (0.126 g, 44.56%) as a colorless liquid. LCMS: 98%, m / z 301 [M+H]+. Step-3: 3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde (5): To stirred solution N-methoxy-N-methyl-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzamide 4 (0.260 g, 0.863 mmol) in 2-Methyltetrahydrofuran (2.60 mL). was added DIBAL-H (1.036 mL, 1M in toluene,1.036 mmol) at -78 °C. The resulting reaction mixture was stirred for 2 h at the same temp. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated and dried using anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to get crude (3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 5 (0.160 g, 75%) as a pale-yellow liquid which was used in the next step without further purification. Step-4: (E)-2-(Difluoromethyl)-N-methyl-N'-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzylidene)benzohydrazide (Example 36): To a stirred solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 5 (0.160 g, 0.66 mmol) and 2-(difluoromethyl)-N-methylbenzohydrazide 6 (0.145 g, 0.7272 mmol) in ethanol (1.3 mL) were added sulphuric acid solution (0.1 mL, 0.1 N) at room temperature. The resulting reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of the starting material, the solvent evaporated under reduced pressure. Then the reaction mass was diluted with water and the formed solid compound was filtered to afford (E)-2-(difluoromethyl)-N-methyl-N'-(3-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzylidene) benzo hydrazide (Example 36) (264 mg, 94%) as off white solid. LC-MS: 98.56%, m / z 425.19 [M+H]+; HPLC: 99.39%;1H NMR (400 MHz, DMSO-d6) δ: 8.18 (s, 1H), 8.12 (s, 1H), 8.01–7.98 (m, 1H), 7.71-7.69 (m, 1H), 7.65-7.58 (m, 4H), 7.49-7.47 (m, 1H), 6.94 (m, 1H), 3.52 (s, 3H). Step-5: (E)-N-methyl-4-(trifluoromethyl)-N'-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzylidene)nicotinohydrazide (Example 37): To a stirred solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 5 (0.300 g, 1.239 mmol) and N-methyl-4-(trifluoromethyl) nicotinohydrazide 7 (0.272 g, 1.239 mmol) in ethanol (1.3 mL) were added sulphuric acid solution (0.07 mL, 0.1 N) at room temperature. The resulting reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of the starting material, the solvent evaporated under reduced pressure. Then the reaction mass was diluted with water and the formed solid compound was filtered to get (E)-N-methyl-4-(trifluoromethyl)-N'-(3-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzylidene)nicotinohydrazide (Example 37) (299 mg, 54%) as off white solid. LC-MS: 98.64%, m / z 444.15 [M+H]+; HPLC: 98.78%;1H NMR (400 MHz, DMSO-d6) δ: 8.95 (d, J = 5.2 Hz, 1H), 8.84 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.60–7.53 (m, 2H), 3.54 (s, 3H). Synthetic Scheme for Example 38 and Example 39:

[0053] Step-1: 4-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (9): To a stirred solution of (Z)-4-(N'-hydroxycarbamimidoyl)benzoic acid 8 (5 g, 27.75 mmol) in pyridine (83 mL) was added 2,2,2-trifluoroacetic anhydride (11.65 mL, 83.25 mmol) at room temperature. Then the resulting reaction mixture was reflux for 3 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (30 mL) and adjusted pH-4 with 1N HCl and extracted with DCM (100 mL x 2), separated organic layer, and concentrated under reduced pressure to get the crude 4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzoic acid 9 (2 g, 34%) as a white solid which was used for next step without further purification. LC-MS: 63% m / z: 257 [M-H]-. Step-2: N-Methoxy-N-methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (10): To stirred solution of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzoic acid 9 (2 g, 7.74 mmol) and N, O-dimethyl hydroxylamine (0.61 g, 10.07 mmol) in DMF (20 mL) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.93 g, 10.07 mmol) 1-hydroxybenzotriazole hydrate (1.36 g, 10.072 mmol) and N, N-diisopropylethylamine (3.38 mL, 19.36 mmol). The resulting reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction was diluted with water (25 mL) and extracted with diethyl ether (50 mL x 3). The organic layer was separated and dried using anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to get crude compound. The crude compound was purified using a GRACE FLASH purification and eluted with 20-30% EtOAc in PE to get N-methoxy-N-methyl-4-(5-(trifluoromethyl)-1,2,4- oxadiazol-3-yl) benzamide 10 (0.750 g, 32%), as a pale-yellow liquid, LCMS: 81%, m / z, 301 [M+H]+. Step-3: 4-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde (11): To stirred solution of N-methoxy-N-methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzamide 10 (1.58 g, 5.24 mmol) in 2-methyl THF (15.8 mL) was added DIBAL-H (6.29 mL, 6.294 mmol, in toluene) at -78 °C. Then the resulting reaction mixture was stirred for 2h at -78 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried with Na2SO4 and concentrated under reduced pressure to get (4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 11 (0.700 g, 55%) as a pale-yellow liquid. Step-4: (E)-2-(Difluoromethyl)-N-methyl-N'-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzylidene)benzohydrazide (Example 38): To a stirred solution of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 11 (0.20 g, 0.82 mmol) and 2-(difluoromethyl)-N-methylbenzohydrazide 6 (0.165 g, 0.82 mmol) in ethanol (5 mL) was added sulphuric acid solution (cat) (0.1 mL, 0.1 N) at room temperature. The resulting reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of the starting material, the solvent evaporated under reduced pressure. Then the reaction mass was diluted with water (5 mL) and the formed solid compound was filtered to get (E)-2-(difluoromethyl)-N-methyl-N'-(4-(5-(trifluoromethyl)-1,2,4- oxadiazol-3-yl)benzylidene)benzohydrazide (Example 38) (310 mg, 86%) as off white solid. LC- MS: 97.66%, m / z 425.19 [M+H]+; HPLC: 98.31%;1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.72–7.62 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.49–7.47 (m, 1H), 6.94 (d, J = 54.8 Hz, 1H), 3.53 (s, 3H). Step-5: (E)-N-methyl-4-(trifluoromethyl)-N'-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzylidene)nicotinohydrazide (Example 39): To a stirred solution of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl) benzaldehyde 11 (0.20 g, 0.82 mmol, 1 equiv.) and N-methyl-4-(trifluoromethyl) nicotinohydrazide 7 (0.18 g, 0.82 mmol) in ethanol (5 mL) were added sulphuric acid solution (cat) (0.1 mL, 0.1 N) at room temperature. The resulting reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC and LC-MS. After complete consumption of the starting material, the solvent evaporated under reduced pressure. Then the reaction mass was diluted with water and the formed solid compound was filtered to get pure compound to afford (E)-N-methyl-4-(trifluoromethyl)-N'- (4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzylidene)nicotinohydrazide (Example 39) (266 mg, 29%) as off white solid. LC-MS: 97.59%, m / z 444.19 [M+H]+; HPLC: 97.51%;1H NMR (400 MHz, DMSO-d6) δ: 8.97 (d, J = 5.6 Hz, 1H), 8.84 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 3.55 (s, 3H). Synthetic Scheme for Int-6: Step-1: Tert-butyl 2-(2-(difluoromethyl) benzoyl)-2-methylhydrazine-1-carboxylate (13): To stir solution of 2-(difluoromethyl) benzoic acid 12 (2 g, 11.61 mmol) in DMF were added tert- butyl 2,2-dimethylhydrazine-1-carboxylate (2.23 g, 13.94 mmol), HATU (5.74 g, 15.10 mmol) and DIPEA (3.042 mL, 17.42 mmol) at rt and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was diluted with water and extracted with diethyl ether (50 mL x 2). The organic layer was separated and dried using anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to get (tert-butyl 2-(2-(difluoromethyl)benzoyl)-2-methylhydrazine-1-carboxylate) 13 (2.1 g, 60%) as brown liquid. LC-MS: 88%, m / z 301 [M+H]+Step-2: 2-(Difluoromethyl)-N-methylbenzohydrazide (Int-6): To a stirred solution of tert-butyl 2-(2-(difluoromethyl) benzoyl)-2-methylhydrazine-1- carboxylate 13 (3.1 g, 10.32 mmol) in DCM (31.0 mL) was added 4 M HCl in dioxane (12.9 mL, 51.61 mmol) at 0 °C. The resulting reaction mixture was stirred for 1 h at rt. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under vacuum and washed with n-pentene, filtered, and concentrated under reduced pressure to get 2-(difluoromethyl)-N-methylbenzohydrazide (1.8 g, 87%) as white solid which was used for the next reaction without further purification. LC-MS: 86%, m / z 201 [M+H]+. Synthetic Scheme for Int-7: Step-1: Tert-butyl 2-methyl-2-(4-(trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate (15): To stir solution of 4-(trifluoromethyl) nicotinic acid 14 (2 g, 10.46 mmol) in DMF (15 mL) were added tert-butyl 2-methylhydrazine-1-carboxylate (1.836 g, 12.5 mmol) HATU (5.17 g, 13.60 mmol, 1.3 equiv.), N, N-diisopropylethylamine (2.74 mL, 15.6 mmol) then the reaction was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture diluted with water (20 mL) and extracted with diethyl ether (50 mL x 3). The organic layer was concentrated under reduced pressure to get crude compound. The crude compound was purified by GRACE FLASH chromatography using 100-200 mesh silica gel and the product was eluted with 15-20% ethyl acetate / pet ether to get tert-butyl 2-methyl-2-(4- (trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate 15 (3.1 g, 92%) as colourless liquid. LC-MS: 87%, m / z 320 [M+H]+. Step-2: N-methyl-4-(trifluoromethyl)nicotinohydrazide hydrochloride (Int-7): To a stirred solution of tert-butyl 2-methyl-2-(4-(trifluoromethyl) nicotinoyl) hydrazine-1- carboxylate 15 (3.1 g, 9.7 mmol) in DCM (31.0 mL) was added TFA (3.74 mL, 48.54 mmol) at 0 °C and stirred for 4 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, reaction mixture was concentrated under vacuum and wash with n-pentene, filtered, and concentrated under reduced pressure to get crude N-methyl-4- (trifluoromethyl) nicotinohydrazide hydrochloride Int-7 (0.64 g, 30%) as a white solid which was used for the next reaction without further purification. LC-MS: 87%, m / z: 320 [M+H]+. Example 40, Example 41, and Example 42: Synthetic scheme of (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-6-(trifluoromethyl)nicotinohydrazide (Example 40):

[0054] Step-1: Tert-butyl 2-methyl-2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate (11): To a stirred solution of 6-(trifluoromethyl)nicotinic acid 9 (2 g, 10.465 mmol) in DMF (20.0 mL) were added tert-butyl 2-methylhydrazine-1-carboxylate 10 (1.989 g, 13.605 mmol), DIPEA (7.297 mL, 41.861 mmol) and HATU (5.173 g, 13.605 mmol) at 25 °C. The resulting reaction mixture was stirred for 12 h at 25 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was quenched with ice water (30 mL), extracted with EtOAc (30 mL × 3). The organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica-gel (100-200 mesh) column chromatography and eluted with 50% EtOAc / pet-ether to afford tert-butyl 2-methyl-2-(6- (trifluoromethyl)nicotinoyl)hydrazine-1-carboxylate 11 (2.1 g, 62.85%) as a brown solid. LC-MS: 99.84%, m / z [M+H]+= 319.23. Step-2: N-Methyl-6-(trifluoromethyl)nicotinohydrazide hydrochloride (12): To a stirred solution of tert-butyl 2-methyl-2-(6-(trifluoromethyl)nicotinoyl)hydrazine-1- carboxylate (2.1 g, 6.577 mmol) in DCM (21.00 mL) was added 4M HCl in 1,4-dioxane (6.577mL, 26.309 mmol) at 0 °C and stirred for 12 h at 25 °C. Progress of the reaction was monitored by LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get N-methyl-6-(trifluoromethyl)nicotinohydrazide hydrochloride (0.8 g, 55.50%) as sticky solid. LC-MS: 76.69% %, m / z [M+H]+= 220.20. Step-3: (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-6- (trifluoromethyl)nicotinohydrazide (Example 40): To a stirred solution of N-methyl-5-(trifluoromethyl)nicotinohydrazide 12 (0.4 g, 1.82 mmol) and 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde 5 (409.125 mg, 1.82 mmol) in ethanol (4.0 mL) and added 1 drop of H2SO4(1 N) . Then the reaction mixture was stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the solids were obtained and then the solid was filtered and washed with water and solid was dried under a vacuum to get compound (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methyl-6-(trifluoromethyl)nicotinohydrazide (Example 40) (0.540 g, 64.41%) as a white solid. LC-MS: 98.75%, m / z [M+H]+= 426.18; HPLC: 98.49%;1H NMR (400 MHz, DMSO-d6) δ: 8.99 (d, J = 1.6 Hz, 1H), 8.34 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 8.23 (s, 1H), 8.10– 8.05 (m, 3H), 7.71 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 51.6 Hz, 1H), 3.57 (s, 3H). Synthetic Scheme of (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-3-(trifluoromethyl)benzohydrazide (Example 41): Step-1: Tert-butyl 2-methyl-2-(3-(trifluoromethyl)benzoyl)hydrazine-1-carboxylate (14): To a stirred solution of 3-(trifluoromethyl)benzoic acid 13 (4 g, 21.03 mmol) in DMF (40.0 mL) were added tert-butyl 2-methylhydrazine-1-carboxylate (3.99 g, 27.351 mmol), DIPEA (14.67 mL, 84.15 mmol) and HATU (10.4 g, 27.351 mmol) at 25 °C. The resulting reaction mixture was stirred for 12 h at 25 °C. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was quenched with ice water (30 mL), extracted with EtOAc (30 mL × 3). The organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica-gel (100-200 mesh) column chromatography and eluted with 50% EtOAc / pet ether to afford tert-butyl 2-methyl-2-(3- (trifluoromethyl)benzoyl)hydrazine-1-carboxylate 14 (5.3 g, 74.19%) as a white solid. LC-MS: 86.27%, m / z [M+H]+= 319.23. Step-2: N-Methyl-3-(trifluoromethyl)benzohydrazide hydrochloride (15): To a stirred solution tert-butyl 2-methyl-2-(3-(trifluoromethyl)benzoyl)hydrazine-1-carboxylate 14 (5.3 g, 16.651 mmol) in DCM (53 mL) was added 4M HCl in 1,4-dioxane (16.65 mL, 66.605 mmol) at 0 °C and stirred for 12 h at 25 °C. Progress of the reaction was monitored by LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get N-methyl-3-(trifluoromethyl)benzohydrazide hydrochloride 15 (3.5 g, 96.34%) as gummy solid. LC-MS: 95.55%, m / z [M+H]+= 219.20. Step-3: (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-3- (trifluoromethyl)benzohydrazide (Example 41): To a stirred solution of N-methyl-3-(trifluoromethyl)benzohydrazide hydrochloride 15 (0.4 g, 1.833 mmol), 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde 5 (410.97 mg, 1.833 mmol) in ethanol (4.0 mL) and added one drop of H2SO4 (1 N). Then the reaction mixture was stirred at 25°C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the solids were obtained and then the solid was filtered and washed with water and solid was dried under a vacuum to get compound (E)-N'-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)benzylidene)-N-methyl-3-(trifluoromethyl) benzohydrazide (Example 41) (0.502 g, 64.27%) as a white solid. LC-MS: 98.69%, m / z [M+H]+= 425.20; HPLC: 98.06%;1H NMR (400 MHz, DMSO-d6) δ: 8.17 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 8.01 (br s, 1H), 7.97–7.92 (m, 2H), 7.77-7.70 (m, 3H), 7.54 (t, J = 51.6 Hz, 1H), 3.55 (s, 3H). Synthetic Scheme of (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N- methyl-4-(trifluoromethyl)benzohydrazide (Example 42):

[0055] Step-1: tert-butyl 2-methyl-2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carboxylate (16): To a stirred solution of 4-(trifluoromethyl)benzoic acid 16 (4 g, 21.039 mmol) in DMF (40.0 mL) was added tert-butyl 2-methylhydrazine-1-carboxylate 10 (3.99 g, 27.351 mmol), HATU (10.40 g, 27.351 mmol) and DIPEA (14.671 mL, 84.157 mmol) at 25 °C. Then the reaction mixture was stirred at rt for 12 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was quenched with ice water (50 mL), extracted with EtOAc (50 mL × 3). The organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica-gel (100-200 mesh) column chromatography and eluted with 50% EtOAc / pet ether to afford tert-butyl 2-methyl-2-(4-(trifluoromethyl)benzoyl)hydrazine-1- carboxylate 17 (5.2 g, 77.65%) as a solid. LC-MS: 96.46%, m / z [M+H]+= 319.23. Step-2: N-Methyl-4-(trifluoromethyl)benzohydrazide hydrochloride (18): To a stirred solution of tert-butyl 2-methyl-2-(4-(trifluoromethyl)benzoyl)hydrazine-1- carboxylate 17 (5.2 g, 16.337 mmol) in DCM (52.0 mL) and cooled at 0 °C and added 4M HCl in 1,4-Dioxane (16.33 mL, 65.34 mmol). Then the reaction mixture was stirred at rt for 12 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get N-methyl-4- (trifluoromethyl)benzohydrazide hydrochloride 18 (3.4 g, 95.39%) as solid. LC-MS: 90.11%, m / z [M+H]+= 219.20. Step-3: (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzylidene)-N-methyl-4- (trifluoromethyl)benzohydrazide (Example 42): To a stirred solution of N-methyl-4-(trifluoromethyl)benzohydrazide hydrochloride 18 (0.4 g, 1.83 mmol) 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde (410.97 mg, 1.83 mmol) in ethanol (4.0 mL) and added one drop of H2SO4 (1 N). Then the reaction mixture was stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the solids were obtained and then the solid was filtered and washed with water and solid was dried under a vacuum to get (E)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methyl-4-(trifluoromethyl) benzohydrazide (Example 42) (0.512 g, 64.27%) as a white solid. LC-MS: 99.64%, m / z [M+H]+= 425.23; HPLC: 99.37%;1H NMR (400 MHz, DMSO-d6) δ: 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.88–7.83 (m, 4H), 7.70 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 51.6 Hz, 1H), 3.56 (s, 3H). Synthesis of (E)-N'-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methylene)-N- methyl-4-(trifluoromethyl)nicotinohydrazide (Example 43): Step-1: 2-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl) thiazole-5-carbaldehyde (9) A stirred solution of 2-(difluoromethyl)-5-(5-vinylthiazol-2-yl)-1,3,4-oxadiazole 6 (1 g, 4.36 mmol) in 1,4-dioxane (7.0 mL) : water (3.0 mL) was added sodium metaperiodate (3.7 g, 17.4 mmol) and 2,6-lutidine (0.95 mL, 8.7 mmol) and stirred for 10 min at 0 °C. Then osmium tetroxide, 4 wt.% solution in water (0.3 mL, 0.87 mmol) was added dropwise and stirred for 12 h at rt. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with the brine solution (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude product. The crude compound was purified using a GRACE FLASH chromatography as an eluted in 20-30% ethyl acetate in pet ether to get 2-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl) thiazole-5-carbaldehyde 9 (0.9 g, 89.23 %) as pale-yellow solid.1H NMR (400 MHz, CDCl3) δ: 10.07 (s, 1H), 8.75 (s, 1H), 6.95 (t, J = 51.96 Hz, 1H). Step-2: (E)-N'-((4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methylene)-N- methyl-4-(trifluoromethyl)nicotinohydrazide (Example 43): To stirred solution of 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) thiazole-5-carbaldehyde 9 (0.3 g, 1.29 mmol) in mixture of ethanol (4 mL) and water (1 mL), was added N-methyl-4- (trifluoromethyl) nicotinohydrazide 10 (0.28 g, 1.29 mmol) and H2SO4(0.01 mL, cat) at 0oC. The resulting reaction mixture was stirred for 20 min at RT (formation of white solid was observed). The progress of the reaction was monitored by TLC. After completion of the starting material, the resultant solid was filtered through the bucker funnel and washed with ethanol (2 x 5 mL). The solid was dried under a vacuum to obtain dried over rotavapor to afford (E)-N'-((4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methylene)-N-methyl-4- (trifluoromethyl)nicotinohydrazide (Example 43) (0.402 mg, 71.65%) as an off white solid. LC- MS: 99.03%, m / z [M+H]+= 433.18; HPLC purity: 99.09%;1H NMR (400 MHz, DMSO-d6) δ: 9.01 (d, J = 5.6 Hz, 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.53 (t, J = 51.2 Hz, 1H), 3.59 (s, 3H). Example 44: Synthesis of (E)-2-(azetidin-3-yloxy)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)benzylidene)-N-methylbenzohydrazide (Example 44):

[0056] Step-1: tert-Butyl 3-(2-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate (2): To stirred solution of methyl 2-fluorobenzoate 1 (2 g, 12.97 mmol) and tert-butyl 3- hydroxyazetidine-1-carboxylate (2.47 g, 14.27 mmol) in DMF (20 mL) was added sodium hydride (0.46 g, 19.46 mmol) at rt. The resulting reaction mass was stirred for 2 h at rt. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction was quenched with ice-cold water (50 mL), and extracted with ethyl acetate (2 x 50 mL). Theorganic layer was washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4,andconcentrated under reduced pressure to give a crude compound. The crude compound was purified by silica-gel (100-200 mesh) column chromatography and eluted with 30% ethyl acetate in pet ether to obtain tert-butyl 3-(2-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate 2 (2 g, 50%) as a colorless oil. LC-MS: 64%, m / z [M+H]+= 308.13. Step-2: 2-((1-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid (3): A solution of tert-butyl 3-(2-(methoxycarbonyl)phenoxy)azetidine-1-carboxylate 2 (1.5 g, 4.88 mmol) in methanol (15 mL), water (3 mL) was added LiOH (0.4 g, 9.76 mmol) at rt and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to get a crude compound, which was dissolved in water adjusted pH ~1 with citric acid, and the solid precipitated out was filtered and dried to get 2-((1-(tert- butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid 3 (1.2 g, 83%) as an off white solid. LCMS: 79.67%, m / z [M+H]+= 294.06. Step-3: tert-Butyl 3-(2-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl) phenoxy) azetidine-1-carboxylate (5): To a stirred solution of 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid 3 (1.2 g, 4.09 mmol) and tert-butyl 2-methylhydrazine-1-carboxylate 4 (0.59 g, 4.09 mmol) in DMF (10 mL) were added 1-hydroxybenzotriazole (0.55 g, 4.09 mmol), HBTU (1.55 g, 4.09 mmol) and DIPEA (1.429 mL, 8.18 mmol) at rt. The resulting reaction mixture was stirred for 16 h at rt. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water (50 mL) and the solid precipitated, was filtered and dried to get tert-butyl 3-(2- (2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)phenoxy)azetidine-1-carboxylate 5 (0.9 g, 52%) as an off white solid. LCMS: 96.79%, m / z 422.17 [M+H]+. Step-4: 2-(Azetidin-3-yloxy)-N-methylbenzohydrazide (6): To a stirred solution of tert-butyl 3-(2-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1- carbonyl)phenoxy)azetidine-1-carboxylate 5 (0.9 g, 2.13 mmol) in DCM (9.0 mL) was added 4M HCl in dioxane (9 mL) at 0 °C and the reaction mixture was stirred for 2 h at rt. After complete consumption of starting material, the reaction mass was directly concentrated to afford 2-(azetidin- 3-yloxy)-N-methylbenzohydrazide 6 (0.4 g, 84%) as a red color oil which was used for next step without further purification. LCMS: 36.77%, m / z 222.0 [M+H]+. Step-5: (E)-2-(Azetidin-3-yloxy)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzylidene)-N-methylbenzohydrazide.HCl (Example 44): To a stirred solution of 2-(azetidin-3-yloxy)-N-methylbenzohydrazide 6 (0.5 g, 2.26 mmol) in EtOH (5 mL) was added 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzaldehyde 5 (0.50 g, 2.26 mmol) at rt. The resulting reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, ethanol was evaporated under reduced pressure and the solid formed was filtered and washed with methanol and dried to get (E)-2-(azetidin-3-yloxy)-N'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzylidene)-N-methylbenzohydrazide.HCl (Example 44) (0.185 g, 19%) as an off-white solid. LC-MS: 94.11%, m / z 428.25 [M+H]+; HPLC: 95.13%:1H NMR (400 MHz, DMSO-d6) δ: 8.89 (br s, 2H), 8.09 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.67–7.41 (m, 4H), 7.35–7.32 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.03 (t, J = 5.6 Hz, 1H), 4.26–4.21 (m, 2H), 3.84–3.80 (m, 2H), 3.52 (s, 3H). Example 45, Example 46, Example 47, and Example 48: Synthetic Scheme for Example 45 and Example 46: General Scheme for Example 45: Step 1:

[0057] TosOH (3.15 g, 18.28 mmol, 0.1 eq.) was added into a solution of compound 1 (30 g, 182.75 mmol, 1 eq.) and ethylene glycol (56.71 g, 913.76 mmol, 50.96 mL, 5 eq.) in toluene (180 mL) at 25 °C. The reaction mixture was stirred at 110 °C for 12 h. LCMS showed compound 1 remained and the peak with desired mass was detected. TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf= 0.42) showed some new spots formed. Saturated aqueous solution of NaHCO3 (150 mL) and EtOAc (120 mL) were added. The organic layers were washed with brine (30 mL) and then dried over Na2SO4, filtered and then concentrated to give a crude product, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=15 / 1 to 5 / 1). Compound 2 (18.6 g, 89.33 mmol, 48.88% yield) was obtained as colorless oil. HNMR confirmed the structure. Step 2: NH2NH2.H2O (40.600 g, 811.03 mmol, 39.34 mL, 18.76 eq.) was added into a solution of compound 2 (9.0 g, 43.23 mmol, 1 eq.) in EtOH (135 mL). The reaction mixture was stirred at 80 °C for 3 h. LCMS showed compound 2 was consumed and the peak with desired mass was detected. The reaction mixture was concentrated to give a crude product under 40 °C. The crude product was used in next step without further purification. Compound 3 was obtained as orange oil. LCMS and 1HNMR confirmed the structure. Step 3: (2,2-difluoroacetyl) 2,2-difluoroacetate (22.57 g, 129.67 mmol, 3.00 eq.) was added into a solution compound 3 (9.00 g, 43.22 mmol, 1 eq.) and TEA (21.87 g, 216.12 mmol, 30.08 mL, 5.00 eq.) in DCM (80 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. LCMS showed compound 3 was consumed and the peak with desired mass was detected. TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.6) showed a product spot formed. The reaction mixture was concentrated and then extracted with EtOAc (100 mL x 3) and water (200 mL). The combined organic layers were dried, filtered and then concentrated to give a crude product, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1). Compound 4 (10.8 g, 40.27 mmol, 93.15% yield) was obtained as yellow oil. Step 4: A mixture of compound 4 (10.8 g, 40.27 mmol, 1 eq.) and HCl (3 M, 30 mL, 2.24 eq.) in THF (100 mL) was stirred at 25 °C for 12 h. LCMS showed compound 4 was consumed and no desired mass was detected. TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf= 0.5) showed a product spot formed. The reaction mixture was extracted with EtOAc (100 mL x 3) and water (200 mL). The combined organic layers were dried over Na2SO4, filtered and then concentrated to give a crude product, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=15 / 1 to 5 / 1). Compound 5 (3.8 g, 15.13 mmol, 37.58% yield, 89.27% purity) was obtained as yellow oil. LCMS and HNMR confirmed the structure. Step 5: TEA (1.35 g, 13.38 mmol, 1.86 mL, 3.0 eq.) was added into a solution of compound 5 (1 g, 4.46 mmol, 1 eq.) and methylhydrazine;sulfuric acid (771.67 mg, 5.35 mmol, 1.2 eq.) in MeOH (7 mL). The reaction mixture was stirred at 25 °C for 3 h. LCMS showed compound 5 remained and the peak with desired mass was detected. TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf= 0.3) showed compound 5 was remained and some new spots formed. The reaction mixture was concentrated to give a crude product, which was purified by pre-TLC (Petroleum ether: Ethyl acetate = 5: 1). Compound 6 (0.45 g, 1.63 mmol, 36.43% yield, 91.1% purity) was obtained as a yellow solid. Step 6: Example 45

[0058] Compound 5a_234 (110.64 mg, 697.80 μmol, 82.75 μL, 1.1 eq.) was added into a solution of compound 6 (0.16 g, 634.37 μmol, 1 eq.), DIEA (163.97 mg, 1.27 mmol, 220.99 μL, 2.0 eq.) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. LCMS and HPLC showed compound 6 was consumed and the peak with desired mass was detected. The mixture was concentrated to give a crude product, which was purified by pre-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%- 65% B over 8.0 min). Example 45 (0.103 g, 269.30 μmol, 42.45% yield, 97.868% purity) was obtained as a white solid and confirmed by LCMS. Synthesis of Example 47: Step 1: EDCI (668.22 mg, 3.49 mmol, 1.5 eq.) was added into a solution of compound a_236 (0.4 g, 2.32 mmol, 1 eq.) and compound 7 (407.66 mg, 2.79 mmol, 1.2 eq.) in pyridine (5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. LCMS showed compound a_236 was consumed and the peak with desired mass was detected. The reaction mixture was concentrated to remove the solvent and then extracted with EtOAc (3 mL x 3) and water (5 mL). The combined organic layers were dried, filtered and then concentrated to give a crude product, which was used to next step directly without further purification. Compound a_236_1 (0.65 g, 1.59 mmol, 68.34% yield, 73.37% purity) was obtained as orange oil. Step 2: HCl / dioxane (4 M, 3.97 mL, 10 eq.) was added into a solution of a_236_1 (0.65 g, 1.59 mmol, 1 eq.) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed a_236_1 was consumed and the peak with desired mass was detected. The reaction mixture was concentrated to give a crude product, which was used to next step without further purification. Compound a_236_2 (0.4 g, 1.23 mmol, 77.27% yield, 72.6% purity, HCl) was obtained as a yellow solid. Step 3 (Example 47): Compound 5 (0.3 g, 1.34 mmol, 1 eq.) was added into a solution of a-236_2 (380.05 mg, 1.61 mmol, 1.2 eq, HCl) and TEA (406.27 mg, 4.01 mmol, 558.83 μL, 3.0 eq.) in MeOH (4 mL). The reaction mixture was stirred at 60 °C for 3 h. LCMS and HPLC showed compound 5 was consumed and the peak with desired mass was detected. The reaction mixture was concentrated to give a crude product, which was purified by pre-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:30%-70% B over 8.0 min). Compound Example 47 (197.34 mg, 479.86 μmol, 35.86% yield, 98.806% purity) was obtained as a white solid and confirmed by LCMS Example 46 and Example 48 are prepared by similar methods. The analytical data for Examples 45, 46, 47, and 48 are provided below. Compound NMR data Physical LCMS Property Result 1H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 8.10 (s, 1H), 8.04 (br d, J = 7.6 Hz, 1H), 375.0 Whit+7.69 (d, J = 8.5 Hz, e [M+H] 1H), 7.66 - 7.61 (m, solid 99.18% Example 45 1H), 7.60 - 7.44 (m, RT=3.337 3H), 7.35 - 7.29 (m, 2H), 3.53 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 1H), 8.03 - 7.96 (m, 425.1 2H), 7.83 (d, J = 7.8 White [M+H]+Hz, 1H), 7.80 - 7.74 solid 99.55% (m, 1H), 7.73 - 7.67 RT=2.733 Example 46 (m, 1H), 7.62 - 7.42 (m, 4H), 3.52 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 8.19 (s, 407.1 1H), 8.06 - 7.99 (m, White [M+H]+2H), 7.75 - 7.42 (m, solid 98.81% 7H), 6.95 (t, J = 55.0 RT=3.080 Example 47 Hz, 1H), 3.53 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 8.96 (d, J = 5.1 Hz, 1H), 8.85 (s, 1H), 8.24 (s, 1H), 426.1 Wh+8.05 - 8.01 (m, 1H), ite [M+H] 7.99 (s, 1H), 7.90 (d, J solid 96.07% = 5.1 Hz, 1 RT=2.895 Example 48 H), 7.70 - 7.43 (m, 3H), 3.55 (s, 3H) Example 49, Example 50, and Example 51:

[0059] Step 1: A mixture of compound 1 (2.00 g, 8.92 mmol, 1.00 eq) and MeMgBr (3.00 M, 20.8 mL, 7.00 eq) in THF (20 mL) was degassed and purged with N2 for 3 times at -70 °C, and then the mixture was stirred at -70 °C for 1 hr under N2 atmosphere. LC-MS showed 0% of Reactant remained. Several new peaks were shown on LC-MS and 74.0% of desired compound was detected. The reaction mixture was quenched by addition saturated NH4Cl water solution 100 mL at 25 °C, and then diluted with EtOAc 100 mL and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1). Compound 2 (1.80 g, 7.49 mmol, 83.9% yield) was obtained as a white oil. For other compounds, the procedure is the same as above with the amounts listed below: Reactant MeMgBr THF T Time Yie Product Compound ld 1 (g) (mL) (mL) (oC) (hrs) (%) Amount (g) 2.0 20.8 20 -70 2 35.8 0.80 2-A02 2.0 44.6 20 -70 2 67.3 1.60 2-A03 Step 2: To a solution of compound 2 (1.80 g, 7.49 mmol, 1.00 eq) in DCM (20 mL) was added DMP (3.81 g, 8.99 mmol, 2.79 mL, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 5 hrs. LC-MS showed 0% of Reactant remained. Several new peaks were shown on LC-MS and 84.2% of desired compound was detected. The reaction mixture was quenched by addition saturated NaHCO3water solution 100 mL at 25 °C, and then diluted with DCM 100 mL, filtered and extracted with DCM 300 mL (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. Compound 3 (1.75 g, 7.35 mmol, 98.0% yield) was obtained as a white solid. For other compounds, the procedure is the same as above with the amounts listed below:

[0060] ound Reactant DM Product Comp P DCMoTime Yield 2 (g) (g) (mL) T ( C) (hrs) (%) Amount (g) 0.80 1.60 10 25 5 94.5 0.75 3-A02 1.60 3.06 20 25 5 97.6 1.55 3-A03 Step 3: To a solution of compound 3 (0.875 g, 3.67 mmol, 1.00 eq) in MeOH (10 mL) was added compound 4 (749 mg, 3.67 mmol, 1.00 eq). The mixture was stirred at 50 °C for 16 hrs. LC-MS showed 0% of Reactant remained. Several new peaks were shown on LC-MS and 72.9% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 5 (1.14 g, 2.69 mmol, 73.1% yield) was obtained as a white solid. For other compounds, the procedure is the same as above with the amounts listed below:

[0061] ompound 3 (g) 4 (g) MeOH Product C (mL) T (oC) Time Yield (hrs) (%) Amount (g) 0.50 0.40 5 50 16 55.2 0.48 5-A02 0.75 0.63 10 50 16 58.6 0.75 5-A03 Step 4: Example 49 To a solution of compound 5 (500 mg, 1.18 mmol, 1.00 eq) in DMF (5 mL) was added MeI (200 mg, 1.41 mmol, 88.0 μL, 1.20 eq) and K2CO3(488 mg, 3.54 mmol, 3.00 eq). The mixture was stirred at 25 °C for 7 hrs. LC-MS showed 0% of Reactant remained. Several new peaks were shown on LC-MS and 82.9% of desired compound was detected. The reaction mixture was partitioned between EtOAc 100 mL and water 100 mL. The organic phase was separated concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1).1HNMR indicated desired compound. Compound (Example 49) (400 mg, 912 μmol, 77.4% yield) was obtained as a yellow solid. For other compound, the procedure is the same as Example 49 above with the amounts listed below: Reactant DMF Tim Product Compound 5 (g) MeI (g) (mL) T (oC) e Yield (hrs) (%) Amount (g) Example 50 0.480.185 25 7 60.5 0.30Example 51 0.750.288 25 7 38.7 0.30

[0062] Analytical information of Example 49, Example 50, and Example 51: Physical LC-MS Compound NMR data Property Result 1H NMR (400 MHz, DMSO-d6) δ = 8.18 (s, 439.1 2H), 7.97 (d, J = 8.4 Hz, Yellow [M+H]+1H), 7.92 - 7.52 (m, 5H), 7.39 (m, 1H), 3.37 soli 95.73% 7.46 - d RT = 3.010 (s, 2H), 3.09 (s, 1H), 2.46 - 2.33 (m, 3H) Example 49 1H NMR (400 MHz, DMSO-d6) δ = 8.22 - 8.08 (m, 2H), 8.01 - 7.80 (m, 2H), 7.77 - 7.63 (m, 2H), 453.1 White soli [M+H]+7.62 - 7.51 (m, 2H), 7.49 d - 7.38 (m, 1H), 3.38 (br s, 96.84% 2H), 3.05 (br s, 1H), 2.97 RT = 3.093 - 2.75 (m, 2H), 1.10 - 0.96 Example 50 (m, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (br dd, J = 8.3, 54.8 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.86 465.1 .34 White s [M+H]+- 7.60 (m, 3H), 7.59 - 7 olid (m, 3H), 3.59 (s, 2H), 98.44% 3.11 (s, 1H), 2.33 - 1.97 RT = 3.077 (m, 1H), 1.25 - 1.00 (m, Example 51 2H), 0.76 - 0.44 (m, 2H) Example 52, Example 53, and Example 54:

[0063] General Scheme for Example 52 To a solution of Cpd.2a (0.5 g, 2.41 mmol, 1 eq), A01 (611 mg, 2.41 mmol, 1 eq) and in DMF (5 mL) was added CMPI (925 mg, 3.62 mmol, 1.5 eq) and DIEA (624 mg, 4.83 mmol, 841 μL, 2 eq). The mixture was stirred at 25 °C for 16hrs. LC-MS showed Cpd.2a was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1). Example 52 (0.3 g, 678 μmol, 28.1% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (d,J = 1.5 Hz, 1H), 8.60 - 8.47 (m, 1H), 8.40 (dd, J = 2.1, 8.4 Hz, 1H), 8.19 - 8.13 (m, 1H), 8.11 - 8.05 (m, 1H), 7.72 - 7.55 (m, 2H), 7.46 - 7.32 (m, 1H), 3.64 - 3.51 (m, 3H) For other compounds, the procedure is the same as Example 52 above with the amounts are listed below: 2b, A01 Solvent Time Yie Product Compound 2c DMF CMPI DIold (mg) EA T ( C) (hrs) (% Amount (mg) (mL) ) (mg) Example 53 500 611 5.00 925 624 25 16 37.5 400 Example 54 500 611 5.00 925.19 624.04 25 16 42.1 450

[0064] Analytical information for Example 52, Example 53, and Example 54: Physical LC-MS Compound NMR data Property Result 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (d,J = 1.5 Hz, 1H), 8.60 - 8.47 (m, 443.1 1H), 8.40 (dd, J = 2.1, 8.4 [M+H]+ Hz, 1H), 8.19 - 8.13 (m, white solid 97.95% 1H), 8.11 - 8.05 (m, 1H), RT = 7.72 - 7.55 (m, 2H), 7.46 - 2.528 Example 52 7.32 (m, 1H), 3.64 - 3.51 (m, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.22 (dd,J = 0.7, 2.1 Hz, 1H), 8.94 - 8.65 443.1 (m, 2H), 8.39 (dd, J = 2.1, [M+H]+ 8.4 Hz, 1H), 8.12 (s, 1H), Off-white 98.05% 7.70 (d, J = 4.6 Hz, 1H), solid RT = 7.60 - 7.43 (m, 1H), 7.34 (d, 2.410 Example 53 J = 8.3 Hz, 1H), 3.59 (s, 3H) 1H NMR (400 MHz, DMSO-d6) δ = 9.21 (d, J = 1.6 Hz, 1H), 8.68 (dd, J = 443.0 1.0, 4.8 Hz, 1H), 8.36 (dd, J [M+H]+ = 2.1, 8.4 Hz, 1H), 8.16 - Off-white 96.21% 8.03 (m, 2H), 7.78 - 7.68 solid RT = (m, 1H), 7.59 - 7.41 (m, 2.403 Example 54 1H), 7.22 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H) Example 55:

[0065] Step 1: To a solution of compound 1 (25.0 g, 152 mmol) and 2,2-dimethoxypropane (23.8 g, 228 mmol) in MeOH (250 mL) was added TsOH (2.62 g, 15.2 mmol). The mixture was stirred at 25 °C for 12 hr. LC-MS showed compound 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound 2 (26.0 g 81.2% yield) as a white solid. LCMS: (product: RT = 0.353 mins) Step 2: To a solution of compound 2 (5.00 g, 23.8 mmol) in EtOH (50 mL) was added N2H4-H2O (2.98 g, 47.6 mmol) at 25 °C. The mixture was stirred at 80 °C for 2 hr. TLC (petroleum ether : ethyl acetate = 1 : 1, Rf = 0.3) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give compound 3 (6.20 g, crude) as a white solid, which was used into the next step without further purification.1H NMR: (400 MHz, DMSO-d6) δ 9.78 (br s, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 5.42 (s, 1H), 3.25 (s, 6H) Step 3: (2,2-difluoroacetyl) 2,2-difluoroacetate (16.6 g, 95.1 mmol) was added to a mixture of compound 3 (5.00 g, 23.8 mmol) and TEA (12.0 g, 118 mmol) in THF (100 mL) at -70 - -50 °C slowly. The mixture was warmed to 15 - 25 °C slowly and stirred for 2 hr. LC-MS showed compound 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O (100 mL) and EtOAc (300 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound 4 (3.20 g 60.0% yield) as a white solid. LCMS: LCMS (product: RT = 0.305 mins) Step 4: To a solution of compound 4 (1.80 g, 8.03 mmol) in MeOH (18.0 mL) was added CH3NHNH2(1.39 g, 12.0 mmol). The mixture was stirred at 20 °C for 2 hr. LC-MS showed compound 4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered, and the filter cake was triturated with MTBE (10 mL) at 25oC for 30 mins to give compound 5 (1.40 g 69.13% yield) as a yellow solid. LCMS: (product: RT = 0.572 mins)1H NMR: (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.55 (s, 1H), 6.92 (t, J = 51.8 Hz, 1H), 3.05 (s, 3H) Step 5: To a solution of 2,3,4,5,6-pentafluorobenzoic acid (1.68 g, 7.93 mmol) in DCM (10.0 mL) was added TCFH (2.00 g, 7.14 mmol), NMI (0.813 g, 9.91 mmol) and compound 5 (1.00 g, 3.96 mmol). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O (30 mL) and DCM (100 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MeCN (30 mL) at 25oC for 30 mins to give compound Example 55 (600.0 mg 33.91% yield) as a yellow solid. LCMS: LCMS (product: RT = 2.342 mins)1H NMR: EC22274-17-P1J3 (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 51.3 Hz, 1H), 3.58 (s, 3H) Example 56:

[0066] Step 1: To a solution of compound 1 (23.0 g, 137 mmol) in DCM (500 mL) was added MnO2 (119 g, 1.38 mol). The mixture was stirred at 25 °C for 4 hr. TLC (petroleum ether : ethyl acetate = 2 : 1, Rf = 0.3) showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure to give compound 2 (23.0 g, crude) as a white solid, which was used into the next step without further purification.1H NMR (400 MHz, CD3Cl) δ 10.17 (d, J = 0.8 Hz, 1H), 9.39 (dd, J = 0.7, 1.9 Hz, 1H), 8.61 - 8.38 (m, 1H), 8.06 (dd, J = 0.8, 8.1 Hz, 1H), 4.03 (s, 3H) Step 2: To a solution of compound 2 (10.0 g, 60.5 mmol) and ethylene glycol (15.0 g, 242 mmol) in toluene (200 mL) was added TsOH (1.04 g, 6.06 mmol). The mixture was stirred at 110 °C for 16 hr. LC-MS showed compound 2 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give compound 3 (12.0 g crude) as a white solid, which was used into the next step without further purification. LCMS: (product: RT = 0.267 mins) Step 3: To a solution of compound 3 (7.00 g, 33.4 mmol) in EtOH (70 mL) was added N2H4-H2O (5.98 g, 117 mmol). The mixture was stirred at 80 °C for 16 hr. LC-MS showed compound 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give compound 4 (6.00 g, crude) as a white solid, which was used into the next step without further purification. LCMS: (product: RT = 0.239 mins) Step 4: To a solution of compound 4 (6.00 g, 28.7 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (29.9 g, 172 mmol) in DCM (120 mL) was added Imidazole (8.79 g, 129 mmol). The mixture was stirred at 40 °C for 2 hr. LC-MS showed compound 4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O (100 mL) and DCM (300 mL). The organic phase was separated, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~15% THF / Petroleum ether @ 100 mL / min) to give compound 5 (6.40 g, 82.9% yield) as a white solid. LCMS: LCMS (product: RT = 0.294 mins)1H NMR:(400 MHz, CD3Cl) δ 9.35 (d, J = 1.4 Hz, 1H), 8.47 (dd, J = 2.1, 8.2 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 51.6 Hz, 1H), 5.95 (s, 1H), 4.23 - 4.11 (m, 4H) Step 5: A solution of compound 5 (600.0 mg, 2.23 mmol) in HCOOH (5 mL) was stirred at 80 °C for 4 hr. LC-MS showed ~48% of desired compound was detected. The reaction mixture was quenched by addition of aq Na2HCO3 (100 mL) at 25 °C, and then diluted with brine (50 mL) and extracted with THF (100 mL * 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give compound 6 (800.0 mg 19.9% yield) as a yellow solid. LCMS: (product: RT = 0.371 mins);1H NMR :EC22274-33-P1(400 MHz, CD3Cl) δ 10.18 (s, 1H), 9.53 (d, J = 1.9 Hz, 1H), 8.61 (dd, J = 1.9, 8.1 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 6.98 (t, J = 51.6 Hz, 1H) Step 6: To a solution of compound 6 (800.0 mg, 3.55 mmol) in MeOH (8.00 mL) was added methylhydrazine (613.0 mg, 5.33 mmol, 40% purity). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 6 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered, and the filter cake was collected to give compound 7 (1.00 g, crude) as a white solid, which was used for next step directly. LCMS: (product: RT = 0.244 mins) Step 7: To a solution of 2,3,4,5,6-pentafluorobenzoic acid (1.01 g, 4.74 mmol) in DCM (10 mL) was added TCFH (1.20 g, 4.27 mmol), NMI (486.0 mg, 5.92 mmol) and compound 7 (600.0 mg, 2.37 mmol). The mixture was stirred at 25 °C for 2 hr. LC-MS showed compound 7 was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between H2O (30 mL) and DCM (100 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~16% THF / Petroleum ether gradient @ 40 mL / min) to give compound Example 56 (460.0 mg 43.4% yield) as a white solid. LCMS: (product: RT = 2.201 mins);1H NMR: (400 MHz, DMSO-d6) δ 9.24 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 2.1, 8.3 Hz, 1H), 8.18 (s, 1H), 7.83 - 7.37 (m, 2H), 3.62 (s, 3H) Example 57, Example 58, and Example 59:

[0067] Step 1: A mixture of compound 1 (2.00 g, 10.5 mmol, 1.00 eq) in dioxane (20 mL) and H2O (4 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5.30 g, 21.1 mmol, 5.90 mL, 2.00eq), K2CO3(4.08 g, 29.5 mmol, 2.80 eq) and Pd(PPh3)4 (1.22 g, 1.06 mmol, 0.100 eq) degassed and purgedwith N2for 3 times and then the mixture was stirred at 110 °C for 12 hrs under N2atmosphere.LC-MS showed compound 1 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and then the filtrate was diluted with H2O 50 mL and extracted with EtOAc 150 mL (50 mL *3). The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 1 / 1). Compound 1a (780 mg, 4.38 mmol, 41.5% yield, 95.0% purity) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 8.52 (dd, J = 8.13, 5.75 Hz, 1 H) 6.96 (dd, J = 9.13, 5.75 Hz, 1 H) 3.85 - 4.06 (m, 3 H) 2.53 - 2.76 (m, 3 H) Step 2: To a solution of compound 1a (680 mg, 4.02 mmol, 1.00 eq) in THF (3 mL) and H2O (3 mL) was added NaOH (192 mg, 4.82 mmol, 1.20 eq). The mixture was stirred at 25 °C for 12 hrs. LC-MS showed compound 1a was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2a (500 mg, crude) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 11.68 - 12.08 (m, 1 H) 11.68 - 12.08 (m, 1 H) 8.43 (dd, J = 8.57, 5.69 Hz, 1 H) 7.18 (dd, J = 9.26, 5.75 Hz, 1 H) 2.50 (br s, 3 H) Step 3: To a solution of compound 2a (500 mg, 3.22 mmol, 1.00 eq) in THF (5 mL) was added compound A01 (815 mg, 3.22 mmol, 1.00 eq), DIEA (1.67 g, 12.89 mmol, 2.25 mL, 4.00 eq) and CMPI (988.15 mg, 3.87 mmol, 1.20 eq). The mixture was stirred at 80 °C for 12 hrs. LC-MS showed 40% of compound 2a remained. Several new peaks were shown on LC-MS and 14% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min). Example 57 (200 mg, 492 μmol, 15.3% yield, 96.1% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3-d) δ ppm 9.29 (d, J=1.38 Hz, 1 H) 8.59 (dd, J=8.34, 5.71 Hz, 1 H) 8.27 (dd, J=8.28, 1.88 Hz, 1 H) 7.96 (s, 1 H) 7.42 (d, J=8.41 Hz, 1 H) 6.78 - 7.14 (m, 2 H) 3.65 (s, 3 H) 2.54 (s, 3 H) 2.02 (s, 1 H) General procedure for preparation of compound 3 To a solution of compound 2 (1.00 g, 5.84 mmol, 1.00 eq) in DMF (7 mL) was added K2CO3 (1.21 g, 8.77 mmol, 1.50 eq) and CH3I (995 mg, 7.01 mmol, 436 μL, 1.20 eq). The mixture was stirred at 25 °C for 2hrs. LC-MS showed compound 2 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was diluted with H2O 50 mL and extracted with EtOAc 150 mL (50 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. Compound 3 (1.10 g, crude) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3-d) δ ppm 8.19 (dd, J = 8.44, 5.87 Hz, 1 H) 6.73 (dd, J = 8.44, 5.87 Hz, 1 H) 3.94 (s, 3 H) 4.01 (s, 3 H) General procedure for preparation of compound 4 To a solution of compound 3 (1.00 g, 5.40 mmol, 1.00 eq) in MeCN (10 mL) was added TMSI (4.32 g, 21.6 mmol, 2.94 mL, 4.00 eq). The mixture was stirred at 25 °C for 2hrs. TLC (DCM: MeOH=10:1 Rf= 0.45) indicated compound 3 was consumed completely and many new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 50 / 1 to 10 / 1). Compound 4 (600 mg, crude) was obtained as a brown solid.1H NMR: (400 MHz, CDCl3-d) δ ppm 11.94 - 12.78 (m, 1 H) 7.76 (t, J = 7.19 Hz, 1 H) 6.29 (t, J = 7.44 Hz, 1 H) 3.92 (s, 3 H) General procedure for preparation of compound 1c To a solution of compound 4 (600 mg, 3.51 mmol, 1.00 eq) in MeCN (6 mL) was added 2, 2- difluoro-2-(fluorosulfonyl) acetic acid (811 mg, 4.56 mmol, 471 μL, 1.30 eq) and Na2SO4 (547 mg, 3.86 mmol, 391 μL, 1.10 eq). The mixture was stirred at 25 °C for 2 hrs. LC-MS showed compound 4 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was diluted with H2O 50 mL and extracted with EtOAc 150 mL (50 mL *3). The combined organic layers were concentrated under reduced pressure to give a residue. Compound 1c (670 mg, crude) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3-d) δ ppm 8.24 (dd, J = 7.94, 5.82 Hz, 1 H) 7.48 (t, J = 71.85 Hz, 1 H) 6.96 (dd, J = 8.25, 5.75 Hz, 1 H) 3.98 (s, 3 H) General procedure for preparation of compound 2c To a solution of compound 1c (530 mg, 2.40 mmol, 1.00 eq) in THF (3 mL) and H2O (3 mL) was added NaOH (115 mg, 2.88 mmol, 1.20 eq). The mixture was stirred at 25 °C for 2hrs. LC-MS showed compound 1c was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2c (450 mg, crude) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3-d) δ ppm 7.38 (dd, J = 8.76, 5.88 Hz, 1 H) 7.76 (t, J = 71.85 Hz, 1 H) 8.40 (dd, J = 8.26, 5.88 Hz, 1 H) General procedure for preparation of Example 58 To a solution of compound 2c (450 mg, 2.17 mmol, 1.00 eq) in THF (5 mL) was added compound A01 (550 mg, 2.17 mmol, 1.00 eq), DIEA (842 mg, 6.52 mmol, 1.14 mL, 3.00 eq) and CMPI (666 mg, 2.61 mmol, 1.20 eq). The mixture was stirred at 80 °C for 2 hrs. LC-MS showed compound 2c was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 22%-57% B over 8.0 min). Example 58 (200 mg, 440 μmol, 20.3% yield, 97.5% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3-d) δ ppm 9.30 (d, J = 1.51 Hz, 1 H) 8.23 - 8.34 (m, 2 H) 7.97 (s, 1 H) 7.28 - 7.67 (m, 2 H) 6.75 - 7.10 (m, 2 H) 3.64 (s, 3 H) General procedure for preparation of compound 1d

[0068] A mixture of compound 1 (2.00 g, 10.5 mmol, 1.00 eq) in Tol. (20 mL) and H2O (4 mL)was added potassium;cyclopropyl(trifluoro)boranuide (3.90 g, 26.4 mmol, 2.50 eq), tricyclohexylphosphane (295 mg, 1.06 mmol, 342μL, 0.100 eq), tripotassium;phosphate (7.84 g, 36.9 mmol, 3.50 eq) and Pd(PPh3)4(1.22 g, 1.06 mmol, 0.100 eq) degassed and purged with N2for 3 times, and then the mixture was stirred at 120 °C for 12 hrs under N2 atmosphere. LC-MS (ET88800-29-P1A1) showed 11% of compound 1 was remained and desired m / z was detected. The reaction mixture was filtered and the filtrate was diluted with H2O 50mL and extracted with EtOAc 150mL (50mL *3). The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1 Plate 1). Compound 1d (550 mg, 2.73 mmol, 25.9% yield, 97.0% purity) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3-d) δ ppm 8.44 (br t, J = 6.88 Hz, 1 H) 6.75 - 6.92 (m, 1 H) 3.99 (d, J = 1.13 Hz, 3 H) 2.17 - 2.31 (m, 1 H) 1.18 (br d, J = 2.13 Hz, 2 H) 1.00 - 1.09 (m, 2 H) General procedure for preparation of compound 2d To a solution of compound 1d (530 mg, 2.72 mmol, 1.00 eq) in THF (3 mL) and H2O (3 mL) was added NaOH (130 mg, 3.26 mmol, 1.20 eq). The mixture was stirred at 25 °C for 12 hrs. LC-MS showed compound 1d was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2d (450 mg, crude) was obtained as a yellow solid. General procedure for preparation of Example 59

[0069] To a solution of compound 2d (450 mg, 2.39 mmol, 1.00 eq) in THF (5 mL) was added compound A01 (603 mg, 2.38 mmol, 1.00 eq), DIEA (611 mg, 4.73 mmol, 1.25 mL, 2.00 eq) and CMPI (733 mg, 2.87 mmol, 1.20 eq). The mixture was stirred at 80 °C for 2 hrs. LC-MS showed compound 2d was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: XPT C18150*307u; mobile phase: [H2O (10mM NH4HCO3)- ACN]; gradient: 25%-55% B over 8.0 min). Example 59 (324 mg, 767 μmol, 32.1% yield, 98.6% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3-d) δ ppm 9.29 (dd, J = 2.13, 0.75 Hz, 1 H) 8.50 (dd, J = 8.47, 5.58 Hz, 1 H) 8.28 (dd, J = 8.41, 2.13 Hz, 1 H) 7.96 (s, 1 H) 7.47 (dd, J = 8.41, 0.63 Hz, 1 H) 6.79 - 7.10 (m, 2 H) 3.67 (s, 3 H) 1.85 - 1.96 (m, 1 H) 1.17 - 1.26 (m, 1 H) 1.08 - 1.15 (m, 1 H) 0.98 - 1.07 (m, 1 H) 0.83 - 0.93 (m, 1 H) Analytical information of Example 57, Example 58, and Example 59:

[0070] Physical LCMS Compound NMR data Property Result 1H NMR: (400 MHz, CDCl3-d) δ ppm 9.29 (d, J=1.38 Hz, 1 H) 8.59 (dd, J=8.34, 5.71 Hz, 1 391.1 H) 8.27 (dd, J=8.28, 1.88 Yellow [M+H]+Hz, 1 H) 7.96 (s, 1 H) solid 96.07 % 7.42 (d, J=8.41 Hz, 1 H) RT = 6.78 - 7.14 (m, 2 H) 3.65 2.428 Example 57 (s, 3 H) 2.54 (s, 3 H) 2.02 (s, 1 H) 1H NMR: (400 MHz, CDCl3-d) δ ppm 9.30 443.1 (d, J = 1.51 Hz, 1 H) 8.23 [+8.34 (m, 2 H) 7.97 (s, 1 Y M+H] - ellow 8 - 7.67 (m, 2 H) soli 97.45% H) 7.2 d RT = 6.75 - 7.10 (m, 2 H) 3.64 2.867 (s, 3 H) Example 58 1H NMR: (400 MHz, CDCl3-d) δ ppm 9.29 (dd, J = 2.13, 0.75 Hz, 1 H) 8.50 (dd, J = 8.47, 5.58 Hz, 1 H) 8.28 (dd, J = 8.41, 2.13 Hz, 1 H) 417.1 [M+H]+7.96 (s, 1 H) 7.47 (dd, J Yellow = 8.41, 0.63 Hz, 1 H) solid 98.56% 6.79 - 7.10 (m, 2 H) 3.67 RT = (s, 3 H) 1.85 - 1.96 (m, 1 2.725 Example 59 H) 1.17 - 1.26 (m, 1 H) 1.08 - 1.15 (m, 1 H) 0.98 - 1.07 (m, 1 H) 0.83 - 0.93 (m, 1 H) Example 60 and Example 61:

[0071] General procedure for preparation of compound 1a To a solution of compound 1 (3.00 g, 12.8 mmol, 1.00 eq) and compound 2 (6.44 g, 25.6 mmol, 7.17 mL, 2.00 eq) in dioxane (30.0 mL) and H2O (6.00 mL) was added K2CO3(4.96 g, 35.8 mmol, 2.80 eq). Then Pd(PPh3)4(1.48 g, 1.28 mmol, 0.100 eq) was added to above mixture. The mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 110 °C for 12 hrs. LC- MS showed compound 1 was consumed completely and desired mass was detected. The reaction mixture was diluted with H2O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-MPLC (SiO2, PE / EA = 3 / 1). Compound 1a (700 mg, 4.14 mmol, 32.3% yield) was obtained as a yellow solid. HNMR: (400 MHz, CHLOROFORM-d) δ ppm 8.41 (s, 1 H), 8.35 (s, 1 H), 3.98 (s, 3 H), 2.41 (s, 3 H) General procedure for preparation of compound 2a To a solution of compound 1a (600 mg, 3.55 mmol, 1.00 eq) in THF (6.00 mL) and H2O (3.00 mL) was added NaOH (242 mg, 5.32 mmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LC-MS showed compound 1a was consumed completely and desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE / EA = 5 / 1). Compound 2a (500 mg, 3.22 mmol, 90.8% yield) was obtained as an off- white solid. HNMR: (400 MHz, METHANOL-d4) δ ppm 8.21 (s, 1 H), 8.18 (s, 1 H), 2.37 (s, 3 H) General procedure for preparation of Example 60 To a solution of compound 2a (500 mg, 3.22 mmol, 1.00 eq), compound A01 (652 mg, 2.58 mmol, 0.800 eq) and DIEA (1.25 g, 9.67 mmol, 1.68 mL, 3.00 eq) in THF (5.00 mL) was added CMPI (988 mg, 3.87 mmol, 1.20 eq). The mixture was stirred at 80 °C for 2 hrs. LC-MS showed Compound 2a was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: WePure Biotech XP tC18 250*70*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 20%-55% B over 20.0 min). Example 60 (340 mg, 871 μmol, 27.0% yield) was obtained as a yellow solid.1HNMR: (400 MHz, CHLOROFORM-d) δ ppm 9.29 (d, J = 1.47 Hz, 1 H), 8.43 (s, 1 H), 8.40 (s, 1 H), 8.27 (dd, J = 8.31, 1.83 Hz, 1 H), 7.98 (s, 1 H), 7.39 (d, J = 8.31 Hz, 1 H), 6.94 (t, J = 51.59 Hz, 1 H), 3.64 (s, 3 H), 2.32 (s, 3 H) General procedure for preparation of compound 1B_1 To a solution of compound 1B (30.0 g, 188 mmol, 1.00 eq) in MeOH (210 mL) was added SOCl2 (33.7 g, 282 mmol, 20.5 mL, 1.50 eq). The mixture was stirred at 70 °C for 12 hrs. LC-MS showed compound 1B was consumed completely and desired mass was detected. The reaction mixture was concentrated, the residue was partitioned between EtOAc (100 mL) and Sat. aq. Na2CO3 (200 mL). The aqueous was extracted with EtOAc (100 mLx2) and the combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 1B_1 (20.0 g, 115 mmol, 61.3% yield) was obtained as a yellow oil. HNMR: (400 MHz, CHLOROFORM-d) δ ppm 8.46 (s, 2 H), 4.01 (s, 3 H) General procedure for preparation of compound 1b To a solution of compound 1B_1 (15.0 g, 86.6 mmol, 1.00 eq) in MeOH (105 mL) was added NaOMe (23.4 g, 130 mmol, 30% purity, 1.50 eq). The mixture was stirred at 25 °C for 1 hr. LC- MS showed compound 1B_1 was consumed completely and desired mass was detected. The reaction mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 1b (10.0 g, 54.0 mmol, 62.3% yield) was obtained as a yellow solid. HNMR: (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J = 2.47 Hz, 2 H), 3.98 (s, 3 H), 3.96 (s, 3 H) General procedure for preparation of compound 2b To a solution of compound 1b (1.00 g, 5.40 mmol, 1.00 eq) in THF (5.00 mL) and H2O (5.00 mL) was added NaOH (281 mg, 7.02 mmol, 1.20 eq). The mixture was stirred at 25 °C for 2 hrs. LC- MS showed compound 1b was consumed completely and desired mass was detected. The reaction mixture was concentrated and dried to give a residue. Compound 2b (700 mg, 4.09 mmol, 75.7% yield) was obtained as a white solid. HNMR: (400 MHz, METHANOL-d) δ ppm 8.31 (s, 3 H) 8.23 (s, 1 H) 4.01 (s, 1 H) General procedure for preparation of Example 61 To a solution of compound 2b (500 mg, 2.92 mmol, 1.00 eq) in THF (5.00 mL) was added compound A01 (591 mg, 2.34 mmol, 0.800 eq), DIEA (1.13 g, 8.77 mmol, 1.53 mL, 3.00 eq) and CMPI (895.77 mg, 3.51 mmol, 1.20 eq). The mixture was stirred at 80 °C for 2 hrs. LC-MS showed compound 2b was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18250*70*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 20%-55% B over 20.0 min). Example 61 (328 mg, 807 μmol, 27.6% yield) was obtained as a yellow solid.1HNMR: (400 MHz, CHLOROFORM -d) δ ppm 9.29 (d, J = 1.22 Hz, 1 H) 8.30 (s, 1 H) 8.25 - 8.29 (m, 2 H) 7.95 (s, 1 H) 7.42 (d, J = 8.31 Hz, 1 H) 6.94 (t, J = 51.65 Hz, 1 H) 3.95 (s, 3 H) 3.62 (s, 3 H) Analytical information of Example 60 and Example 61: Physical LCMS Compound NMR data Property Result 1H NMR: (400 MHz, CDCl3-d) δ ppm 9.29 (d, J = 1.47 Hz, 1 H), 8.43 (s, 1 H), 8.40 (s, 1 H), 391.1 dd, J = 8.31, 1.83 Hz, 1 Yellow [M++8.27 ( H] H), 7.98 (s, 1 H), 7.39 (d, J = solid 99.89 % 8.31 Hz, 1 H), 6.94 (t, J = 51.59 RT = Hz, 1 H), 3.64 (s, 3 H), 2.32 (s, 2.583 Example 60 3 H) 1HNMR: (400 MHz, CDCl3-d) δ ppm 9.29 (d, J = 1.22 Hz, 1 H) 407.1 8.30 (s, 1 H) 8.25 - 8.29 (m, 2+Yel [M+H] H) 7.95 (s, 1 H) 7.42 (d, J = 8.31 low 1 H) 6.94 (t, J = 51.65 Hz, s 98.68% Hz, olid RT = 1 H) 3.95 (s, 3 H) 3.62 (s, 3 H) 2.550 Example 61 Example 62:

[0072] To a solution of compound 1 (500 mg, 2.91 mmol, 1.00 eq) in DMF (5.00 mL) was added DIEA (1.13 g, 8.74 mmol, 1.52 mL, 3.00 eq), HATU (1.22 g, 3.21 mmol, 1.10 eq), compound 1A (420 mg, 2.91 mmol, 1.00 eq). The mixture was stirred at 50 °C for 2 hrs. Compound A01 (656.11 mg, 2.91 mmol, 1 eq) was added to the mixture was stirred at 50 °C for 2 hrs. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected. Filtered the mixture and the filtrate was concentrated to get the crude product. The residue was purified by prep-HPLC (column: Welch Xtimate C18 180*70mm#10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:30%-60% B over 21.0 min). Example 62 (312 mg, 1.03 mmol, 35.3% yield, 98.8% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.21 (d, J = 1.6 Hz, 1H), 8.41 - 8.36 (m, 2H), 8.12 (s, 1H), 7.71 - 7.41 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.22 (s, 3H) Example 63:

[0073] General procedure for preparation of Cpd.2_2 To a solution of Cpd.2_1 (5.00 g, 22.2 mmol, 1 eq) in DMF (50.0 mL) was added K2CO3(4.60 g, 33.3 mmol, 1.5 eq) and CH3I (3.78 g, 26.6 mmol, 1.66 mL, 1.2 eq). Stir the mixture at 25 °C for 16 hrs. LC-MS showed Cpd.1_1 was consumed and one main peak with desired mass was detected. Filter and concentrate the organic layers under reduced pressure to give a residue. Obtain the desired product Cpd.1_2 (4.70 g, crude) as yellow oil. General procedure for preparation of Cpd.2_3 To a solution of Cpd.1_2 (4.70 g, 19.6 mmol, 1 eq) and cyclopropylboronic acid (2.53 g, 29.4 mmol, 1.5 eq) in dioxane (47.0 mL) and H2O (5.00 mL) was added Pd(dppf)Cl2 (1.44 g, 1.96 mmol, 0.1 eq) and K2CO3(8.13 g, 58.8 mmol, 3 eq). Stir the mixture at 100 °C for 16 hrs. LC-MS showed Cpd.2_2 was consumed and one main peak with desired mass was detected. Concentrate the organic layers under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 3 / 1). Obtain the desired product Cpd.2_3 (2.80 g, 11.4 mmol, 58.2% yield) as yellow solid. General procedure for preparation of Cpd.2_4 To a solution of methyl Cpd.2_3 (2.80 g, 11.4 mmol, 1 eq) in MeOH (28.0 mL) and H2O (28.0 mL) was added NaOH (913 mg, 22.8 mmol, 2 eq). Stir the mixture at 50 °C for 36 hrs. LC-MS showed Cpd.2_3 was consumed and one main peak with desired mass was detected. Concentrated under reduced pressure to give a residue, and then diluted with H2O 10.0 mL and extracted with DCM 30.0 mL (10.0 mL * 3). Adjust pH=3 by addition 1 N HCl, and extracted with DCM 30 mL (10 mL * 3). Obtain the desired product Cpd.2_4 (2.30 g, crude) as white solid. General procedure for preparation of Cpd.2_6 To a solution of Cpd.2_4 (2.10 g, 9.08 mmol, 1 eq) and tert-butyl N-(methylamino)carbamate (1.59 g, 10.9 mmol, 1.2 eq) in THF (21.0 mL) was added BOP-Cl (2.78 g, 10.9 mmol, 1.2 eq) and DIEA (3.52 g, 27.3 mmol, 4.75 mL, 3 eq). Stir the mixture at 25 °C for 16 hrs. LC-MS showed Cpd.2_4 was consumed and one main peak with desired mass was detected. Concentrate the organic layers under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1). Obtain the desired product Cpd.2_6 (2.60 g, 7.24 mmol, 79.7% yield) as white solid. General procedure for preparation of Cpd.2_7 To a solution of Cpd.2_6 (1.00 g, 2.78 mmol, 1 eq) in TFE (10.0 mL) was added TMSCl (605 mg, 5.57 mmol, 706 μL, 2 eq). Stir the mixture at 25°C for 16 hrs. LC-MS showed Cpd.2_6 was consumed and one main peak with desired mass was detected. Concentrate the organic layers under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 5 / 1). Obtain the desired product Cpd.2_7 (0.7 g, crude, HCl) as white solid. General procedure for preparation of Example 63

[0074] To a solution of Cpd.2_7 (400 mg, 1.35 mmol, 1 eq, HCl) and Cpd.a (305 mg, 1.35 mmol, 1 eq) in THF (4.00 mL). Stir the mixture at 40 °C for 16 hrs. LC-MS showed Cpd.2_7 was consumed and one main peak with desired mass was detected. Concentrate the organic layers under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB SiO210u 100*30mm;mobile phase: [Heptane-EtOH];gradient:5%-80% B over 10.0 min). Obtain Example 63 (400 mg, 858 μmol, 63.4% yield) as white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.31 (d, J = 1.5 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.27 (dd, J = 2.1, 8.4 Hz, 1H), 7.96 (s, 1H), 7.39 (d, J = 5.3 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.14 - 6.79 (m, 1H), 3.69 (s, 3H), 1.95 - 1.83 (m, 1H), 1.34 - 1.22 (m, 1H), 1.13 - 0.98 (m, 2H), 0.95 - 0.84 (m, 1H). Example 64: General procedure for preparation of compound 2 A mixture of 2,2,6,6-tetramethylpiperidine (4.43 g, 31.40 mmol, 3 eq) in THF (30 mL) was degassed and purged with N2 for 3 times. The mixture was cooled to -70 °C and then n-BuLi (2.5 M, 16.74 mL, 4 eq) was added dropwise and then the mixture was stirred at -70 °C for 1 hr. Then a solution of compound 1 (2.00 g, 10.47 mmol, 1 eq) in THF was added at -70°C and the mixture was slowly warmed to -50 °C over 1 hr. And then C2Cl6 (7.43 g, 31.40 mmol, 3 eq) was added and the mixture was slowly warmed to 0 °C. The mixture was stirred at 0 °C for 1 hr under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition of HCl (2 M) at 0 °C until pH = 7, and then diluted with brine (50 mL) and extracted with EtOAc (75 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 2 (2.00 g, 42.36% yield) was obtained as a brown oil, which was used into the next step without further purification. General procedure for preparation of compound 3 A solution of compound 2 (2.00 g, 8.87 mmol, 1 eq) in NaOMe (10 mL, 30% in MeOH) was stirred at 30 °C for 12 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (10 mL) and HCl (2 M) was added until pH = 7. The mixture was extracted with EtOAc (25 mL * 2). The aqueous phase was lyophilized to remove water. The residue was then triturated with MeOH / DCM (v / v=1 / 1). The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 3 (1.50 g, 75.11% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.33 (d, J = 5.5 Hz, 1H), 7.15 (d, J = 5.6 Hz, 1H), 3.80 (s, 3H) General procedure for preparation of compound Example 64 A solution of compound 3 (800.0 mg, 3.62 mmol, 1 eq), compound 4 (916.04 mg, 3.62 mmol, 1 eq), DIEA (2.34 g, 18.09 mmol, 3.15 mL, 5 eq) and CMPI (1.85 g, 7.24 mmol, 2 eq) in THF (10 mL) was stirred at 80 °C for 16 hr. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL) at 20 °C, and extracted with EtOAc (50.0 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase flash (H2O / MeOH = 1:0,0:1). Compound Example 64 (320.0 mg, 19.38% yield) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.75 (d, J = 5.8 Hz, 1H), 8.36 (dd, J = 1.7, 8.4 Hz, 1H), 8.06 (s, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.56 (t, J = 51.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.56 (s, 3H) Analytical information of Example 64: Physical LC-MS Structure NMR data Property Result 1H NMR (400 MHz, DMSO- d6) δ = 9.20 (s, 1H), 8.75 (d, 457.1 J = 5.8 Hz, 1H), 8.36 (dd, J = [M+H]+1.7, 8.4 Hz, 1H), 8.06 (s, 1H), Yellow 98.93% 7.52 (d, J = 5.6 Hz, 1H), 7.56 solid RT = (t, J = 51.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 1.771 Example 64 3.56 (s, 3H) Example 65 and Example 66: General procedure for preparation of compound Example 65 To a solution of compound 1 (1.00 g, 5.84 mmol, 1.00 eq) in THF (1 mL) was added TCFH (2.95 g, 10.5 mmol, 1.80 eq), NMI (1.20 g, 14.61 mmol, 1.16 mL, 2.50 eq) and N-[(E)-[5-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyleneamino]methanamine (1.48 g, 5.84 mmol, 1.00 eq). The mixture was stirred at 25 °C for 12 hr. LC-MS showed compound 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase flash (CH3CN / H2O = 0-100%). Compound Example 65 (430.00 mg, 78.5% yield) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.22 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 2.0, 8.4 Hz, 1H), 8.30 (d, J = 5.9 Hz, 1H), 8.08 (s, 1H), 7.58 (t, J = 51.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 3.90 (s, 3H), 3.56 (s, 3H) General procedure for preparation of compound 2 To a mixture of compound 1 (5.00 g, 28.41 mmol, 1.00 eq) in THF (50 mL) was added LDA (2.50 M, 23.87 mL, 2.10 eq) under N2 atmosphere, and then the mixture was stirred at -78 °C for 0.5 hr. Then Boc2O (13.02 g, 59.66 mmol, 13.71 mL, 2.10 eq) was added and then the mixture was stirred at 25 °C for 1.5 hr under N2atmosphere. LC-MS showed compound 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of saturated NH4Cl aq. (30 mL) at 0 °C under N2 atmosphere, and then diluted with EtOAc (500 mL) and extracted with H2O (500 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound 2 (5.40 g, 68.8% yield) was obtained as a white solid. General procedure for preparation of compound 3 A mixture of cyclopropylboronic acid (2.47 g, 28.8 mmol, 1.50 eq), compound 2 (5.3 g, 19.2 mmol, 1.00 eq), K3PO4 (12.2 g, 57.6 mmol, 3.00 eq) and Pd(dppf)Cl2.CH2Cl2 (1.57 g, 1.92 mmol, 0.10 eq) in dioxane (70 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 96 °C for 12 hr under N2atmosphere. LC-MS showed no compound 2 remained. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was diluted with EtOAc (200 mL) and extracted with H2O (200 mL). The organic layerwas washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound 3 (3.80 g, 83.4% yield) was obtained as a yellow oil. General procedure for preparation of compound 4 To a solution of compound 3 (500.0 mg, 2.11 mmol, 1.00 eq) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 12 hr. LC-MS showed compound 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse- phase flash (CH3CN / H2O = 0-100%). Compound 4 (500.0 mg, crude) was obtained as a white solid. General procedure for preparation of compound Example 66 To a solution of N-[(E)-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyleneamino] methanamine (307.5 mg, 1.21 mmol, 1.00 eq) in ACN (5 mL) was added TCFH (613.3 mg, 2.19 mmol, 1.80 eq), NMI (249.3 mg, 3.04 mmol, 242.0 μL, 2.50 eq) and compound 4 (220.0 mg, 1.21 mmol, 1.00 eq). The mixture was stirred at 80 °C for 3 hr. LC-MS showed compound 4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (column: Welch Ultimate XB-Diol 250*50*10um; mobile phase: [Hexane-EtOH]; gradient:10%-40% B over 20 min). Compound Example 66 (319.26 mg, 52.7% yield) was obtained as a white gum.1H NMR: (400 MHz, CHLOROFORM-d) δ 9.31 (dd, J = 0.8, 2.1 Hz, 1H), 8.42 (s, 1H), 8.28 (dd, J = 1.9, 8.2 Hz, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 51.6 Hz, 1H), 3.67 (s, 3H), 1.96-1.75 (m, 1H), 1.09-0.98 (m, 1H), 0.96-0.86 (m, 2H), 0.70-0.61 (m, 1H) Analytical information of Example 65 and Example 66: Compound NMR data Physical LCMS Property Result 1H NMR: (400 MHz, DMSO-d6) δ = 9.22 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 407.4 [M++2.0, 8.4 Hz, 1H), 8.30 (d, J = H] 5.9 Hz, 1H), 8.08 (s, 1H), Yellow 99.83 7.58 (t, J = 51.2 Hz, 1H), solid % 7.39 (d, J = 8.4 Hz, 1H), 7.25 RT = (d, J = 5.9 Hz, 1H), 3.90 (s, 1.523 Example 65 3H), 3.56 (s, 3H) 1H NMR: (400 MHz, CHLOROFORM-d) δ = 9.31 (dd, J = 0.8, 2.1 Hz, 1H), 8.42 (s, 1H), 8.28 (dd, J 417.0 = 1.9, 8.2 Hz, 1H), 8.23 (s,+(s, 1H), 7.39 (d, J Whit [M+H] 1H), 7.99 e 97.9 Hz, 1H), 6.95 (t, J = gu 9% = 8.4 m RT = 51.6 Hz, 1H), 3.67 (s, 3H), 2.531 1.96-1.75 (m, 1H), 1.09-0.98 Example 66 (m, 1H), 0.96-0.86 (m, 2H), 0.70-0.61 (m, 1H) Example 67 and Example 68:

[0075] General procedure for preparation of compound b: Solution 1: cpd.4 (8 g, 54.06 mmol, 1 eq) in THF (80 mL); solution 2: {LDA (1 M, 70.28 mL, 1.3 eq). The solution 1 was pumped by Pump 1 {S1,P1,9.277 mL / min} to flow reactor 1 {FLR1,PFA,Coils reactor,3.175(1 / 8’’) mm,17.097 mL,-60 °C}. The solution 2 was pumped by Pump 2 {S2,P2,7.82 mL / min} to flow reactor 1 {FLR1,PFA,Coils reactor,3.175(1 / 8’’) mm,17.097 mL,-60 °C}. The residence time of flow reactor 1 was {FLR1,1 min}. The mixture was collected with a bottle (contained 8 g dry CO2 (2.38 g, 54.06 mmol, 1 eq)). The Pump 1 and Pump 2 was started at the same time. The reaction mixture was collected after running 1 min. Take a sample for analysis after 3 mins. LCMS showed desired MS was detected. The mixture was quenched with H2O (300 mL). The mixture was acidified by 12 M HCl until pH = 3-4. Lots of white solid formed. The mixture was filtered and collected the solid. The crude solid was dired under reduced pressure and used for next step directly. Cpd. b (5 g, 26.04 mmol, 48.17% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1 H), 8.84 (s, 1 H). General procedure for preparation of Example 68 To a mixture of N-[(E)-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro- phenyl]methyleneamino]methanamine (0.3 g, 1.11 mmol, 1.00 eq) and cpd. b (255.80 mg, 1.33 mmol, 1.20 eq) in DCM (2 mL) was added TCFH (404.97 mg, 1.44 mmol, 1.30 eq) and NMI (182.31 mg, 2.22 mmol, 177.00 μL, 2.00 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed desired MS was detected and starting material was consumed. The mixture was concentrated. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:41%-71% B over 8.0 min). Example 68 (0.32 g, 720.41 μmol, 64.89% yield, 95.83% purity) was obtained as an off-white solid.1HNMR: 400 MHz, DMSO-d6δ 8.91 (s, 1 H), 8.63 (s, 1 H), 8.18 (s, 1 H), 7.85 - 7.96 (m, 2 H), 7.55 (s, 1 H), 7.42 - 7.45 (m, 1 H), 3.59 (s, 3 H) General procedure for preparation of Example 67

[0076] To a mixture of N-[(E)-[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2- pyridyl]methyleneamino]methanamine (0.30 g, 1.18 mmol, 1.00 eq) and cpd. b (272.98 mg, 1.42 mmol, 1.20 eq) in DCM (5 mL) was added NMI (194.55 mg, 2.37 mmol, 188.89 μL, 2.00 eq) and TCFH (398.92 mg, 1.42 mmol, 1.20 eq). The mixture was stirred at 20 °C for 16 hrs. LCMS showed desired MS was detected and starting material was consumed. The mixture was concentrated. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:30%-60% B over 8.0 min). Example 67 (0.21 g, 491.58 μmol, 41.49% yield, 98.88 purity) was obtained as a white solid. HNMR: 400 MHz, DMSO-d6 δ 9.23 (d, J=1.63 Hz, 1 H), 8.93 (s, 1 H), 8.67 (s, 1 H), 8.40 (dd, J=8.38, 1.88 Hz, 1 H), 8.13 (s, 1 H), 7.57 (t, J=51.22 Hz, 1 H), 7.36 (d, J=8.38 Hz, 1 H), 3.61 (s, 3 H)

[0077] Analytical information of Example 67 and Example 68: Physical LC-MS Compound NMR data Property Result 1H NMR (400 MHz, DMSO-d 444.0 6) δ 8.91 (s, 1 63 (s, 1 H), 8.18 (s, Off- [M+H), 8. +H] 1 H), 7.85 - 7.96 (m, 2 H), White 95.83% 7.55 (s, 1 H), 7.42 - 7.45 solid RT = (m, 1 H), 3.59 (s, 3 H) 3.022 Example 68 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J=1.63 Hz, 1 H), 8.93 (s, 427.0 1 H), 8.67 (s, 1 H), 8.40+White [M+H] (dd, J=8.38, 1.88 Hz, 1 98.8 ), 8.13 (s, 1 H), 7.57 (t, so 8% H lid RT = J=51.22 Hz, 1 H), 7.36 2.770 (d, J=8.38 Hz, 1 H), 3.61 Example 67 (s, 3 H) Example 69, Example 70, Example 71, and Example 72 Schemes:

[0078]

[0079] General procedure for preparation of compound 6: To a mixture of cpd 2A (7.50 g, 43.7 mmol, 1.00 eq) and 2,2,2-trifluoroethanol (5.25 g, 52.4 mmol, 3.77 mL, 1.20 eq) in NMP (70 mL) was added t-BuOK (9.81 g, 87.4 mmol, 2.00 eq). Then the mixture was stirred at 90 °C for 12 hrs. LCMS showed trace desired MS was detected. The residue was purified by prep-HPLC (neutral condition, 10-40% 30min; 40% 10 min). Cpd 6 (1.60 g, 6.80 mmol, 15.5% yield) was obtained as a black solid. General procedure for preparation of compound 7

[0080] To a solution of H2O (1 mL) in THF (2 mL) was added MeOH (3 mL), LiOH.H2O (2.57 g, 61.2 mmol, 2.00 eq) and cpd 6 (7.20 g, 30.6 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 40 °C for 16hrs. LCMS showed cpd 6 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O 2 mL and extracted with DCM 6 mL (2 mL *3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was acidified with aqueous 2N HCl till PH = 6 and extracted with organic solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70mm, 15 um); mobile phase: [H2O (0.04%HCl)-ACN]; gradient: 1%-20% B over 20.0 min). Cpd 7 (0.50 g, 2.26 mmol, 7.38% yield) was obtained as a white solid. General procedure for preparation of compound 8 To a solution of cpd 7 (0.350 g, 1.58 mmol, 1.00 eq) in DMF (5 mL) was added NMI (324 mg, 3.96 mmol, 315 μL, 2.50 eq), tert-butyl N-(methylamino)carbamate (254 mg, 1.74 mmol, 1.10 eq) and TCFH (532 mg, 1.90 mmol, 1.20 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS showed cpd 7 was consumed completely and one main peak with desired m / z was detected. TLC (EA) indicated cpd 7 was consumed completely and one new spot formed. The reaction was clean according to TLC. The residue was diluted with H2O 10 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 0 / 1). Cpd 8 (0.450 g, 1.29 mmol, 81.3% yield) was obtained as yellow oil. General procedure for preparation of Example 70 To a solution of TFA (1 mL) in DCM (5 mL) was added cpd 8 (0.500 g, 1.43 mmol, 1.00 eq) and cpd a (322 mg, 1.43 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS and HPLC showed cpd 8 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under reduced pressure to remove DCM / TFA. Pour the reaction to NaHCO3,and extracted with DCM 60 mL (20 mL * 3). The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18150 * 40 * 7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 min). Example 70 (0.300 g, 656 μmol, 45.8% yield, 99.8% purity) was obtained as a white solid. LCMS showed the purity is 98.8%.1H NMR confirmed the obtained compound is the desired compound.1H NMR: (400 MHz, DMSO-d6) δ 9.20 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 5.9 Hz, 1H), 8.48 (s, 1H), 8.35 (dd, J = 2.0, 8.4 Hz, 1H), 8.03 (s, 1H), 7.72 - 7.55 (m, 1H), 7.46 - 7.31 (m, 2H), 4.92 (q, J = 8.7 Hz, 2H), 3.54 (s, 3H). For other compounds, the procedure is the same as Example 70 above with the amounts listed below: Compound Reagent Solvent Temperature Time Yiel Product Example No. 5, 3D, (mg) a (mg) DCM / TFA d (mL) (oAmount 2D C) (hrs) (%) (mg) 69 (5) 460 298 6 25 2 17.2 104 71 (3D)350 216 6 25 2 33.0 300 72 (2D)1000 557 10 25 2 43.6 300 Analytical data:

[0081] Compound NMR data Physical LC-MS Property Result 1H NMR (400 MHz, DMSO- d6) δ = 9.21 (d, J = 1.6 Hz, 1H), 8.61 (d, J = 5.3 Hz, 1H), 455.1 8.53 (s, 1H), 8.37 (dd, J = , 8.08 (s, 1H), whi [M+H]+ 2.1, 8.4 Hz, 1H) te solid 99.28% 7.73 - 7.47 (m, 2H), 7.45 - RT = 7.31 (m, 1H), 3.60 (s, 3H), 2.693 2.82 - 2.74 (m, 2H), 2.64 - Example 69 2.56 (m, 2H) 1H NMR (400 MHz, DMSO- d6) δ = 9.20 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 5.9 Hz, 1H), 457.1 8.48 (s, 1H), 8.35 (dd, J = white [M+H]+ 2.0, 8.4 Hz, 1H), 8.03 (s, 1H), solid 98.88% 7.72 - 7.55 (m, 1H), 7.46 - RT = 7.31 (m, 2H), 4.92 (q, J = 8.7 2.518 Example 70 Hz, 2H), 3.54 (s, 3H) 1H NMR (400 MHz, DMSO- d6) δ = 9.20 (d, J = 1.6 Hz, 1H), 8.61 (d, J = 5.9 Hz, 1H), 471.1 8.44 - 8.33 (m, 2H), 7.99 (s, .70 - 7.54 (m, 1H), yel [M+H]+ 1H), 7 low 7.33 (m, 1H), 7.25 (d, J so 99.80% 7.45 - lid RT = = 5.9 Hz, 1H), 4.27 (t, J = 5.6 2.539 Example 71 Hz, 2H), 3.50 (s, 3H), 2.63 (tq, J = 5.7, 11.2 Hz, 2H) 1H NMR (400 MHz, DMSO- d6) δ = 9.21 (d, J = 1.4 Hz, 1H), 8.61 - 8.50 (m, 1H), 8.46 (s, 1H), 8.39 (dd, J = 431.1 1.9, 8.4 Hz, 1H), 8.06 (s, 1H), yellow [M+H]+ 7.77 - 7.31 (m, 2H), 6.84 (d, J solid 96.90% = 5.9 Hz, 1H), 5.40 (quin, J = RT = 5.4 Hz, 1H), 4.79 (t, J = 6.8 2.122 Example 72 Hz, 2H), 4.35 (dd, J = 5.3, 6.8 Hz, 2H), 3.58 (s, 3H) Example 73:

[0082] Step 1 To a mixture solution of E28-1 (2.5 g, 13.08 mmol) and E28-1’ (1.91 g, 13.08 mmol) in DMF (25 mL) were added DIPEA (3.38 g, 26.16 mmol) and HATU (5.97 g, 15.70 mmol). The mixture was stirred at 20°C for 1 h until LCMS indicated the SM was consumed. The mixture was eluted with water (200 mL) and the suspension was extracted with EA (200 mL×3). The combined organic layer was then washed with brine (300 mL×2). The mixture was dried with Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was then purified by MPLC to provide E28-2 (3.5 g, 10.96 mmol, 83.80% yield). Step 2 To a stirred of HCl / dioxane (5 mL, 4M) was added E28-2 (1.4 g, 4.38 mmol) and then stirred at 20°C for 4 h until LCMS indicated the SM was consumed. The mixture was concentrated directly to provide E28-3 (900 mg, 4.11 mmol, 93.65% yield) as a crude product which used for next step without further purification. Step 3 To a suspension of E28-3 (1 g, 4.56 mmol) in MeOH (10 mL) was added E28-3’ (1.03 g, 4.56 mmol). The mixture was stirred at 20 °C for 20 min until LCMS indicated the SM was consumed. The mixture was concentrated and the residue was purified by prep-HPLC to provide Example 73 (300 mg, 703.73 μmol, 15.42% yield). LCMS (E+) m / z: 427.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.21 (dd, J = 2.2, 0.9 Hz, 1H), 8.99 (dd, J = 5.3, 0.8 Hz, 1H), 8.89 (s, 1H), 8.36 (dd, J = 8.4, 2.2 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.57 (t, J = 51.3 Hz, 1H), 7.26 (dd, J = 8.4, 0.9 Hz, 1H), 3.61 (s, 3H). Example 74: Step 1 To a mixture solution of E29-1 (2.5 g, 13.08 mmol) and E29-1’ (1.91 g, 13.08 mmol) in DMF (25 mL) were added DIPEA (3.38 g, 26.16 mmol) and HATU (5.97 g, 15.70 mmol). The mixture was stirred at 20°C for 1 h until LCMS indicated the SM was consumed. The mixture was eluted with water (200 mL) and then extracted with DCM (200 mL×3). The combined organic layer was washed with brine (300 mL×2) and then dried over Na2SO4. The solution was filtered and concentrated. The residue was purified by MPLC to provide E29-2 (3.8 g, 11.90 mmol, 90.98% yield). Step 2 To a stirred solution of HCl / dioxane (5 mL, 4 M) was added E29-2 (1.4 g, 4.38 mmol). The mixture was stirred at 20°C for 4 h until LCMS indicated the SM was consumed. The mixture was concentrated directly to provide E29-3 (900 mg, 4.11 mmol, 93.65% yield) as a crude product which was used for next step without further purification. Step 3 To a solution of E29-3 (1 g, 4.56 mmol) in MeOH (10 mL) was added E29-3’ (1.03 g, 4.56 mmol). The mixture was then stirred at 20 °C for 20 min until LCMS indicated the SM was consumed. The mixture was concentrated and the residue was purified by prep-HPLC to provide Example 74 (240 mg, 562.98 μmol, 12.34% yield). LCMS (E+) m / z: 427.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.21 (dd, J = 2.2, 0.9 Hz, 1H), 9.12 (s, 1H), 9.00 (d, J = 5.0 Hz, 1H), 8.37 (dd, J = 8.4, 2.2 Hz, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.69 – 7.42 (m, 1H), 7.26 (dd, J = 8.4, 0.8 Hz, 1H), 3.59 (s, 3H). Example 75: Step 1 To a stirred solution of E30-1 (2.5 g, 13.08 mmol) and E30-1’ (1.91 g, 13.08 mmol) in DMF (25 mL) were added DIPEA (3.38 g, 26.16 mmol) and HATU (5.97 g, 15.70 mmol). The mixture was stirred at 20°C for 1 h until LCMS indicated the SM was consumed. The mixture was poured into water (200 mL) and the suspension was extracted with DCM (200 mL×3). The combined organic layer was washed with brine (300 mL×3) and then dried over Na2SO4. The mixture was filtered and concentrated. The residue was purified by MPLC to provide E30-2 (2.3 g, 7.20 mmol, 55.07% yield). Step 2 To a solution of HCl / dioxane (5 mL, 4M) was added E30-2 (1.4 g, 4.38 mmol). The mixture was stirred at 20°C for 4 h until LCMS indicated the SM was consumed. The mixture was concentrated directly to provide E30-3 (900 mg, 4.11 mmol, 93.65% yield) as a crude product which used for next step without further purification. Step 3 To a solution of E30-3 (1 g, 4.56 mmol) in MeOH (10 mL) was added E30-3’ (1.03 g, 4.56 mmol). The mixture was stirred at 20 °C for 20 min until LCMS indicated the SM was consumed. The mixture was concentrated and the residue was purified by prep-HPLC to provide Example 75 (290 mg, 680.27 μmol, 14.91% yield). LCMS (E+) m / z: 427.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 2.1 Hz, 1H), 8.93 (dd, J = 4.9, 1.4 Hz, 1H), 8.40 (dd, J = 8.3, 1.4 Hz, 1H), 8.33 (dd, J = 8.4, 2.2 Hz, 1H), 8.07 (s, 1H), 7.80 (ddd, J = 8.1, 4.9, 0.9 Hz, 1H), 7.57 (t, J = 51.3 Hz, 1H), 7.15 (dd, J = 8.4, 0.9 Hz, 1H), 3.60 (s, 3H). Example 76: Step 1 To a stirred solution of E31-1 (2.01 g, 8.18 mmol) were added NaHCO3 (3.43 g, 40.88 mmol), KBr (195 mg, 1.64 mmol) in DMSO (5 mL). The mixture was stirred at 100 °C for 3 h. Then the mixture was cooled down and poured into water (30 mL). The suspension was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with water (1 x 100 mL), followed by saturated NaCl aqueous solution (2 x 100 mL). The solution was dried over anhydrous Na2SO4and then concentrated. The residue was purified by flash column chromatography to provide E31-2 (230 mg, 1.03 mmol, 12.55 % yield) as the first part and the intermediate (1.20 g, 5.31 mmol, 64.89 % yield). To a stirred solution of intermediate (1.20 g, 5.31 mmol) in DCM (15 mL) was added Dess-Martin (3.40 g, 7.96 mmol) under 0°C. The mixture was stirred at 25°C for 2 h. After the completion of the reaction, the mixture was filtered and the cake was washed with DCM (50 mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution (1 x 100 mL) and brine ((2 x 100 mL). The solution was dried over anhydrous Na2SO4. The solution was concentrated and purified by flash column chromatography E31-2 (760 mg, 3.39 mmol, 63.9 % yield) as the second part. Step 2 To a stirred solution of E31-2 (600.00 mg, 2.68 mmoL) in methanol (10 mL) were added acetic acid (0.23 mL, 4.02 mmol) and E31-2’ (430.00 mg, 2.94 mmoL). After being stirred at 25°C for 3 h, the resulting mixture was concentrated and purified by MPLC to provide E31-3 (505 mg, 2.25 mmol, 84.17% yield). Step 3 To a stirred solution of E31-3 (505.00 mg, 2.25 mmol) in DCM (6 mL) was added TFA (3 mL) slowly under 0°C. The reaction mixture was then stirred at 25 °C for 1h until TLC showed SM consumed. The mixture was concentrated directly to provide E31-4 (500 mg, crude, TFA salt). The crude compound was used for the next step without further purification. Step 4 To a stirred solution of E31-4’ (419.00 mg, 2.18 mmol) in DMF (10 mL) were added HATU (1.1 g, 2.97 mmol) and DIPEA (1.4 mL, 7.94 mmol) under 0°C. After being stirred at 25 °C for 15 min, E31-5 (500 mg, crude, TFA salt) was added. The reaction was stirred at 25 C for 3 h until LCMS showed starting material was almost consumed. The mixture was then purified by prep-HPLC to provide Example 75 (405 mg, 0.75 mmol, 43.64 % yield, 96.27% purity). LCMS (E+) m / z: 427.3 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 8.98 – 8.89 (m, 2H), 8.12 (s, 1H), 8.05 – 8.00 (m, 2H), 7.52 – 7.47 (m, 2H), 7.20 (t, J = 51.7 Hz, 1H), 3.62 (s, 3H). Example 77:

[0083] Step 1 To a stirred solution of E32-1 (300.00 mg, 1.56 mmol) in DMF (6 mL) were added HATU (710.00 mg, 1.87 mmol) and DIPEA (1.4 mL, 7.94 mmol) under 0°C. After being stirred at 25 °C for 15 min, E32-1’ (337.00 mg, 1.87 mmol) was added. The reaction was stirred at 25 °C for another 3 h until LCMS showed starting material was almost consumed. The mixture was then purified by MPLC to provide E32-2 (210 mg ,0.59 mmol, 26.9 % yield). Step 2 To a stirred solution of E32-2 (160 mg, 0.45 mmol) in MeOH (3 mL) were added Pd / C (32 mg, with 45 % water, 20% MW%). After degassed with H2 for three times, the reaction was stirred at 25 °C for 3 h under N2atmosphere until TLC showed SM was almost consumed. The mixture was filtered and the filtrate was concentrated directly to afford the crude E32-3 for the next step without further purification. Step 5 To the stirred solution of E32-3 in MeOH (3 mL) were added acetic acid (40.5 mg, 0.66 mmol, 0.039 mL) and E32-3’ (100 mg, 0.45 mmol). And then the mixture was stirred at 25 °C for 3 h until LCMS showed SM was almost consumed. The mixture was then concentrated under reduced pressure and the residue was purified by MPLC to provide Example 77 (50 mg, 0.12 mmol, 26.17 % yield, 98.47% purity). LCMS (E+) m / z: 427.1 [M+H]+.1H NMR (600 MHz, Methanol-d4) δ 9.47 (s, 1H), 9.09 (s, 1H), 8.13 (s, 1H), 8.07 – 8.02 (m, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.30 – 7.10 (m, 1H), 3.62 (s, 3H). Exam...

Claims

CLAIMS 1. A compound of Formula (Ia): (Ia) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1is H, C1-C6alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6alkyl group substituted with 4-6 membered aryl; Y1 and Y2 are independently N or CR2, wherein R2is H, alkyl, or halogen; X1, X2, X3, X4, and X5are independently N or CR3, wherein each R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms.

2. The compound of claim 1, wherein R1is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclobutyl, or CH2-phenyl.

3. The compound of claim 1, wherein R1is methyl.

4. The compound of any one claims 1-3, wherein Y1and Y2are both CR2, and wherein R2is H, alkyl, or halogen.

5. The compound of claim 4, wherein each R2is H.

6. The compound of claim 4, wherein each R2is F.

7. The compound of any one claims 1-3, wherein Y1 is N and Y2 is CR2, and wherein R2is hydrogen or fluoro.

8. The compound of claim 7, wherein R2is fluoro.

9. The compound of any one of claims 1-8, wherein X1, X2, X3, X4, and X5 are each CR3, wherein each R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom.

10. The compound of claim 9, wherein each wherein each R3 is independently selected from the group consisting of H, -CF3, -NH2, -Cl, -O-azetidine, -OCH3, -cyclopropyl, -F, -CH3, , -OCF, -OCH2CH3, -OCH2CF3, -OCH2CH2CH3, , , -NH2, F, ,optionally substituted piperazine, , is , , optionally substituted morpholine, , optionally substituted azetidine, , , and .

11. The compound of any one of claims 1-10, wherein X5 is CR3, and R3 is -CF3.

12. The compound of any one of claims 1-8, wherein one of X1, X2, X3, X4, or X5is N.

13. The compound of any one of claims 1-8, wherein two of X1, X2, X3, X4, or X5 are N.

14. The compound of any one of claims 1-8, wherein three of X1, X2, X3, X4, or X5are N.

15. The compound of any one of claims 1-15, wherein when X1, X2, X3, X4, or X5 are CR3; each R3 is independently selected from the group consisting of H, -CF3, -NH2, -Cl, -O- azetidine, -OCH3, -cyclopropyl, -F, -CH3, , -OCF,-OCH2CH3, -OCH2CF3, - OCH2CH2CH3, , , -NH2, F, ,optionally substituted piperazine, , is , , optionally substituted morpholine, , optionally substituted azetidine, , , and .

16. The compound of claim 15, wherein each R3 is H, F, or -CF3.

17. The compound of claim 15, wherein each R3is H, -CH3, or cyclopropyl.

18. The compound of claim 15, wherein R3 is H, -OCH3, or CHF2.

19. The compound of claim 15, wherein R3is cyclopropyl.

20. A compound selected from the group consisting of:Example 1 Example 2 Example 4 Example 3 Example 5 Example 6 Example 7 Example 9 Example 11 Example 12Example 13 Example 14 Example 15 Example 17 Example 18 Example 19 Example 20 Example 56 Example 21 Example 22Example 27 Example 26 Example 28 Example 31 Example 32 Example 33 Example 16 Example 34 Example 73 Example 74Example 75 Example 76 Example 77 Example 79 Example 83 Example 84 Example 86 Example 87Example 89Example 90Example 104 Example 105 Example 106 Example 107 Example 108 Example 109 Example 110 Example 111 Example 113 Example 115Example 117 Example 118 Example 119 Example 120 Example 122 Example 123 Example 124 Example 125 Example 133 Example 134Example 136 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

21. A compound of Formula (Ib): (Ib) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6 alkyl group substituted with 4-6 membered aryl; Y1and Y2are independently N, S, O, or CR2, wherein R2is H, C1-C6alkyl, or halo; Z1, Z2, and Z3are independently selected from C, CH, N and O; R4 is -CHF2 or -CF3; R5 is H, C1-C4 alkyl, or C3-C4 cycloalkyl; and X1, X2, X3, X4, and X5are independently N or CR3, whereineach R3is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms.

22. A compound of Formula (Ic): (Ic) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1 is H, C1-C6 alkyl, 3-6 membered cycloalkyl, 4-6 membered aryl, or C1-C6 alkyl group substituted with 4-6 membered aryl; Y1and Y2are independently N, S, O, or CR2, wherein R2is H, C1-C6alkyl, or halo; Z1, Z2, and Z3 are independently selected from C, CH, N and O; R4 is -CHF2 or -CF3; R5is H, C1-C4alkyl, or C3-C4cycloalkyl; and X1, X2, X3, X4, and X5are independently N or CR3, wherein each R3 is independently selected from H, halogen, -CN, -OR, -N(R)2, optionally substituted C1-C6alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl withN and / or O as heteroatoms; or two R3taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom; and R is H, optionally substituted C1-C6 alkyl, 4-6 cycloalkyl or heterocycloalkyl having N or S as heteroatoms.

23. The compound of claim 22, wherein the compound is of Formula (1d): (Id) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1, R4, Z1, Z2, Z3, X1, X2, X3, X4, and X5 are as defined in claim 22.

24. The compound of any one of claims 21-23, wherein R1is selected from the group consisting of -CH3, ethyl, propyl, butyl, -CH2-isopropyl, -CH2-phenyl, -cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.

25. The compound of claim 24, wherein R1is methyl.

26. The compound of any one of claims 21-25, wherein Y1 and Y2 are independently N or CR2, wherein R2is H, C1-C6alkyl, or halogen.

27. The compound of claim 26, wherein R2is H, -CH3, or F.

28. The compound of any one of claims 21-25 wherein Y1 and Y2 are CH.

29. The compound of any one of claims 21-28, wherein Y1is N and Y2is CR2.

30. The compound of any one of claims 21-29, wherein X1, X2, X3, X4, and X5 are CR3.

31. The compound of claim 30, wherein each R3is independently selected from H, halogen, - CN, -OR, -N(R)2, optionally substituted C1-C6alkyl, optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl with N and / or O as heteroatoms; or two R3 taken together with their intervening atoms form an optionally substituted fused heterocycle or heteroaryl with N as the heteroatom.

32. The compound of claim 31, wherein each R3 is independently selected from the group consisting of: H, -CF3, -NH2, -F, -Cl, -O-azetidine, O-oxetane, -OCH3, -cyclopropyl, - CH3, -CHF2, -OCF3, -CH2-CF3, - CH2-CH2-CF3, -OCHF2, -OCH3, -CH(phenyl)2, isopropyl, and optionally two R3 groups may form an optionally substituted fused heterocycle with N as the heteroatom.

33. The compound of claim 30, wherein each R3is independently selected from the group consisting of H, -CF3, -NH2, -Cl, -O-azetidine, -OCH3, -cyclopropyl, -F, -CH3, , - OCF, -OCH2CH3, -OCH2CF3, -OCH2CH2CH3, , , -NH2, F, ,optionally substituted piperazine, , is , , optionally substituted morpholine, , optionally substituted azetidine, , , and ..

34. The compound of any one of claims 21-33, each R3 is H.

35. The compound of any one of claims 21-33, wherein each R3is selected from the group consisting of -H, CHF2, and CF3.

36. The compound of any one of claims 21-33, wherein at least one R3is -OCF3or -OCHF2.

37. The compound of any one of claims 21-33, wherein at least one R3is -CH3, -OCH3or cyclopropyl.

38. The compound of any one of claims 21-29, wherein one of X1, X2, X3, X4, and X5is N.

39. The compound of claim 38, wherein one of X2 and X3 is N.

40. The compound of any one of claims 21-40, wherein R4 is -CHF2.

41. The compound of any one of claims 21-40, wherein R4is -CF3.

42. A compound selected from the group consisting of: Example 38 Example 35 Example 36 Example 39Example 42 Example 37 Example 40 Example 41 Example 43 Example 44 Example 45 Example 8 Example 46 Example 47Example 48 Example 10 Example 49 Example 54 Example 50 Example 51 Example 52 Example 53 Example 95Example 55 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64Example 65 Example 66 Example 23 Example 24 Example 29 Example 25 Example 30 Example 69Example 70 Example 71 Example 72 Example 67 Example 68 Example 78 Example 80 Example 81Example 82 Example 85 Example 88 Example 91 Example 92 Example 93 Example 98 Example 94 Example 99 Example 96Example 97 Example 100 Example 102 Example 101 Example 103 Example 112 Example 114 Example 116Example 126 Example 121 Example 127 Example 128 Example 129 Example 130 Example 131 Example 132 Example 135or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

43. A compound of Formula (II): (II) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R2and R3are H or halogen; and A is an optionally substituted 4-8 membered heterocycle having N or O as heteroatoms, wherein said one or more substitutions on the Ring A are selected from the group consisting of H, C1-C6alkyl, and halogen.

44. The compound of claim 42, wherein R1 is H.

45. The compound of claim 42, wherein R1is F.

46. The compound of claim 42, wherein R2is H.

47. The compound of claim 42, wherein R2is F.

48. The compound of any one of claims 43-47, wherein A is piperazine.

49. The compound of any one of claims 43-47, wherein piperazine is substituted with one, two, or three methyl groups.

50. The compound of any one of claims 43-47, wherein A is difluoro azetidine or methyl azetidine.

51. The compound of any one of claims 43-47, A is morpholine.

52. The compound of any one of claims 43-47, wherein A is diazepane is substituted with one, two, or three methyl groups 53. A compound selected from the group consisting of: Example 137 Example 138 Example 139 Example 140 Example 141 Example 142Example 143 Example 144 Example 145 Example 146 Example 147 Example 148 Example 149 Example 150 Example 151 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

54. A compound of Formula (III):(III) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1is C1-C6alkyl, 6-membered aryl, alkyl substituted aryl; and R2’ is optionally substituted C1-C6 alkyl, optionally substituted saturated or partially unsaturated 4-10 membered cycloalkyl or heterocycloalkyl having N as heteroatom, wherein cycloalkyl or heterocycloalkyl is optionally bridged or spiro, or an optionally substituted 6-10 membered heteroaryl having N as heteroatom.

55. The compound of claim 54, wherein R1 is methyl.

56. The compound of claim 54, wherein R1is phenyl.

57. The compound of claim 54, wherein R1 is -CH2-phenyl.

58. The compound of any one of claims 54-57, wherein R2’ is methyl.

59. The compound of any one of claims 54-57, wherein R2’ is ethyl.

60. The compound of any one of claims 54-57, wherein R2’ is selected from the group consisting of:

61. and ..

62. The compound of any one of claims 54-57, wherein R2’ is: .

63. The compound of any one of claims 54-57, wherein R2’ is: .

64. The compound of any one of claims 54-57, wherein R2’ is: .

65. The compound of any one of claims 54-57, wherein R2’ is: .

66. A compound selected from the group consisting of: Example 152 Example 155Example 153 Example 154 Example 157 Example 156 Example 158 Example 159 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

67. A compound of Formula (IV):(IV) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R1is C1-C6alkyl, 6-membered aryl, alkyl substituted aryl; Y1 and Y2 are independently N or CR2, wherein R2is H, C1-C6 alkyl, or halogen; R2’’ is H, optionally substituted C1-C6 alkyl, -N(R)2 optionally substituted phenyl, 3-6- membered cycloalkyl, 3-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, with N or O as heteroatoms in said heterocycloalkyl or N as heteroatom in said heteroaryl ; A’ is H, optionally substituted C1-C6 alkyl, optionally substituted 4-10 membered cycloalkyl wherein said cycloalkyl is optionally bridged; 6-membered heterocycloalkyl having N, O as heteroatoms, phenyl, or 6-membered heteroaryl having N as heteroatom; and R is H or C1-C6 alkyl.

68. The compound of claim 67, wherein R1is selected from the group consisting of methyl, ethyl, propyl, cyclopentyl, phenyl, and -CH2-phenyl.

69. The compound of any one of claims 67-68, wherein R1 is methyl.

70. The compound of any one of claims 67-68, wherein R1is phenyl or -CH2-phenyl.

71. The compound of any one of claims 67-70, wherein R2’’ is selected from the group consisting of H, methyl, morpholine, -NH-CH3, N-(CH3)2, oxetane, tetrahydropyran, substituted or unsubstituted piperazine, pyridine, and phenyl.

72. The compound of claim 71, wherein R2’’ is morpholine.

73. The compound of claim 71, wherein R2’’ is piperazine or methyl-piperazine.

74. The compound of any one of claims 67-73, wherein A’ is phenyl or pyridine.

75. A compound selected from the group consisting of: Example 161 Example 163 Example 164 Example 166Example 167 Example 168 Example 170 Example 173 Example 187 Example 175 Example 190 Example 189Example 191 Example 192 Example 194 Example 196 Example 197 Example 198 Example 201 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

76. A compound selected from the group consisting of: Example 160 Example 162 Example 169 Example 165 Example 171 Example 172Example 174 Example 176 Example 177 Example 179 Example 181 Example 180 Example 182 Example 183Example 184 Example 185 Example 188 Example 186Example 193Example 195 Example 199 Example 200Example 188a or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

77. A compound of Formula (V): (V) or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: is a single or double bond; Y1 is N or CR2; wherein R2is H or halogen; R1is optionally substituted C1-C6alkyl; X1, X2, X3, and X4are independently N, O, S, CR3, or NR3, wherein each R3is independently H, -OR, optionally substituted C1-C6 alkyl wherein substitutions are one or more halogen; andR is H, C1-C6alkyl. Optionally substituted 3-6-membered cycloalkyl, or optionally substituted 3-6-membered heterocycloalkyl.

78. The compound of claim 77, wherein R1 is methyl.

79. The compound of any one of claims 77-78, wherein Y1 is N.

80. The compound of any one of claims 77-78, wherein Y1is CH.

81. The compound of any one of claims 77-80, wherein X1 and X3 are N and S respectively.

82. The compound of anyone of claims 77-81, wherein when any one of X1, X2, X3, and X4are CR3, or NR3, each of R3 is independently H or CH3.

83. The compound of anyone of claims 77-82, wherein each R3is independently H, -CH3, - CF3, -CHF2, -OCH3, -CH2CF3, or cyclopropyl.

84. The compound of anyone of claims 77-82, wherein R3is -CF3or -CHF2.

85. A compound selected from the group consisting of: Example 233 Example 221Example 256 Example 257 Example 262 Example 258 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

86. A compound selected from the group consisting of: Example 202 Example 203 Example 204 Example 205 Example 206 Example 207Example 208 Example 209 Example 210 Example 211 Example 212 Example 213 Example 214 Example 215 Example 216 Example 217 Example 218 Example 219Example 220 Example 222 Example 223 Example 224 Example 225 Example 226 Example 227 Example 228Example 229Example 230 Example 231 Example 232Example 234 Example 235 Example 236 Example 237 Example 238 Example 239 Example 240 Example 241 Example 242 Example 243 Example 244 Example 245Example 246 Example 247 Example 248 Example 249 Example 250 Example 251 Example 252 Example 253 Example 254 Example 255 Example 259 Example 260Example 261 Example 263 Example 264 or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

87. A compound selected from: Example 1 Example 2 Example 4 Example 3 Example 5 Example 6 Example 7 Example 8Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28Example 29 Example 30 Example 31 Example 32 Example 33 Example 34 Example 36 Example 35 Example 38 Example 37Example 39Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50Example 51 Example 52 Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70Example 71 Example 72 Example 73 Example 74 Example 75 Example 76 Example 77 Example 78 Example 79 Example 80Example 82 Example 81 Example 83 Example 84 Example 85 Example 86 Example 87 Example 88 Example 89 Example 90Example 91 Example 92 Example 94 Example 93 Example 95 Example 96 Example 98 Example 97 Example 99 Example 100Example 102 Example 101 Example 103 Example 104 Example 105 Example 106 Example 107 Example 108 Example 109 Example 110Example 111 Example 112 Example 113 Example 114 Example 115 Example 116 Example 117 Example 118 Example 119 Example 120Example 122 Example 121 Example 124 Example 123 Example 125 Example 126 Example 127 Example 128 Example 129 Example 130Example 131 Example 132 Example 134 Example 133 Example 135 Example 136 Example 137 Example 138 Example 139 Example 140 Example 141 Example 142Example 143 Example 144 Example 146 Example 145 Example 147 Example 148 Example 149 Example 150 Example 151 Example 152 Example 153 Example 154Example 155 Example 156 Example 157 Example 158 Example 159 Example 160 Example 161 Example 162Example 163 Example 164 Example 166 Example 165 Example 167 Example 168 Example 169 Example 170Example 171 Example 172 Example 173 Example 174 Example 175 Example 176 Example 177 Example 178Example 179 Example 180 Example 181 Example 182 Example 183 Example 184 Example 185 Example 186Example 187Example 188 Example 188a Example 189 Example 190 Example 191 Example 192 Example 193 Example 194 Example 195Example 196 Example 197 Example 198 Example 199 Example 200 Example 201 Example 202 Example 203 Example 204 Example 205Example 206 Example 207 Example 208 Example 209 Example 210 Example 211 Example 212 Example 213 Example 214 Example 215 Example 216 Example 217Example 218 Example 219 Example 220 Example 221 Example 223 Example 222 Example 224 Example 225 Example 226 Example 227 Example 228 Example 229Example 231 Example 230 Example 232 Example 233 Example 234 Example 235 Example 236 Example 237 Example 238 Example 239 Example 240 Example 241Example 242 Example 243 Example 244 Example 245 Example 246 Example 247 Example 248 Example 249 Example 250 Example 251 Example 252 Example 253Example 254 Example 255 Example 256 Example 257 Example 258 Example 259 Example 260 Example 261 Example 262 Example 263 Example 265 Example 264 Example 267 Example 266Example 269 Example 268 Example 270 Example 271 Example 272 Example 273 Example 274 Example 275 Example 276 Example 277Example 278 Example 279 Example 280 Example 281 Example 282 Example 283 Example 284 Example 285 Example 286 Example 287 Example 288 Example289Example 290 Example 291 Example 292 Example 293 Example 294 Example 295 Example 296 Example 297 Example 298 Example 299or a tautomer, an isomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

88. A pharmaceutical composition comprising a compound of any one of claims 1-87.

89. A method of inhibiting HDAC6 in a patient, comprising administering an effective amount of a compound of any one of claims 1-87 or a pharmaceutical composition of claim 88.

90. A method of treating cancer, an inflammatory disorder, an autoimmune disorder, a neurological disorder, or a neurodegenerative disorder comprising administering an effective amount of a compound of any one of claims 1-87 or a pharmaceutical composition of claim 88.

91. Use of a compound of any one of claims 1-87 or a pharmaceutical composition of claim 88 in the manufacture of a medicament for inhibiting HDAC6 in a patient.

92. Use of a compound of any one of claims 1-87 or a pharmaceutical composition of claim 88 in the manufacture of a medicament for treating cancer, an inflammatory disorder, an autoimmune disorder, a neurological disorder, or a neurodegenerative disorder in a patient.

93. A compound of any one of claims 1-87 for use in therapy, such as for treating cancer, an inflammatory disorder, an autoimmune disorder, a neurological disorder, or a neurodegenerative disorder in a patient, and / or for inhibiting HDAC6 in a patient.

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