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 a compound of Formula (VI): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1 is N, or CR1or CR2; Y1is N, N+-O-, S, O, CR3, or CH; Y2 is N, N+-O-, S, O, or CR3; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N; or R1and R2are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is H or halogen; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VI’): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1is N or CR1;Y1is N, N+-O-, S, O, or CR3; Y2 is N, N+-O-, S, O, or CR3; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is H or halogen; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VIa):

[0002] or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 X2, X3, are independently Nor CR1or CR2; Y1 is N, N+-O-, CR3or CR4; Y2is N, N+-O-, CR3,or CR4; L1is a single bond or C1-C4alkyl; A is an optionally substituted phenyl, optionally substituted 5-7 membered cycloalkyl ring, optionally substituted aryl, optionally substituted 4-6 membered heterocycloalkyl ring, or optionally substituted 5-6 membered heteroaryl ring, wherein said heterocycloalkyl ring includes N, S, or O as heteroatoms, and said heteroaryl ring includes N as heteroatom; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3and R4are independently selected from the group consisting of H or halogen; and R5is H or F.; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VIa’): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 X2, X3, and X4 are independently N, or CR1or CR2; Y1 is N, N+-O-, CR3or CR4; Y2is N, N+-O-, CR3or CR4; L1 is a single bond or C1-C4 alkyl; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6 cycloalkyl; or R1 and R2 are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 is H or F; and R3and R4are independently selected from the group consisting of H or halogen; and R5is H or F. In certain embodiments, the invention provides a compound of Formula (VIb): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1is N, or CR1, or CR2; Y1 is N or CR3; Y2 is N or CR3; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3and R4are independently selected from the group consisting of H or halogen; and R5 is H or F. In some embodiments, represents a single or double bond when allowed. As defined above and described herein, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. As defined above and described herein, Y1 is N, N+-O-, S, O, or CR3. In some embodiments, n is 0 and Y1is N. S, or O. In some embodiments, n is 0 and Y1is N. In some embodiments, n is 0 and Y1is S. In some embodiments, n is 0 and Y1is O. In some embodiments, n is 1 and Y1is N or CR3. As defined above and described herein, Y2 is N, N+-O-, S, O, or CR3. In some embodiments, n is 0 and Y1is N. S, or O. In some embodiments, n is 0 and Y1is N. In some embodiments, n is 0 and Y1 is S. In some embodiments, n is 0 and Y1 is O. In some embodiments, n is 1 and Y1 is N or CR3. As defined above and described herein, R1is selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, -C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R1 is H. In certain embodiments, R1 is halogen. In certain embodiments, R1is -CN. In certain embodiments, R1is -OR. In certain embodiments, R1is -N(R)2.In certain embodiments, R1 is -C(O)OR. In certain embodiments, R1 is -C(O)N(R)2, In certain embodiments, R1 is -C(R)2C(O)OR. In certain embodiments, R1 is -C(R)2C(O)N(R)2. In certain embodiments, R1is an optionally substituted C1-C6alkyl. certain embodiments, R1is an optionally substituted C3-C6cycloalkyl. In certain embodiments, R1is an optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R1is an optionally substituted phenyl. In certain embodiments, R1is an optionally substituted 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R1 is -CN. In certain embodiments, R1 is -C(O)OH. In certain embodiments, R1is -C(O)NH2. In certain embodiments, R1is -CH3. In certain embodiments, R1is -CH2CH3. In certain embodiments, R1 is propyl. In certain embodiments, R1 is isopropyl. In certain embodiments, R1 is -CHF2. In certain embodiments, R1is -CF3. In certain embodiments, R1is -CH2NH2. In certain embodiments, R1 is -CH2CH2NH2. In certain embodiments, R1 is .In certain embodiments, R1 is .In certain embodiments, R1 is .In certain embodiments, .In certain embodiments, R1 is .In certain embodiments, R1 is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, . In certain embodiments, R1is . In certain embodiments, R1is certain embodiments, R1 is . In certain embodiments, R1 is certain embodiments, R1 is.In certain embodiments, R1 is In certain embodiments, R1 is optionally substituted cyclopropyl. In certain embodiments, R1 is cyclopropyl. In certain embodiments, R1is optionally substituted phenyl. In certain embodiments, R1is certain embodiments, certain embodiments, R1 is . In certain embodiments, embodiments, certain embodiments, R1is is In certain embodiments, R1 is phenyl. In certain embodiments, R1is -OH. In certain embodiments, R1is -OCH3. In certain embodiments, R1 is -OCF3. In certain embodiments, R1 is -OCHF2. In certain embodiments, R1 is -OCH2CHF2. In certain embodiments, R1 is -OCH2CF3. In certain embodiments, In certain embodiments, R1is -NH2. In certain embodiments, R1is -N(CH3)2. In certain embodiments, R1 is optionally substituted azetidine. In certain embodiments, R1 . In certain embodiments, embodiments, . In certain embodiments, . In certain embodiments, R1 is azetidine. In certain embodiments, R1is . In certain embodiments, R1 is optionally substituted pyridine. In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1is pyridine. In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, . In certain embodiments, R1 is optionally substituted pyrimidine. In certain embodiments, R1is pyrimidine. In certain embodiments, R1is . In certain embodiments, certain embodiments, R1 is . In certain embodiments, R1 is halogen. In certain embodiments, R1 is Cl. In certain embodiments, R1is optionally substituted piperidine. In certain embodiments, certain embodiments, R1is piperidine. In certain embodiments, R1is optionally substituted piperazine. In certain embodiments, certain embodiments, R1 is piperazine. In certain embodiments, R In certain embodiments, R1is optionally substituted morpholine. In certain embodiments, R1is morpholine. In certain embodiments, In certain embodiments, R1 is optionally substituted thiomorpholine. In certain embodiments, certain embodiments, R1 is thiomorpholine. In certain embodiments, R1 is optionally substituted oxetane. In certain embodiments, R1is oxetane. In certain embodiments, R1 . In certain embodiments, R1 is optionally substituted pyridazine. In certain embodiments, R1 is pyridazine. In certain embodiments, R1 . In certain embodiments, In certain embodiments, R1 is optionally substituted pyrazine. In certain embodiments, R1 is pyrazine. In certain embodiments, R1is . In some embodiments, R1 is selected from those groups depicted in Table 1. As defined above and described herein, R2 is selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, -C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R2is H. In certain embodiments, R2is halogen. In certain embodiments, R2 is -CN. In certain embodiments, R2 is -OR. In certain embodiments, R2 is -N(R)2. In certain embodiments, R2 is -C(O)OR. In certain embodiments, R2 is -C(O)N(R)2, In certain embodiments, R2is -C(R)2C(O)OR. In certain embodiments, R2is -C(R)2C(O)N(R)2. In certain embodiments, R2 is an optionally substituted C1-C6alkyl. certain embodiments, R2 is an optionally substituted C3-C6 cycloalkyl. In certain embodiments, R2 is an optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2is an optionally substituted phenyl. In certain embodiments, R2 is an optionally substituted 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R2is -CN. In certain embodiments, R2is -C(O)OH. In certain embodiments, R2 is -C(O)NH2. In certain embodiments, R2 is -CH3. In certain embodiments, R2 is -CH2CH3. In certain embodiments, R2is propyl. In certain embodiments, R2is isopropyl. In certain embodiments, R2is -CHF2. In certain embodiments, R2is -CF3. In certain embodiments, R2is -CH2NH2. In certain embodiments, R2is -CH2CH2NH2. In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, R2is . In certain embodiments, . In certain embodiments, R2is . In certain embodiments, R2is.In certain embodiments, R2 is.In certain embodiments, R1 is . In certain embodiments, R2 is .In certain embodiments, R2 is . In certain embodiments, R2is optionally substituted cyclopropyl. In certain embodiments, R2is cyclopropyl. In certain embodiments, R2 is optionally substituted phenyl. In certain embodiments, R2 is . In certain embodiments, certain embodiments, R2 is . In certain embodiments, R2 is . In certain embodiments, certain embodiments, R2 is . In certain embodiments, R2 is . In certain embodiments, R2 is phenyl. In certain embodiments, R2is -OH. In certain embodiments, R2is -OCH3. In certainembodiments, R2is -OCF3. In certain embodiments, R2is -OCHF2. In certain embodiments, R2is -OCH2CHF2. In certain embodiments, R2 is -OCH2CF3. In certain embodiments, certain embodiments, . In certain embodiments, In certain embodiments, R2 is -NH2. In certain embodiments, R2 is -N(CH3)2. In certain embodiments, R2is optionally substituted azetidine. In certain embodiments, R2is . In certain embodiments, . In certain embodiments, R certain embodiments, .In certain embodiments, certain embodiments, R2 is azetidine. In certain embodiments, R2 is . In certain embodiments, R2is optionally substituted pyridine. In certain embodiments, R2i . In certain embodiments, R2is . In certain embodiments, R2is .n certain embodiments, R2 is .In certain embodiments, R2 is pyridine. In certain embodiments, R2 is . In certain embodiments, R2 is . In certain embodiments, R . In certain embodiments, R2is optionally substituted pyrimidine. In certain embodiments, R2 is pyrimidine. In certain embodiments, R2 is .In certain embodiments, certain embodiments, R2 is . In certain embodiments, R2is halogen. In certain embodiments, R2is Cl. In certain embodiments, R2is optionally substituted piperidine. In certain embodiments, certain embodiments, R2 is piperidine. In certain embodiments, R2is optionally substituted piperazine. In certain embodiments, .In certain embodiments, R2 is optionally substituted morpholine. In certain embodiments, R2is morpholine. In certain embodiments, In certain embodiments, R2is optionally substituted thiomorpholine. In certain embodiments, R2is . In certain embodiments, R2is thiomorpholine. In certain embodiments, R2is optionally substituted oxetane. In certain embodiments, R2is oxetane. In certain embodiments, R2is . In certain embodiments, R2 is optionally substituted pyridazine. In certain embodiments, R2 is pyridazine. In certain embodiments, R2 is . In certain embodiments, In certain embodiments, R2 is optionally substituted pyrazine. In certain embodiments, R2 is pyrazine. In certain embodiments, R2 is .In some embodiments, R2is selected from those groups depicted in Table 1. As defined above and described herein, R1 and R2 are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R1and R2are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form certain embodiments, R1 and R2 are taken together!with their intervening to form .In certain embodiments, R1 and R2 are taken together!with their intervening to form certain embodiments, R1 and R2 are taken together!with their intervening to form embodiments, R1 and R2 are taken together!with their intervening to form embodiments, R1and R2are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form .In certain embodiments, R1 and R2 are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form . As defined above and described herein A is an optionally substituted 5-7 membered cycloalkyl ring, aryl, 4-6 membered heterocycloalkyl ring, or a 5-6 membered heteroaryl ring, wherein said heterocycloalkyl ring includes N, S, or O as heteroatoms, and said heteroaryl ring includes N as heteroatom. In some embodiments, A is an optionally substituted 5-7 membered cycloalkyl ring. In some embodiments, A is optionally substituted aryl. In some embodiments, A is an optionally substituted 4-6 membered heterocycloalkyl ring, wherein said heterocycloalkyl includes N, S, or O as heteroatoms. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl ring, wherein said heteroaryl ring contains N as heteroatom. In some embodiments, A is an optionally substituted 4-6 membered heterocycloalkyl ring having 1 to 4 heteroatoms independently selected from N, S, or O. In some embodiments, Ring A is an optionally substituted 5-6 membered heteroaryl ring having 2-3 N as heteroatom. In some embodiments A is optionally substituted with one or more groups selected from =O, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, optionally substituted 4-6 membered heterocycloalkyl ring, and halogen. In certain embodiments, A is optionally substituted phenyl. In certain embodiments, A is certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, A is In certain embodiments, A is certain embodiments, A is certain embodiments, A is phenyl. In certain embodiments, A is optionally substituted pyridine. In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is pyridine. In certain In certain embodiments, A is optionally substituted pyrimidine. In certain embodiments, A is pyrimidine. In certain embodiments, A is . In certain embodiments, certain embodiments, A is . In certain embodiments, A is optionally substituted piperidine. In certain embodiments, A certain embodiments, A is piperidine. In certain embodiments, A is optionally substituted piperazine. In certain embodiments, R2 is . In certain embodiments, A is piperazine. In certain embodiments, A is . In certain embodiments, A is optionally substituted morpholine. In certain embodiments, A is morpholine. In certain embodiments, A is . In certain embodiments, A is optionally substituted thiomorpholine. In certain embodiments, certain embodiments, A is thiomorpholine. In certain embodiments, A is optionally substituted oxetane. In certain embodiments, R2is oxetane. In certain embodiments, A is . In certain embodiments, A is optionally substituted azetidine. In certain embodiments, A is , , . In certain embodiments, . In certain embodiments, A is azetidine. In certain embodiments, A is . In some embodiments, A is selected from those groups depicted in Table 1. As defined above and described herein R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is H. In certain embodiments, R is optionally substituted C alkyl. In certain embodiments, R is optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R r two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. 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. Table 1.

[0003]

[0004]

[0005] In some embodiments, the present disclosure provides a compound set forth in Table 1, above, or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1is N+-O-. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1 is S. In certain embodiments, in the compounds of Formula (VI), Y1is O.In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1is CH or CR3. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1 is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1is CH. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1is CR1or CR2. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), when n is 0, Y2 is O, S, or N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), when n is 1, Y2is CH or CR3. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3 is H. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3 is halogen. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3is F. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R1and R2are independently selected from the group consisting of H, methyl, optionally substituted phenyl, pyridine, pyrimidine, and cyclopropyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R1and R2are independently H or methyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1and R2is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is phenyl-CF3. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1 is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is pyridine. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1and R2is pyrimidine. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is cyclopropyl. In certain embodiments, in the compounds of Formula (VI), the compound is a compound selected from the group consisting of: In certain embodiments, in the compounds of Formula (VI), the compound is a compound selected from the group consisting of:

[0006]

[0007] In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), or (VIb), Y1is N. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), Y1 is CH or CR3. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), X1is N. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), X1 is CH. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3and R4are independently selected from the group consisting of H and halogen. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3and R4are H. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3 and R4 are F. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3is F and R4is H. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R1 is selected from the group consisting of H, methyl, isopropyl and -OCH3. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R1is cyclopropyl. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X1 and X3 are C or CH and X2 is N. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X1and X2are CR1or CR2and X3 is N. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X2 and X3 are CR1or CR2and X1is N. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted 6-membered aryl or heteroaryl, wherein the heteroaryl comprises N as heteroatom. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), the one or more optional substitutions on A are selected from the group consisting of C1-C3 alkyl, partially halogenated C1-C3-alkyl, and halogen. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is selected from group consisting of optionally substituted phenyl, pyridine, and pyrimidine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyridine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyrimidine. In certain embodiments, in the compounds of Formula (VI), (VI’), at least one of R1and R2 is cyclopropyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted 6-membered aryl or heteroaryl, wherein the heteroaryl comprises N as heteroatom. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), the one or more optional substitutions on A are selected from the group consisting of C1-C3alkyl, partially halogenated C1-C3-alkyl, and halogen. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is selected from group consisting of optionally substituted phenyl, pyridine, and pyrimidine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyridine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyrimidine. In certain embodiments, in the compounds of Formula (VI), Formula (VIa), or Formula (VIb), the compound is a compound selected from the group consisting of:

[0008] 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 the 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 R2 can be substituted alkyls, or R1 can be hydrogen and R2 can 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-C10 means 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-OCH3and -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-C20inclusive 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-C4 alkyl, and -NO2 in 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., -CF3and -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-, -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 - =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 -NH2 group 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 -NO2 group. 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 - SO4 group. 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 the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 ( 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 in 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 a compound of Formula (VI): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1is N or CR1or CR2; Y1 is N, N+-O-, S, O, CR3, or CH; Y2 is N, N+-O-, S, O, or CR3; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N; or R1 and R2 are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3 is H or halogen; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VI’): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1 is N or CR1; Y1is N, N+-O-, S, O, or CR3; Y2is N, N+-O-, S, O, or CR3; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6 cycloalkyl; or R1 and R2 are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3 is H or halogen; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VIa): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1X2, X3, are independently N orCR1or CR2; Y1 is N, N+-O-, CR3or CR4; L1is a single bond or C1-C4alkyl; A is an optionally substituted phenyl, an optionally substituted 5-7 membered cycloalkyl ring, and optionally substituted aryl, an optionally substituted 4-6 membered heterocycloalkyl ring, or an optionally substituted 5-6 membered heteroaryl ring, wherein said heterocycloalkyl ring includes N, S, or O as heteroatoms, and said heteroaryl ring includes N as heteroatom; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N; or R1and R2are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3and R4are independently selected from the group consisting of H or halogen; and R5 is H or F.; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In certain aspects, the invention provides a compound of Formula (VIa’): or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 X2, X3, and X4 are independently N, or CR1or CR2; Y1 is N, N+-O-, CR3or CR4; Y2is N, N+-O-, CR3or CR4; L1is a single bond or C1-C4alkyl; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5is H or F; and R3 and R4 are independently selected from the group consisting of H or halogen; and R5 is H or F. In certain embodiments, the invention provides a compound of Formula (VIb):

[0009] or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 is N or CR1or CR2; Y1 is N or CR3; Y2isN or CR3; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6 cycloalkyl; or R1 and R2 are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3and R4are independently selected from the group consisting of H or halogen; and R5is H or F. As defined above and described herein, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. As defined above and described herein, Y1 is N, N+-O-, S, O, or CR3. In some embodiments, n is 0 and Y1is N. S, or O. In some embodiments, n is 0 and Y1is N. In some embodiments, n is 0 and Y1 is S. In some embodiments, n is 0 and Y1 is O. In some embodiments, n is 1 and Y1 is N or CR3. As defined above and described herein, Y2is N, N+-O-, S, O, or CR3. In some embodiments, n is 0 and Y1is N. S, or O. In some embodiments, n is 0 and Y1is N. In some embodiments, n is 0 and Y1 is S. In some embodiments, n is 0 and Y1 is O. In some embodiments, n is 1 and Y1 is N or CR3. As defined above and described herein, R1is selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, -C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R1 is H. In certain embodiments, R1 is halogen. In certain embodiments, R1is -CN. In certain embodiments, R1is -OR. In certain embodiments, R1is -N(R)2.In certain embodiments, R1is -C(O)OR. In certain embodiments, R1is -C(O)N(R)2, In certain embodiments, R1 is -C(R)2C(O)OR. In certain embodiments, R1 is -C(R)2C(O)N(R)2. In certain embodiments, R1 is an optionally substituted C1-C6alkyl. certain embodiments, R1 is an optionally substituted C3-C6cycloalkyl. In certain embodiments, R1is an optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R1 is an optionally substituted phenyl. In certain embodiments, R1is an optionally substituted 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R1 is -CN. In certain embodiments, R1 is -C(O)OH. In certain embodiments, R1is -C(O)NH2. In certain embodiments, R1is -CH3. In certain embodiments, R1is -CH2CH3. In certain embodiments, R1 is propyl. In certain embodiments, R1 is isopropyl. In certain embodiments, R1 is -CHF2. In certain embodiments, R1 is -CF3. In certain embodiments, R1 is -CH2NH2. In certain embodiments, R1 is -CH2CH2NH2. In certain embodiments, R1 is .In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is .In certain embodiments, R1is . In certain embodiments, R1 is optionally substituted cyclopropyl. In certain embodiments, R1is cyclopropyl. In certain embodiments, R1is optionally substituted phenyl. In certain embodiments, R1is certain embodiments, .In certain embodiments, R1 is .In certain embodiments, R1 is embodiments, certain embodiments, R1 is is .In certain embodiments, R1is phenyl. In certain embodiments, R1 is -OH. In certain embodiments, R1 is -OCH3. In certain embodiments, R1 is -OCF3. In certain embodiments, R1 is -OCHF2. In certain embodiments, R1 is -OCH2CHF2. In certain embodiments, R1is -OCH2CF3. In certain embodiments, In certain embodiments, R1is -NH2. In certain embodiments, R1is -N(CH3)2. In certain embodiments, R1is optionally substituted azetidine. In certain embodiments, R1 certain embodiments, . In certain embodiments, R1 is.In certain embodiments, R1 is.In certain embodiments, R1 is azetidine. In certain embodiments, R1 is . In certain embodiments, R1is optionally substituted pyridine. In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is pyridine. In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, In certain embodiments, R1is optionally substituted pyrimidine. In certain embodiments,R1 is pyrimidine. In certain embodiments, R1 is .In certain embodiments, R certain embodiments, R1is . In certain embodiments, R1 is halogen. In certain embodiments, R1 is Cl. In certain embodiments, R1is optionally substituted piperidine. In certain embodiments, certain embodiments, R1is piperidine. In certain embodiments, R1 is optionally substituted piperazine. In certain embodiments, certain embodiments, R1 is piperazine. In certain embodiments, . In certain embodiments, R1 is optionally substituted morpholine. In certain embodiments, R1 is morpholine. In certain embodiments, R In certain embodiments, R1is optionally substituted thiomorpholine. In certain embodiments, certain embodiments, R1 is thiomorpholine. In certain embodiments, R1 is optionally substituted oxetane. In certain embodiments, R1 is oxetane. In certain embodiments, R1 is .In certain embodiments, R1is optionally substituted pyridazine. In certain embodiments, R1is pyridazine. In certain embodiments, R1is . In certain embodiments, In certain embodiments, R1is optionally substituted pyrazine. In certain embodiments, R1 In some embodiments, R1is selected from those groups depicted in Table 1. As defined above and described herein, R2 is selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, -C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R2is H. In certain embodiments, R2is halogen. In certain embodiments, R2is -CN. In certain embodiments, R2is -OR. In certain embodiments, R2is -N(R)2.In certain embodiments, R2 is -C(O)OR. In certain embodiments, R2 is -C(O)N(R)2, In certain embodiments, R2is -C(R)2C(O)OR. In certain embodiments, R2is -C(R)2C(O)N(R)2. In certain embodiments, R2is an optionally substituted C1-C6alkyl. certain embodiments, R2is an optionally substituted C3-C6 cycloalkyl. In certain embodiments, R2 is an optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2is an optionally substituted phenyl. In certain embodiments, R2 is an optionally substituted phenyl 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N. In certain embodiments, R2is -CN. In certain embodiments, R2is -C(O)OH. In certain embodiments, R2is -C(O)NH2. In certain embodiments, R2 is -CH3. In certain embodiments, R2 is -CH2CH3. In certainembodiments, R2is propyl. In certain embodiments, R2is isopropyl. In certain embodiments, R2 is -CHF2. In certain embodiments, R2is -CF3. In certain embodiments, R2is -CH2NH2. In certain embodiments, R2is -CH2CH2NH2. In certain embodiments, R2is . In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, R2 is .In certain embodiments, .In certain embodiments, R2 is .In certain embodiments, R2 is , , In certain embodiments, R2is optionally substituted cyclopropyl. In certain embodiments, R2is cyclopropyl. In certain embodiments, R2 is optionally substituted phenyl. In certain embodiments, R2 is certain embodiments, . In certain embodiments, R2 is . In certain embodiments, certain embodiments, certain embodiments, R2 is .In certain embodiments, R2 is . In certain embodiments, R2 is phenyl. In certain embodiments, R2is -OH. In certain embodiments, R2is -OCH3. In certain embodiments, R2is -OCF3. In certain embodiments, R2is -OCHF2. In certain embodiments, R2is -OCH2CHF2. In certain embodiments, R2 is -OCH2CF3. In certain embodiments, In certain embodiments, R2 is -NH2. In certain embodiments, R2 is -N(CH3)2. In certain embodiments, R2 is optionally substituted azetidine. In certain embodiments, R2 is . In certain embodiments, . In certain embodiments, .In certain embodiments, certain embodiments, R2 is azetidine. In certain embodiments, R2 is . In certain embodiments, R2is optionally substituted pyridine. In certain embodiments, R2i . . In certain embodiments, R2is .n certain embodiments, R2 is .In certain embodiments, R2 is pyridine. In certain embodiments, R2 is . In certain embodiments, R2 is . In certain embodiments, . In certain embodiments, R2is optionally substituted pyrimidine. In certain embodiments, R2 is pyrimidine. In certain embodiments, certain embodiments, R2 is . In certain embodiments, R2is halogen. In certain embodiments, R2is Cl. In certain embodiments, R2is optionally substituted piperidine. In certain embodiments, . In certain embodiments, R2 is piperidine. In certain embodiments, R2is optionally substituted piperazine. In certain embodiments, . In certain embodiments, R2is optionally substituted morpholine. In certain embodiments, R2is morpholine. In certain embodiments, In certain embodiments, R2 is optionally substituted thiomorpholine. In certain embodiments, R2 is . In certain embodiments, R2 is thiomorpholine. In certain embodiments, R2 is optionally substituted oxetane. In certain embodiments, R2 is oxetane. In certain embodiments, R2 is . In certain embodiments, R2is optionally substituted pyridazine. In certain embodiments,R2 is pyridazine. In certain embodiments, R2 is .In certain embodiments, In certain embodiments, R2is optionally substituted pyrazine. In certain embodiments, R2is pyrazine. In certain embodiments, R2is . In some embodiments, R2 is selected from those groups depicted in Table 1. As defined above and described herein, R1 and R2 are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R1and R2are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form certain embodiments, R1 and R2 are taken together!with their intervening to form R1 and R2 are taken together!with their intervening to form certain embodiments, R1 and R2 are taken together! with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form embodiments, R1and R2are taken together!with their intervening to form embodiments, R1and R2are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form . In certain embodiments, R1 and R2 are taken together!with their intervening to form . As defined above and described herein A is an optionally substituted 5-7 membered cycloalkyl ring, aryl, 4-6 membered heterocycloalkyl ring, or a 5-6 membered heteroaryl ring, wherein said heterocycloalkyl ring includes N, S, or O as heteroatoms, and said heteroaryl ring includes N as heteroatom. In some embodiments, A is an optionally substituted 5-7 membered cycloalkyl ring. In some embodiments, A is optionally substituted aryl. In some embodiments, A is an optionally substituted 4-6 membered heterocycloalkyl ring, wherein said heterocycloalkyl includes N, S, or O as heteroatoms. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl ring, wherein said heteroaryl ring contains N as heteroatom. In some embodiments, A is an optionally substituted 4-6 membered heterocycloalkyl ring having 1 to 4 heteroatoms independently selected from N, S, or O. In some embodiments, Ring A is an optionally substituted 5-6 membered heteroaryl ring having 2-3 N as heteroatom. In some embodiments A is optionally substituted with one or more groups selected from =O, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, optionally substituted 4-6 membered heterocycloalkyl ring, and halogen. In certain embodiments, A is optionally substituted phenyl. In certain embodiments, A is embodiments, certain embodiments, A is is certain embodiments, A is phenyl. In certain embodiments, A is optionally substituted pyridine. In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is pyridine. In certain In certain embodiments, A is optionally substituted pyrimidine. In certain embodiments, A is pyrimidine. In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is . In certain embodiments, A is optionally substituted piperidine. In certain embodiments, A certain embodiments, A is piperidine. In certain embodiments, A is optionally substituted piperazine. In certain embodiments, R2 . In certain embodiments, A is optionally substituted morpholine. In certain embodiments, A is morpholine. In certain embodiments, In certain embodiments, A is optionally substituted thiomorpholine. In certain embodiments, A certain embodiments, A is thiomorpholine. In certain embodiments, A is optionally substituted oxetane. In certain embodiments, R2 is oxetane. In certain embodiments, A is . In certain embodiments, A is optionally substituted azetidine. In certain embodiments, A is . In certain embodiments, . In certain embodiments, . In certain embodiments, azetidine. In certain embodiments, A is . In some embodiments, A is selected from those groups depicted in Table 1. Exemplary compounds of the invention are set forth in Table 1, below. Table 1.

[0010]

[0011]

[0012] In some embodiments, the present disclosure provides a compound set forth in Table 1, above, or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1 is N+-O-. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1is S.In certain embodiments, in the compounds of Formula (VI), Y1is O. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), Y1 is CH orCR3.In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1is CH. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1is CR1or CR2. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), when n is 0, Y2is O, S, or N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), when n is 1, Y2 is CH or CR3. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3is H. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3is halogen. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R3 is F. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R1and R2are independently selected from the group consisting of H, methyl, optionally substituted phenyl, pyridine, pyrimidine, and cyclopropyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), R1 and R2 are independently H or methyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1and R2is phenyl-CF3. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), X1 is N. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1and R2is pyridine. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is pyrimidine. In certain embodiments, in the compounds of Formula (VI) or Formula (VI’), at least one of R1 and R2 is cyclopropyl. In certain embodiments, in the compounds of Formula (VI), the compound is a compound selected from the group consisting of: In certain embodiments, in the compounds of Formula (VI), the compound is a compound selected from the group consisting of:

[0013] In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), or (VIb), Y1is N. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), Y1 is CH or CR3. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), X1is N. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), X1 is CH. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3and R4are independently selected from the group consisting of H and halogen. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3and R4are H. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3 and R4 are F. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R3is F and R4is H. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R1 is selected from the group consisting of H, methyl, isopropyl and -OCH3. In certain embodiments, in the compounds of Formula (VI), (VI’), (VIa), (VIa’), or (VIb), R1is cyclopropyl. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X1 and X3 are C or CH and X2 is N. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X1and X2are CR1or CR2and X3 is N. In certain embodiments, in the compounds of Formula (VIa) and (VIa’), X2 and X3 are CR1or CR2and X1is N. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted 6-membered aryl or heteroaryl, wherein the heteroaryl comprises N as heteroatom. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), the one or more optional substitutions on A are selected from the group consisting of C1-C3 alkyl, partially halogenated C1-C3-alkyl, and halogen. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is selected from group consisting of optionally substituted phenyl, pyridine, and pyrimidine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyridine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyrimidine. In certain embodiments, in the compounds of Formula (VI), (VI’), at least one of R1and R2 is cyclopropyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted 6-membered aryl or heteroaryl, wherein the heteroaryl comprises N as heteroatom. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), the one or more optional substitutions on A are selected from the group consisting of C1-C3alkyl, partially halogenated C1-C3-alkyl, and halogen. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is selected from group consisting of optionally substituted phenyl, pyridine, and pyrimidine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted phenyl. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyridine. In certain embodiments, in the compounds of Formula (VIa), (VIa’), and (VIb), A is optionally substituted pyrimidine. In certain embodiments, in the compounds of Formula (VI), Formula (VIa), or Formula (VIb), the compound is a compound selected from the group consisting of:

[0014] 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 disease 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, 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 composition 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:

[0015] Example 265, Example 266, and Example 267: Synthetic Scheme for 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl)methyl)-5- methyl-2-phenylpyrimidin-4(3H)-one (Example 265): To a stirred solution of 6-methylnicotinohydrazide 1 (20 g, 132.4 mmol) in DMF (200 mL) was added 2,2-difluoroacetic anhydride 2 (46.09 g, 264.9 mmol) and the reaction mixture was stirred for 16 h at 90 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (250 mL) and extracted with diethyl ether (2 x 100 mL). The organic layer was washed with the brine solution (250 mL) and dried over Na2SO4and concentrated under reduced pressure to get the crude product. The crude product was purified by the GRACE FLASH column chromatography and eluted with 15% ethyl acetate in pet- ether to get the 3-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole 3 (12 g, 43%) as an off white solid. LCMS: 99.12%, m / z 212.2 [M+H]+. Step-2: 2-(6-(Bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (4): To a stirred solution of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole 3 (10 g, 47.3 mmol) and in carbon tetrachloride (100 mL) were added N-bromo succinimide (8.43 g, 47.3 mmol) and AIBN (0.77 g, 4.73 mmol) at room temperature. Then the resulting reaction mixture was stirred for 12 h at 80oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to get the crude compound, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with the brine solution (100 mL), dried over Na2SO4,and concentrated under reduced pressure to get the crude product. The crude product was purified by the combi flash column chromatography and eluted with 15% ethyl acetate in pet-ether to obtain 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (4.5 g, 33%) as an off white solid. LCMS: 87.9%, m / z-290.1 [M+H]+(Bromo pattern). Step-3: 3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- methylpyrimidin-4(3H)-one (6):

[0016] To a stirred solution of 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (1.0 g, 3.46 mmol) and 5-methylpyrimidin-4(3H)-one 5 (0.38 g, 3.44 mmol) in ACN (10 mL) was added cesium carbonate (1.68 g, 5.17 mmol) at room temperature. The resulting reaction mixture was stirred 90 °C for 2 h. After complete consumption of starting material, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by the crude compound was purified by column chromatography (100-200 mesh silica gel, 100% ethyl acetate as an eluent) to afford 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl)-5- methylpyrimidin-4(3H)-one 6 (0.6 g, 54%) as a pale-yellow solid. LC-MS: 83.2%, m / z [M+H]+= 320.2;1H NMR (400 MHz, CDCl3) δ: 9.25 (d, J = 1.6 Hz, 1H), 8.39 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 8.29 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H ), 6.93 (t, J = 51.6 Hz, 1H), 5.25 (s, 2H), 2.07 (s, 3H). Step-4: 3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-methyl-2- phenylpyrimidin-4(3H)-one (Example 265): To stirred solution of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl)-5- methylpyrimidin-4(3H)-one 6 (0.6 g, 1.87 mmol) in DMF (6 mL) were added iodobenzene (0.76 g, 3.75 mmol), cesium fluoride (0.34 g, 2.25 mmol) and TPP (0.1 g, 0.37 mmol), followed by copper iodide (0.71 g, 3,76 mmol), the reaction mixture was degassed by argon for 10 mins. Then palladium (II)acetate (0.042 g, 0.19 mmol) was added to the reaction mixture and stirred for 16 h at 150 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (25 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by GRACE FLASH chromatography (silica gel, 100-200 mesh) using 70-80% ethyl acetate in n-hexane to get 3-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl) pyridin-2-yl) methyl)-5-methyl-2-phenylpyrimidin-4(3H)-one (Example 265) (0.05g, 6%) as a pale-yellow solid. LCMS: 99.94%, m / z 396.3 [M+H]+; HPLC: 99.82%,1H NMR (400 MHz, DMSO-d6) δ: 9.10 (d, J = 1.6 Hz, 1H), 8.34 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.69-7.37 (m, 7H), 5.25 (s, 2H), 2.00 (s, 3H). Synthetic Scheme for 3-((5-(5-(difluoro methyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl)- 5-methoxy-2-phenylpyrimidin-4(3H)-one (Example 266): Step-5: 3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- methoxypyrimidin-4(3H)-one (8): To a stirred solution of 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (1.0 g, 3.44 mmol) and 5-methoxypyrimidin-4(3H)-one 7 (0.43 g, 3.44 mmol) in ACN (10 mL) was added cesium carbonate (1.68 g, 5.17 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 2 h. After the complete consumption of the starting material, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get crude compound which was purified by column chromatography (100-200 mesh silica gel, 100% ethyl acetate as an eluent) to afford 3-((5-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-methoxypyrimidin-4(3H)-one 8 (0.5 g, 43%) as a pale yellow solid. LC-MS: 76.01%, m / z [M+H]+= 336.2;1H NMR (400 MHz, DMSO-d6) δ: 9.12 (d, J = 1.6 Hz, 1H), 8.34 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 8.29 (s, 1H), 7.69–7.44 (m, 3H), 5.35 (s, 2H), 3.75 (s, 3H). Step-6: 3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-methoxy-2- phenylpyrimidin-4(3H)-one (Example 266): To stirred solution of afford 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 5-methoxypyrimidin-4(3H)-one 8 (0.5 g, 1.49 mmol) in DMF (5 mL) were added Iodobenzene (0.6 g, 2.98 mmol), cesium fluoride (0.27 g, 1.79 mmol) and TPP (0.08 g, 0.29 mmol), followed by copper iodide (0.57 g, 2.98 mmol), the reaction mixture was degassed by argon for 10 mins. Then palladium (II)acetate (0.033 g, 0.15 mmol) was added to the reaction mixture and stirred for 16 h at 150 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (25 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by GRACE FLASH chromatography (silica gel, 100-200 mesh) using 80% ethyl acetate in n-hexane to get 3-((5-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-methoxy-2-phenylpyrimidin- 4(3H)-one (Example 266) (0.065g, 10%) as a pale-yellow solid. LCMS: 95.22%, m / z 412.28 [M+H]+; HPLC: 95.27%;1H NMR (400 MHz, DMSO-d6) δ: 9.09 (d, J = 1.6 Hz, 1H), 8.34 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.73 (s, 1H), 7.69-7.35 (m, 7H), 5.24 (s, 2H), 3.83 (s, 3H). Synthetic Scheme for 5-cyclopropyl-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin- 2-yl) methyl)-2-phenylpyrimidin-4(3H)-one (Example 267): Step-7: 5-Cyclopropyl-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)pyrimidin-4(3H)-one (10): To a stirred solution of 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 4 (1.3 g, 4.48 mmol) and 5-cyclopropylpyrimidin-4(3H)-one 9 (0.6 g, 4.48 mmol) in ACN (15 mL) was added cesium carbonate (2.18 g, 6.72 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 2 h. After the complete consumption of the starting material, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by column chromatography (100-200 mesh silica gel, 100% ethyl acetate as an eluent) to get 5-cyclopropyl- 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyrimidin-4(3H)-one 10 (0.65 g, 44.8%) as a pale yellow solid. LC-MS: 76.01%, m / z [M+H]+= 336.2;1H NMR (400 MHz, CDCl3) δ: 9.25 (d, J = 1.6 Hz, 1H), 8.38 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 8.26 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.24 (s, 2H), 1.91–1.84 (m, 1H), 0.96–0.91 (m, 2H), 0.72–0.71 (m, 2H). Step-8: 5-Cyclopropyl-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl)- 2-phenylpyrimidin-4(3H)-one (Example 267):

[0017] To stirred solution of 5-cyclopropyl-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)pyrimidin-4(3H)-one 10 (0.65 g, 1.88 mmol) in DMF (7 mL) were added were added iodobenzene (0.76 g, 3.76 mmol), cesium fluoride (0.34 g, 2.26 mmol) and TPP (0.1 g, 0.37 mmol), followed by copper iodide (0.72 g, 23.76 mmol), the reaction mixture was degassed by argon for 10 mins. Then palladium (II)acetate (0.042 g, 0.19 mmol) was added to the reaction mixture and stirred for 16 h at 150 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (25 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by prep HPLC to get 5-cyclopropyl-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl)-2- phenylpyrimidin-4(3H)-one (Example 267) (0.09 g, 11.3%) as a pale-yellow solid. LCMS: 95.17%, m / z 422.3 [M+H]+; HPLC: 95.09%;1H NMR (400 MHz, DMSO-d6) δ: 9.10 (d, J = 1.6 Hz, 1H), 8.35 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.74 (s, 1H), 7.69–7.36 (m, 7H), 5.24 (s, 2H), 1.90– 1.84 (m, 1H), 0.89–0.85 (m, 2H), 0.83–0.81 (m, 2H). Synthetic Scheme for 5-cyclopropylpyrimidin-4(3H)-one: Step-9: 4-Chloro-5-cyclopropylpyrimidine (12):

[0018] To a stirred solution of afford 4-chloro-5-iodopyrimidine 11 (10.0 g, 41.6 mmol) in 1,4-dioxane (80 mL) and water (20 mL) were added cyclopropyl boronic acid (3.54 g, 41.6 mmol), cesium carbonate (27.0 g, 83.2 mmol), the reaction mixture was de-gassed by argon for 20 mins, then added PdCl2(dppf) (3.4 g, 4.16 mmol) the reaction mixture was again degassed by argon for 10 mins. The reaction mixture was stirred for 12 h at 100°C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by GRACE FLASH chromatography (silica gel, 100-200 mesh) using 5-10% ethyl acetate in n-hexane to get 4-chloro-5- cyclopropylpyrimidine 12 (1.8 g, 27%) as a colorless liquid LCMS: 64.59%, m / z 412.3 [M+H]+. Step-10: Synthetic Scheme for 5-cyclopropylpyrimidin-4(3H)-one (9): To a stirred solution of 4-chloro-5-cyclopropylpyrimidine 12 (1.7 g, 10.8 mmol), and in 1,4- dioxane (4 mL), was added 3N NaOH (5 mL) at room temperature. The resulting reaction mixture was stirred at 100 °C for 6 h. After complete consumption of the starting material, the reaction mixture was diluted with water (30 mL), then acidified with 10% dilute acetic acid PH~5-6, aq layer was extracted with ethyl acetate (80 mL×2). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by the crude compound was purified by column chromatography (100-200 mesh silica gel, 70% ethyl acetate in pet ether as eluent) to afford 5- cyclopropylpyrimidin-4(3H)-one 9 (0.7 g, 43%) as an off-white solid; LC-MS: 42.5%, m / z [M+H]+= 137.2; Example 268, Example 269, Example 270, and Example 271: Synthetic Scheme of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-5- phenylpyrimidin-4(3H)-one (Example 268): Step-1: Methyl 3-fluoro-4-((6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzoate (3): To a stirred solution of methyl 4-(bromomethyl)-3-fluorobenzoate 1 (1.2 g, 4.85 mmol) and 5- phenylpyrimidin-4-ol 2 (585.43 mg, 3.40 mmol) in DMF (12 mL) was added cesium carbonate (2.37 g, 7.28 mmol) and the reaction mixture was stirred at 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting the product in 30% ethyl acetate in pet ether to get methyl 3-fluoro-4-((6-oxo-5-phenylpyrimidin- 1(6H)-yl)methyl)benzoate 3 (0.6 g, 36.51%) as brownish semi solid. LC-MS purity: 92.13%, m / z [M+H]+= 339.22. Step-2: 3-Fluoro-4-((6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzohydrazide (4): To a stirred solution of methyl 3-fluoro-4-((6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzoate 3 (0.600 g, 1.77 mmol) in ethanol (3.0 mL) was added hydrazine hydrate (0.266 mL, 5.32 mmol) at rt. The resulting reaction mixture was stirred at 90oC for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated and then the crude compound was washed with diethyl ether and filtered the solid and washed with diethyl ether and dried under reduced pressure to get crude 3-fluoro-4-((6-oxo- 5-phenylpyrimidin-1(6H)-yl)methyl)benzohydrazide 4 (0.500 g, 83.33%) as a yellowish solid which was used in the next step without further purification. LCMS purity: 90%, m / z [M+H]+= 339.21. Step-3: 3-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-5-phenylpyrimidin- 4(3H)-one (Example 268):

[0019] To a stirred solution of 3-fluoro-4-((6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzohydrazide 4 (0.6 g, 1.77 mmol) in DMF (3.0 mL) was added difluoroacetic anhydride 5 (0.441 mL, 3.54 mmol) at rt. Then the reaction mixture was refluxed for 12 h at 100oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (10 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to get crude compound (2 x 25 mL). The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting the product in 50% ethyl acetate in pet-ether to get the compound. Further purification by revers phase prep- HPLC for further purification to get 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2- fluorobenzyl)-5-phenylpyrimidin-4(3H)-one (Example 268) (0.222 g, 31.43%) as an off white solid. LC-MS purity: 99.88%, m / z [M+H]+= 399.20; HPLC: 99.70%;1H NMR (400 MHz, DMSO-d6) δ: 8.33 (d, J = 1.2 Hz, 1H), 8.07 (s, 1H), 7.91–7.89 (m, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.64–7.61 (m, 2H), 7.44–7.37 (m, 3H), 6.91 (t, J = 51.6 Hz, 1H), 5.25 (s, 2H). Synthetic Scheme of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2- methyl-5-phenylpyrimidin-4(3H)-one (Example 269):

[0020] To a stirred solution of 5-bromo-2-methylpyrimidin-4-ol 1 (2 g, 10.58 mmol) and phenylboronic acid 2 (2.58 g, 21.16 mmol) in 1,4-dioxane (20.0 mL) and water (6.0 mL) was added potassium carbonate (4.38 g, 31.74 mmol) at rt. The resulting reaction mixture was degassed for 10 min under argon and then Pd(dppf)Cl2 (387.122 mg, 0.52 mmol) was added to the reaction mixture. The reaction mixture was heated at 100 °C for 6 h. Progress of the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered on a celite pad, and the pad was washed with ethyl acetate (50 mL). Filtrate was diluted with ice water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure to get crude compound. The obtained crude was washed with diethyl ether and dry properly to get 2-methyl-5-phenylpyrimidin-4(3H)-one 3 (1.1 g, 55.83%) as a brown solid. HPLC: 82.89%; LC-MS: 68.93%, m / z [M+H]+= 187.23. Step-2: Methyl 3-fluoro-4-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzoate (5): To a stirred solution of methyl 4-(bromomethyl)-3-fluorobenzoate 4 (1.5 g, 6.07 mmol) and 2- methyl-5-phenylpyrimidin-4-ol 3 (904.46 mg, 4.85 mmol) in DMF (15.0 mL) was added cesium carbonate (2.96 g, 9.10 mmol) at rt. The resulting reaction mixture was stirred at 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting the product in 30% ethyl acetate in pet ether to get methyl 3-fluoro-4- ((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzoate 5 (0.50 g, 23.37%) as brown semisolid. LC-MS: 92.13%, m / z [M+H]+= 353.20. Step-3: 3-Fluoro-4-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl) benzohydrazide (6): To a stirred solution of methyl 3-fluoro-4-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)- yl)methyl)benzoate 5 (0.500 g, 1.41 mmol) in ethanol (2.5 mL) was added hydrazine hydrate (0.213 mL, 4.25 mmol) at rt. Then the reaction mixture was refluxed for 4 h at 90oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated and then added diethyl ether and filtered the solid. The solid compound was again washed with diethyl ether and dried under reduced pressure to get compound 3-fluoro- 4-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)benzohydrazide 6 (0.450 g, 90%) as off white solid. LC-MS: 93%, m / z [M+H]+= 353.20. Step-4: 3-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2-methyl-5- phenylpyrimidin-4(3H)-one (Example 269): To a stirred solution of 3-fluoro-4-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)- yl)methyl)benzohydrazide 6 (0.450 g, 1.27 mmol) in DMF (4.5 mL) was added difluoroacetic anhydride 7 (0.318 mL, 2.55 mmol) at rt. Then the reaction mixture was refluxed for 12 h at 100oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting the product in 30% ethyl acetate in pet ether to get the compound. The crude compound was purified by revers phase prep-HPLC to get 3-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-2-methyl-5-phenylpyrimidin-4(3H)-one (Example 269) (0.112 g, 21.27%) as an off white solid. LC-MS: 99.09 %, m / z [M+H]+= 413.29; HPLC: 99.40%;1H NMR (400 MHz, DMSO-d6) δ: 8.06 (s, 1H), 7.90-7.86 (m, 2H), 7.69-7.67 (m, 2H), 7.52-7.41 (m, 2H), 7.40-7.33 (m, 2H), 6.91 (t, J = 51.6 Hz, 1H), 5.48 (s, 2H), 2.57 (s, 3H). Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5- phenylpyrimidin-4(3H)-one (Example 270):: To a stirred solution of 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 1 (1.0 g, 3.44 mmol) and 5-phenylpyrimidin-4(3H)-one 2 (0.59 g, 3.44 mmol) in ACN (10 mL) was added cesium carbonate (1.68 g, 5.17 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 2 h. After the complete consumption of the starting material, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by column chromatography (100-200 mesh silica gel), 70% EtOAc in pet ether as an eluent to afford 3-((5- (5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenylpyrimidin-4(3H)-one (Example 270) (0.184 g, 15%) as a pale yellow solid. LC-MS: 96.76%, m / z [M+H]+= 382.2; HPLC purity: 95.94%;1H NMR (400 MHz, DMSO-d6) δ: 9.14 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.45 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 8.22 (s, 1H), 7.71–7.34 (m, 7H), 7.43–7.33 (m, 3H), 5.42 (s, 1H). Synthetic Scheme of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2- methyl-5-phenylpyrimidin-4(3H)-one (Example 271):

[0021] Step-1: Methyl 6-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)nicotinate (3): To a stirred solution of methyl 6-(bromomethyl) nicotinate 1 (0.7 g, 3.04 mmol) and 2-methyl-5- phenylpyrimidin-4-ol 2 (453.27 mg, 2.43 mmol) in DMF (7.0 mL) was added caesium carbonate (1.48 g, 4.56 mmol) at rt. The resulting reaction mixture was stirred at 80 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was dilute with ice water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting the product in 30% ethyl acetate in pet ether to get compound methyl 6-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)nicotinate 3 (0.500 g, 49%) as brownish semi solid. LC-MS: 81.50%, m / z [M+H]+= 336.23. Step-2: 6-((2-Methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)nicotinohydrazide (4): To a stirred solution of methyl 6-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl)nicotinate 3 (0.460 g, 1.37 mmol) in ethanol (2.3 mL) was added hydrazine hydrate (0.206 mL, 4.11 mmol) at rt. Then the resulting reaction mixture was reflux for 4 h at 90oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was concentrated and then added diethyl ether and filtered the solid. The solid compound was washed with diethyl ether and dried under reduced pressure to get crude 6-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)- yl)methyl)nicotinohydrazide 4 (0.430 g, 93.48%) as a brownish semi solid. LC-MS: 89.48%, m / z [M+H]+= 336.20. Step-3: 3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2-methyl-5- phenylpyrimidin-4(3H)-one (Example 271): To a stirred solution of 6-((2-methyl-6-oxo-5-phenylpyrimidin-1(6H)- yl)methyl)nicotinohydrazide 4 (0.430 g, 1.28 mmol) in DMF (4.3 mL) was added difluoroacetic anhydride (0.319 mL, 2.56 mmol) at rt. Then the reaction mixture was reflux for 12 h 100oC. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with ice water (10 mL) and extracted with ethyl acetate (25 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by (100-200 silica gel) column chromatography by eluting with 30% ethyl acetate in pet-ether to get tital compound which was purified again by reverse phase prep-HPLC to get 3-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl) pyridin-2-yl)methyl)-2-methyl-5-phenylpyrimidin-4(3H)-one (Example 271) (0.107 g, 21.11%) as an off white solid. LC-MS: 99.59%, m / z [M+H]+= 396.31; HPLC:99.43%;1H NMR (400 MHz, DMSO-d6) δ: 9.25 (d, J = 1.6 Hz, 1H), 8.37 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 8.04 (s, 1H), 7.65-7.62 (m, 3H), 7.43-7.33 (m, 3H), 6.93 (t, J = 51.6 Hz, 1H), 5.49 (s, 2H), 2.74 (s, 3H). Example 272, Example 273, and Example 274: Synthetic Scheme for 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-5- phenylpyridin-2(1H)-one (Example 272): Step-1: 4-Methylbenzohydrazide (1): A stirred solution of methyl 4-methylbenzoate 1 (20 g, 133.32 mmol) in hydrazine hydrate 97% (25.0 mL) was heated at 100 °C for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated and then it was co-distilled with toluene (20 mL) under reduced pressure to get 4-methylbenzohydrazide 2 (16 g, 80%) as a white solid. This material was used as such in the next step without further purification. LCMS purity: 98%; m / z [M+H]+= 151.17;1H NMR (500 MHz, DMSO-d6) δ: 9.74 (br s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H), 2.34 (s, 3H). Step-2: 2-(Difluoromethyl)-5-(p-tolyl)-1,3,4-oxadiazole (2): To a stirred solution of 4-methylbenzohydrazide 2 (20 g, 86.66 mmol) in DMF (200 mL) was added difluoro acetic anhydride (14 mL, 112.6 mmol) at 0 °C. The resulting reaction mixture was stirred for 2 h at 70 °C. The resulting reaction mixture was stirred for another 10 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 water (130 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, ~0-3% EtOAc in pet ether as an eluent) to obtain 2-(difluoro methyl)-5-(p-tolyl)-1, 3,4- oxadiazole 3 (10 g, 54%), LCMS purity: 99.58%, 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-3: 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 (10 g, 47.43 mmol) in CCl4(100 mL) were added N-bromo succinimide (8.4 g,47.43 mmol) and AIBN (1.56 g, 9.48 mmol) at 0 °C. The resulting reaction mixture was stirred at 70 °C for 2 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 g, 43%) 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-4: 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-5-phenylpyridin-2(1H)-one (Example 272): To a stirred solution of 2-(4-(bromomethyl) phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.0 g, 3.47 mmol), and 5-phenyl pyridine-2(1H)-one (0.59 g, 3.47 mmol), in DMF (10 mL), was added cesium carbonate (1.69 g, 5.21 mmol) at room temperature. The resulting reaction mixture was stirred 90 °C for 16 h. After complete consumption of starting material, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by revers phase prep-HPLC to afford 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzyl)-5-phenylpyridin-2(1H)-one (Example 272) (0.47 g, 36%) as an off white solid. The structure was confirmed by NOE and HSQC analysis. LC-MS: 98.69%, m / z [M+H]+= 380.16; HPLC purity: 98.92%;1H NMR (400 MHz, DMSO-d6) δ: 8.33 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.90 (dd, J = 2.8 Hz, J = 9.6 Hz, 1H), 7.67– 7.41 (m, 7H), 7.33–7.29 (m, 1H), 6.56 (d, J = 9.2 Hz, 1H), 5.29 (s, 2H). Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-6-phenylpyrimidin-4(3H)- one (Example 273): To a stirred solution of 2-(4-(bromomethyl) phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 5 (1.0 g, 3.47 mmol) and 6-phenyl pyrimidin-4(3H)-one 7 (0.59 g, 3.47 mmol) in DMF (10 mL), was added cesium carbonate (1.69 g, 5.21 mmol) at room temperature. The resulting reaction mixture was stirred 90 °C for 16 h. After complete consumption of starting material, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound which was purified by reversed phase prep-HPLC to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzyl)-6-phenylpyrimidin-4(3H)-one (Example 273) (0.307 g, 23%) as a yellow solid. The structure was confirmed by NOE and HSQC analysis. LC-MS: 98.21%, m / z [M+H]+= 381.1; HPLC: 97.62%;1H NMR (400 MHz, DMSO-d6) δ: 8.83 (s, 1H), 8.11–8.05 (m, 4H), 7.67–7.41 (m, 6H), 7.03 (s, 1H), 5.26 (s, 2H). Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-5-phenylpyrimidin-4(3H)- one (Example 274):

[0022] To a stirred solution of 2-(4-(bromomethyl) phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 5 (1.0 g, 3.47 mmol) and 5-phenyl pyrimidin-4(3H)-one 8 (0.59 g, 3.47 mmol) in DMF (10 mL), was added cesium carbonate (1.69 g, 5.21 mmol) at room temperature. The resulting reaction mixture was stirred 90 °C for 16 h. After complete consumption of starting material, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get crude compound which was purified by revers phase prep-HPLC to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) benzyl)-5-phenylpyrimidin-4(3H)-one (Example 274) (0.38 g, 29%) as a pale-yellow solid. The structure was confirmed by NOE and HSQC analysis. LC-MS: 99.53%, m / z [M+H]+= 381.19; HPLC purity: 99.61%;1H NMR (400 MHz, DMSO-d6) δ: 8.77 (s, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.69–7.34 (m, 8H), 5.30 (s, 2H). Example 275: Synthetic Scheme for 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-6-methyl-5- phenylpyridin-2(1H)-one (Example 275):

[0023] Step 1 To a solution of E123-1 (2 g, 10.64 mmol) in DMF (30 mL) was added Sodium hydride (468.03 mg, 11.70 mmol, 60% purity) at 0°C. After being stirred at 0-5 °C for 10 min, potassium bromide (2.53 g, 21.27 mmol) and E123-1’ (2.73 g, 11.17 mmol) was added. The reaction mixture was then stirred at 65°C for 16 h until LCMS showed ~ 20% desired compound was generated. The reaction mixture was directly purified by MPLC to afford E123-2 (0.75 g, 1.89 mmol, 17.80% yield). Step 2 To a sealed tube were added E123-2 (700 mg, 1.77 mmol), phenylboronic acid (323.15 mg, 2.65 mmol), Pd(dppf)Cl2.CH2Cl2(144.17 mg, 176.68 μmol), sodium carbonate (468.17 mg, 4.42 mmol), H2O (3 mL) and dioxane (6 mL). After being degassed with N , the mixture was stirred at 90°C for 2h until LCMS indicated ~80% desired compound was generated. The mixture was then concentrated, and the residue was purified by MPLC to afford 1-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)benzyl)-6-methyl-5-phenylpyridin-2(1H)-one (Example 275) (0.5 g, 1.26 mmol, 71.07% yield, 98.82% purity). LCMS (E+) m / z: 394.3 [M+H]+.,1H NMR (600 MHz, DMSO-d6) δ 8.09 – 8.04 (m, 2H), 7.55 (t, J = 51.4 Hz, 1H), 7.46 – 7.41 (m, 5H), 7.37 – 7.34 (m, 1H), 7.32 – 7.29 (m, 2H), 6.51 (d, J = 9.3 Hz, 1H), 5.51 (s, 2H), 2.22 (s, 3H). Example 276: Synthetic Scheme for 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6- phenylpyridin-2(1H)-one (Example 276): Step 1 To a solution of E39-1 (10.50 g, 62.44 mmol) in EtOH (230 mL) was added N2H4.H2O (62.44 g, 1.25 mol). The mixture was stirred at 80°C for 16 h and then concentrated under reduced pressure. The resulting white solid was dried in a vacuum to give product E39-2 (10.30 g, 61.25 mmol, 98.09% yield) as a white solid. Step 2 To a solution of E39-2 (11.30 g, 67.19 mmol) in THF (800 mL) was added E39-2’ (46.78 g, 268.78 mmol) and TEA (34.00 g, 335.97 mmol, 46.86 mL). The reaction mixture was heated to reflux for 1 h and then concentrated under reduced pressure. The residue was purified by prep- HPLC to give E39-3 (12.88 g, 56.45 mmol, 84.01% yield) as a white solid. Step 3 To a solution of E39-3 (5.80 g, 25.42 mmol) in dry CCl4(52 mL) was added AIBN (417.42 mg, 2.54 mmol) and NBS (4.66 g, 26.18 mmol). The reaction mixture was stirred at 80°C for 10 h under N2 atmosphere and then concentrated under reduced pressure. the mixture was quenched with water (100 mL), extracted with DCM (100 mL×3). The combined organic layer was wash with brine (100 mL×2), dried over Na2SO4. The solution was concentrated and purified by column chromatography on silica gel (PE:EA= 10:1) to give E39-4 (7.00 g, 22.80 mmol, 89.68% yield) as a white solid. Step 4 To a solution of E39-4’ (3.11 g, 18.17 mmol) in DMF (9 mL) and DME (36 mL) under N2 was added NaH (457.79 mg, 19.07 mmol) at 0°C. LiBr (3.16 g, 36.33 mmol) was then added 10 min later. After being stirred for 15 min at room temperature, E39-4 (5.54 g, 18.17 mmol) was added, and the reaction was heated to 65°C for 16 h. After being cooled to room temperature, the mixture was quenched with saturated NH4Cl (100 mL), extracted with DCM (100 mL×3). The combined organic layer was washed with brine (100 mL×2) and dried over Na2SO4. The solution was concentrated, and the residue was purified by column chromatography on silica gel (PE:EA=2:1- 1:2) to give 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6-phenylpyridin- 2(1H)-one (Example 276) (1.21 g, 3.05 mmol, 16.76% yield) as a white solid. LCMS (E+) m / z: 398.1 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 7.82 (dd, J = 8.1, 1.6 Hz, 1H), 7.66 (dd, J = 10.1, 1.7 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.16 – 7.08 (m, 2H), 6.91 (t, J = 51.7 Hz, 1H), 6.71 (dd, J = 9.2, 1.4 Hz, 1H), 6.17 (dd, J = 6.8, 1.4 Hz, 1H), 5.25 (s, 2H). Example 277: Synthetic Scheme for 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6- phenylpyridin-2(1H)-one (Example 277):

[0024] Step 1 To a mixture solution of E38-1 (6.60 g, 37.93 mmol) in dioxane / H2O=3:1 (189 mL) were added K2CO3 (10.48 g, 75.86 mmol), E38-1’ (6.94 g, 56.90 mmol) and Pd(PPh3)4 (4.38 g, 3.79 mmol). The reaction mixture was stirred at 100°C for 16 h under N2. After being cooled to room temperature, the mixture was eluted with water (100 mL), extracted with DCM (100 mL×3). The combined organic layer was then wash with brine (100 mL×2) and then dried over Na2SO4. The solution was filtered and concentrated, the residue was purified by column chromatography on silica gel (DCM:MeOH= 40:1) to give E38-2 (5.72 g, 33.41 mmol, 88.08% yield) as a white solid. Step 2 To a solution of E38-2 (2.52 g, 14.72 mmol) in MeOH (73 mL) was added Pd / C (400 mg). After being degassed with H2 three times, the mixture was stirred at 50°C for 16 h under H2. After being cooled to room temperature, the reaction mixture was filtered through a pad of Celite, washed with MeOH (30 mL×2). The filtrate was concentrated under reduced pressure to give E38-3 (2.33 g, 13.30 mmol, 90.33% yield) which was used for the next step without further purification. Step 3 To a solution of E38-4 (8.00 g, 37.88 mmol) in dry CCl4(76 mL) was added AIBN (622.10 mg, 3.79 mmol) and NBS (6.94 g, 39.02 mmol). The reaction mixture was allowed to stir at 80°C for 10 h under N2 atmosphere. The mixture was concentrated under reduced pressure and then quenched with water (100 mL). The suspension was extracted with DCM (100 mL×3). The combined organic layer was washed with brine (100 mL) and then dried over Na2SO4. The solution was concentrated, and the residue was purified with column chromatography on silica gel (PE:EA= 10:1) to give E38-5 (800.00 mg, 2.76 mmol, 7.28% yield) as a white solid. Step 4 To a solution of E38-3 (1.81 g, 10.33 mmol) in THF (31 mL) NaH (280.14 mg, 11.67 mmol) was added at 0°C. After being stirred for 10 min at 0°C, E38-5 (3.00 g, 10.33 mmol) was added in portions. The reaction mixture was then allowed to warm to at room temperature and stirred for 16 h. The mixture was quenched with saturated NH4Cl (5 mL). The suspension was concentrated under reduced pressure and purified directly by prep-HPLC to give E38-6 (1.63 g, 4.24 mmol, 41.05% yield) as a white solid. Step 5 To a solution of E38-6 (1.93 g, 5.02 mmol) in DCE (50 mL) were added 2-Chloroanthraquinone (304.60 mg, 1.26 mmol), Cobalt acetate tetrahydrate (125.07 mg, 502.11 μmol) and dimethylglyoxime (291.52 mg, 2.51 mmol) under N2. The mixture was sealed and stirred in dark for 30 min at room temperature. And then the reaction was irradiated with LEDs (12 V, 450 nm) for 36 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified prep-HPLC and re-purified by silica gel column chromatography using PE:EA=1:3-EA to give 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-6-phenylpyridin-2(1H)-one (Example 277) as a yellow solid. LCMS (E+) m / z: 381.1 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 9.18 (dd, J = 2.2, 0.8 Hz, 1H), 8.30 (dd, J = 8.2, 2.2 Hz, 1H), 7.45 (dd, J = 9.2, 6.8 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.5 Hz, 3H), 6.93 (t, J = 51.7 Hz, 1H), 6.67 (dd, J = 9.2, 1.4 Hz, 1H), 6.19 (dd, J = 6.9, 1.3 Hz, 1H), 5.28 (s, 2H). Example 278: Synthetic Scheme for 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(2- (trifluoromethyl)phenyl)pyrimidin-4(3H)-one (Example 278):

[0025] Step 1 To a stirred solution of tert-butyl N-aminocarbamate (30.76 g, 232.76 mmol) and DIPEA (136.73 g, 1.06 mol, 184.28 mL) in DCM (250 mL) was added E6-1 (40.00 g, 211.60 mmol) in portions at 0-10 °C under N2atmosphere. And then the mixture was stirred at 25 °C for 1h. After monitored by LCMS, the mixture was poured into water (200 mL). The suspension was separated. And the water phase was extracted with DCM (3 x 100 mL). The combined organic phase was washed with water (2 x 100 mL) and brine (100 mL). The organic phase was then concentrated under reduced pressure to give E6-2 (58.00 g, 203.70 mmol, 96.27% yield) as a solid without further purification. Step 2: To a solution of E6-2 (58.00 g, 203.70 mmol) in DCM (200 mL) was added trifluoroacetic acid (200 mL) slowly at 0-10 °C. Then the mixture was stirred at 20°C for 1h. After monitored by LCMS, the mixture was concentrated under reduced pressure to provide E6-3 (60.00 g, 200.91 mmol, 98.63% yield, TFA salt) as a solid without further purification. Step 3 To a mixture of E6-3 (60.00 g, 200.91 mmol) in THF (500 mL) was added a liquid of (2,2- difluoroacetyl) 2,2-difluoroacetate (69.94 g, 401.81 mmol) at 25 °C. After being stirred for 5 min, TEA (40.66 g, 401.81 mmol, 56.04 mL) was added slowly. The mixture was stirred at 25 °C for another 2h until LCMS showed SM was consumed. The mixture was concentrated under reduced pressure and purified by HPLC to provide E6-4 (19.00 g, 77.67 mmol, 38.66% yield) as a solid. Step 4 To a sealed tube were added E6-5 (6.00 g, 45.97 mmol), [2-(trifluoromethyl)phenyl]boronic acid (17.46 g, 91.93 mmol), sodium carbonate (9.74 g, 91.93 mmol), toluene (40.00 mL), water (20.00 mL), ethanol (20.00 mL) and tetrakis(triphenylphosphine)palladium (5.31 g, 4.60 mmol). After being degassed with N2atmosphere for 3 times, the mixture was then stirred at 80 °C for 2h. After monitored by LCMS, the mixture was concentrated under reduced pressure and purified by HPLC to provide E6-6 (2.40 g, 9.99 mmol, 21.74% yield) as a solid. Step 5 To a mixture of E6-6 (730 mg, 3.04 mmol) and lithium carbonate (336.87 mg, 4.56 mmol) in DMF (7 mL) was added a solid of E6-4 (743.51 mg, 3.04 mmol). The mixture was then allowed to heat to 80 °C for 24h. After monitored by LCMS, the mixture was then purified by HPLC to provide 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(2-(trifluoromethyl)phenyl)pyrimidin- 4(3H)-one (Example 278) (310 mg, 691.43 μmol, 22.75% yield, 100.00% purity) as a solid. LCMS (E+) m / z: 449.0 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 6.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.65 – 7.41 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 6.6 Hz, 1H), 5.18 (d, J = 16.1 Hz, 1H), 4.92 (d, J = 16.1 Hz, 1H). Example 279: Synthetic Scheme for 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2- phenylpyrimidin-4(3H)-one (Example 279): Step 1 To a sealed tube were added E7-1 (7.00 g, 53.63 mmol), phenylboronic acid (13.08 g, 107.25 mmol), sodium carbonate (11.37 g, 107.25 mmol), toluene (60.00 mL), water (30.00 mL), ethanol (30.00 mL) and tetrakis(triphenylphosphine)palladium (6.20 g, 5.36 mmol). After being degassed with N2for 3 times, the mixture was then stirred at 80 °C for 2h. The mixture was concentrated under reduced pressure. The residue was purified by HPLC to provide E7-2 (8.00 g, 46.46 mmol, 86.64% yield) as a solid. Step 2 To a mixture of E7-2 (8.00 g, 46.46 mmol) and lithium carbonate (5.15 g, 69.69 mmol) in DMF (50 mL) was added a solid of E6-4 (11.37 g, 46.46 mmol). And then the mixture was stirred at 80 °C for 24h. After monitored by LCMS, the mixture was purified by HPLC to provide 3-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-phenylpyrimidin-4(3H)-one (Example 279) (323 mg, 824.42 μmol, 1.77% yield, 97.08% purity) as a solid. LCMS (E+) m / z: 381.1 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.14 (d, J = 6.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.69 – 7.53 (m, 2H), 7.50 – 7.43 (m, 4H), 7.23 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 6.6 Hz, 1H), 5.25 (s, 2H) Example 280: Synthetic Scheme for 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-6- phenylpyridin-2(1H)-one (Example 280)

[0026] Step 1 To a solution of E37-1 (50.00 g, 264.50 mmol) in DCM (850 mL) E37-1’ was added (41.95 g, 317.40 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was filtered, and the cake was washed with water (100 mL×2) and DCM (100 mL×2). The resulting white solid was dried to give product E37-2 (60.00 g, 210.72 mmol, 79.67% yield). Step 2 To a solution of E37-2 (40.00 g, 140.48 mmol) in DCM (140 mL) was added slowly TFA (140 mL) at 0°C. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give product E37-3 (54.68 g, crude, TFA salt) which was used for next step without further purification. Step 3 To a solution of E37-3 (54.00 g, 180.82 mmol) in THF (1300 mL) were added E37-3’ (94.41 g, 542.45 mmol) and TEA (109.78 g, 1.08 mol, 151.32 mL). The reaction mixture was stirred at 70℃ for 1.5 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give E37-4 (32.07 g, 131.10 mmol, 72.50% yield). Step 4 To a solution of E37-5 (6.60 g, 37.93 mmol) in 1,4-Dioxane / H2O=3:1 (189 mL) were added K2CO3 (10.48 g, 75.86 mmol), E37-5’ (6.94 g, 56.90 mmol) and Pd(PPh3)4 (4.38 g, 3.79 mmol). The reaction mixture was then heated to 100°C under N2 for 16 h. After being cooled to room temperature, the mixture was eluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic layer was then wash with brine (100 mL×2). The solution was dried over Na2SO4 and then concentrated. The residue was purified with column chromatography (CH2Cl2 / MeOH = 40 / 1) to afford E37-6 (5.72 g, 33.41 mmol, 88.08% yield). Step 5 To a solution of E37-6 (1.26 g, 7.36 mmol) in DMF (22 mL) was added 60% NaH (185.47 mg, 7.73 mmol) at 0°C under N2. After being stirred for 10 min, LiBr (1.28 g, 14.72 mmol) was added. After being stirred for another 15 min, E37-4 (2.34 g, 9.57 mmol) was added. The suspension was heated at 65°C for 16 h. After being cooled to room temperature, the mixture was quenched with saturated NH4Cl (100 mL) and extracted with DCM (100 mL×3). The combined organic layer was wash with brine (100 mL×2) and then dried over Na2SO4. The solution was concentrated, and the residue was purified with column chromatography to provide 1-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-6-phenylpyridin-2(1H)-one (Example 280) (389.00 mg, 1.03 mmol, 13.93% yield). LCMS (E+) m / z: 380.3 [M+H]+.1 NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 9.2, 6.9 Hz, 2H), 7.37 – 7.30 (m, 2H), 7.14 – 7.09 (m, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.90 (t, J = 51.8 Hz, 1H), 6.71 (dd, J = 9.2, 1.4 Hz, 1H), 6.13 (dd, J = 6.8, 1.4 Hz, 1H), 5.25 (s, 2H). Example 281: Synthetic Scheme for 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-methyl-5- phenylpyrimidin-4(3H)-one (Example 281)

[0027] Step 1 To a solution of E125-1 (1.75 g, 9.26 mmol) in Acetonitrile (25 mL) was added potassium carbonate (2.56 g, 18.52 mmol) and E125-1’ (2.49 g, 10.18 mmol). The reaction mixture was stirred at 70°C for 16 h until LCMS showed ~ 20% desired compound was generated. The reaction mixture was purified by MPLC to afford E125-2 (1.2 g, 2.81 mmol, 30.35% yield, 93% purity). Step 2 To a sealed tube were added E125-2 (0.7 g, 1.76 mmol), phenylboronic acid (322.34 mg, 2.64 mmol), Pd(dppf)Cl2.CH2Cl2(143.82 mg, 176.25 μmol), sodium bicarbonate (296.13 mg, 3.52 mmol), dioxane (6 mL) and H2O (3 mL). After being degassed with N2, the mixture was stirred at 80°C for 3.5 h until ~70% desired compound was generated. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was purified by MPLC to give 3-(4- (5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-methyl-5-phenylpyrimidin-4(3H)-one (Example 281) (0.5 g, 1.26 mmol, 71.23% yield, 99.02% purity). LCMS (E+) m / z: 395.1 [M+H]+.,1H NMR (600 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.09 – 8.05 (m, 2H), 7.75 – 7.70 (m, 2H), 7.55 (t, J = 51.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.43 (dd, J = 8.4, 6.9 Hz, 2H), 7.39 – 7.35 (m, 1H), 5.48 (s, 2H), 2.50 (s, 3H). Example 282: Synthetic Scheme for 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-methyl-6- phenylpyrimidin-4(3H)-one (Example 282) Step 1 To a solution of E124-1 (12 g, 67.35 mmol), acetamidine hydrochloride (12.73 g, 134.69 mmol) in Ethanol (120 mL) was added Sodium ethoxide (13.75 g, 202.04 mmol). The reaction mixture was stirred at 95℃ for 24 h until LCMS showed the reaction was complete. After being cooled to room temperature, the reaction mixture was acidified with 1M HCl to pH=4. Theresulting precipitate was collected by filtration. The cake was washed with EtOH (10 mL 2) andthen dried to afford E124-2 (2.15 g, 10.97 mmol, 16.29% yield, 95% purity). Step 2 To a stirred solution of E124-2 (2 g, 10.74 mmol) in DMF (30 mL) was added Sodium hydride (283.55 mg, 11.81 mmol) at 0°C. After being stirred at 0°C for 10min, potassium bromide (2.56 g, 21.48 mmol) and E124-2’ (2.89 g, 11.81 mmol) were added. The reaction mixture was then stirred at 65°C for 16 h until LCMS showed ~ 40% desired compound was generated. The reaction mixture was purified by MPLC to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)- 2-methyl-6-phenylpyrimidin-4(3H)-one (Example 282) (1.6 g, 3.92 mmol, 36.49% yield, 96.60% purity). LCMS (E+) m / z: 395.1 [M+H]+.,1H NMR (600 MHz, DMSO-d6) δ 8.14 – 8.09 (m, 2H), 8.09 – 8.05 (m, 2H), 7.55 (t, J = 51.4 Hz, 1H), 7.53 – 7.47 (m, 5H), 7.02 (s, 1H), 5.44 (s, 2H), 2.53 (s, 3H). Example 283: Synthetic Scheme for 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-2- yl)pyrimidin-4(3H)-one (Example 283) Step 1 To a solution of E8-1 (5.00 g, 36.72 mmol) in methanol (50 mL) was added sodium methoxide (198.38 mg, 3.67 mmol). The mixture was then stirred at 25 °C for 4 h. After the reaction was complete monitored by TLC, ammonium chloride (3.93 g, 73.45 mmol) was added. The reaction mixture was stirred at 60 °C for another 16 h. After monitored by LCMS, the mixture was filtered and the liquid was concentrated under reduced pressure to give the crude product E8-2 (5.70 g, 36.17 mmol, 98.48% yield) as a solid without further purification. Step 2 To a solution of E8-2 (5.70 g, 47.05 mmol) in ethanol (40 mL) was added methyl prop-2-ynoate (7.91 g, 94.11 mmol) at 25 °C. and then the mixture was allowed to heat to 90 °C for 16 h. After monitored by LCMS, the mixture was concentrated under reduced pressure and the residue was purified by HPLC to afford the E8-3 (1.50 g, 8.66 mmol, 18.41% yield) as a solid. Step 3 To a stirred solution of E8-3 (1.45 g, 8.40 mmol) and lithium carbonate (0.93 g, 12.60 mmol) in DMF (7 mL) was added E6-4 (2.05 g, 8.40 mmol). The mixture was then stirred at 80 °C for 40 h. After monitored by LCMS, the mixture was purified by HPLC to give the 3-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-2-yl)pyrimidin-4(3H)-one (Example 283) (0.275 g, 713.60 μmol, 99.21% purity, 8.50% yield) as a solid. LCMS (E+) m / z: 382.0 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.61 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.13 (d, J = 6.5 Hz, 1H), 7.94-7.90 (m, 3H), 7.67 (d, J = 7.9 Hz, 1H), 7.63 – 7.42 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 6.6 Hz, 1H), 5.49 (s, 2H). Example 284: Step 1 To a solution of E9-1 (9.00 g, 85.63 mmol) in methanol (50 mL) was added sodium methoxide (925.20 mg, 17.13 mmol). And then the mixture was stirred at 25 °C for 4 h until TLC indicated the SM consumed. Ammonium chloride (9.16 g, 171.27 mmol) was added, and the mixture was then stirred at 60 °C for another 16 h. After monitored by LCMS, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product E9-2 (13.00 g, 81.97 mmol, 95.72% yield, HCl salt) as a solid without further purification. Step 2 To a solution of E9-2 (13.00 g, 81.97 mmol) in ethanol (80 mL) was added methyl prop-2-ynoate (13.78 g, 163.95 mmol). The mixture was then stirred at 90 °C for 16 h. After monitored by LCMS, the mixture was concentrated under reduced pressure and purified by HPLC to give the E9-3 (1.60 g, 9.19 mmol, 11.21% yield) as a solid. Step 3 To a solution of E9-3 (1.50 g, 8.62 mmol) and lithium carbonate (0.95 g, 12.90 mmol) in DMF (7 mL) was added E6-4 (2.10 g, 8.62 mmol). The mixture was then stirred at 80 °C for 40 h. After monitored by LCMS, the mixture was purified by HPLC to give the Example 284 (0.53 g, 1.36 mmol, 15.78% yield, 98.34% purity) as a solid. LCMS (E+) m / z: 383.0 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.91 (d, J = 5.0 Hz, 2H), 8.12 (d, J = 6.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.67 (t, J = 5.0 Hz, 1H), 7.54 (t, J = 51.4 Hz, 1H), 7.24 – 7.16 (m, 2H), 6.69 (d, J = 6.6 Hz, 1H), 5.27 (s, 2H). Example 285:

[0028] Step 1 To a mixture of E152-1 (10.0 g, 63.62 mmol) and AIBN (2.09 g, 12.72 mmol) in chloroform (80 mL) was added NBS (22.65 g, 127.23 mmol) at 25 °C. The mixture was stirred at 60 °C for 16h under nitrogen. After monitored by lcms, the reaction mixture was concentrated under reduced pressure and purified by silica gel (PE / EA) to provide E152-2 (6.3 g, 26.69 mmol, 41.95% yield) as a solid. Step 2 To a mixture of E152-2 (6.2 g, 26.26 mmol) and lithium carbonate (3.88 g, 52.52 mmol) in DMF (40 mL) was added 2-chloro-1H-pyrimidin-6-one (2.57 g, 19.70 mmol) at 25 °C. The mixture was stirred at 60 °C for 16h. After monitored by lcms, the reaction mixture was filtered and the liquid was purified by RP-LC to provide E152-3 (1.88 g, 6.58 mmol, 25.06% yield) as a solid. Step 3 To a mixture of E152-3 (1.78 g, 6.23 mmol), phenylboronic acid (1.52 g, 12.46 mmol) and sodium carbonate (1.98 g, 18.69 mmol) in dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium (359.97 mg, 311.51 μmol) at 25 °C. The mixture was stirred at 80 °C for 4h under nitrogen. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide E152-4 (1.20 g, 3.67 mmol, 58.84% yield) as a solid. Step 4 To a mixture of methyl E152-4 (1.20 g, 3.67 mmol) in methanol (10 mL) was added hydrazine hydrate (1 mL, 80% purity) at 25 °C. The mixture was stirred at 25 °C for 4h. After monitored by LCMS, to the mixture was added trifluoroacetic acid (1.5 mL) till the final pH < 7. The reaction mixture was concentrated under reduced pressure and purified by RP-LC to E152-5 (0.91 g, 2.78 mmol, 75.83% yield) as a solid. Step 5 To a mixture of E152-5 (0.86 g, 2.63 mmol) and TEA (1.06 g, 10.51 mmol, 1.47 mL) in THF (7 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (548.69 mg, 3.15 mmol) at 25 °C. The mixture was stirred at 25 °C for 1h. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide E152-6 (0.90 g, 2.22 mmol, 84.51% yield) as a solid. Step 6 To a mixture of E152-6 (0.8 g, 1.97 mmol) and TEA (1.20 g, 11.84 mmol, 1.65 mL) in THF was added p-toluenesulfonic acid (1.02 g, 5.92 mmol) at 25 °C. The mixture was stirred at 60 °C for 6h. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide Example 285 (0.312 g, 766.30 μmol, 38.83% yield, 95.14% purity) as a solid. LCMS (E+) m / z: 388.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.09 (d, J = 6.6 Hz, 1H), 7.75 – 7.36 (m, 6H), 6.57 (d, J = 6.6 Hz, 1H), 5.40 (s, 2H). Example 286: Step 1 To a mixture of E153-1 (10.0 g, 70.86 mmol) and AIBN (2.33 g, 14.17 mmol) in chloroform (80 mL) was added NBS (12.61 g, 70.86 mmol) at 25 °C. The mixture was stirred at 60 °C for 16h under nitrogen. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by silica gel (PE / EA) to provide E153-2 (5.4 g, 24.54 mmol, 34.64% yield) as a solid. Step 2 To a mixture of E153-2 (5.4 g, 24.54 mmol) and lithium carbonate (1.81 g, 24.54 mmol) in DMF (40 mL) was added 2-chloro-1H-pyrimidin-6-one (2.40 g, 18.41 mmol) at 25 °C. The mixture was stirred at 60 °C for 16h. After monitored by LCMS, the reaction mixture was filtered and the liquid was purified by RP-LC to provide E153-3 (1.2 g, 4.45 mmol, 18.13% yield) as a solid. Step 3 To a mixture of E153-3 (1.10 g, 4.08 mmol), phenylboronic acid (994.82 mg, 8.16 mmol) and sodium carbonate (1.30 g, 12.24 mmol) in dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium (235.71 mg, 203.97 μmol) at 25 °C. The mixture was stirred at 80 °C for 4h under nitrogen. After monitored by lcms, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide E153-4 (0.80 g, 2.57 mmol, 63.00% yield) as a solid. Step 4 To a mixture of methyl E153-4 (0.80 g, 2.57 mmol) in methanol (10 mL) was added hydrazine hydrate (1 mL, 80% purity) at 25 °C. The mixture was stirred at 25 °C for 4h. After monitored by LCMS, trifluoroacetic acid (1.5 mL) was added to the mixture till the final pH < 7. The reaction mixture was concentrated under reduced pressure and purified by RP-LC to E153-5 (0.71 g, 2.28 mmol, 88.75% yield) as a solid. Step 5 To a mixture of E153-5 (0.16 g, 513.99 μmol) and TEA (208.04 mg, 2.06 mmol, 286.76 μL) in THF (3 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (107.35 mg, 616.79 μmol) at 25 °C. The mixture was stirred at 25 °C for 1h. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide E153-6 (0.12 g, 308.24 μmol, 59.97% yield) as a solid. Step 6 To a mixture of E153-6 (95 mg, 244.02 μmol) and TEA (148.15 mg, 1.46 mmol, 204.21 μL) in THF was added p-toluenesulfonic acid (126.06 mg, 732.06 μmol) at 25 °C. The mixture was stirred at 60 °C for 6h. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by RP-LC to provide Example 286 (28 mg, 73.37 μmol, 30.07% yield, 97.29% purity) as a solid. LCMS (E+) m / z: 372.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.10 (d, J = 6.6 Hz, 1H), 7.78 – 7.30 (m, 6H), 6.55 (d, J = 6.6 Hz, 1H), 5.25 (s, 2H). Example 287: Synthesis toward 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6-[2- (trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one. Step 1: 6-[2-(trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one (1) A mixture of 2-bromo-6-hydroxypyridine (1.0 eq), 4,4,5,5-tetramethyl-2-[2- (trifluoromethyl)phenyl]-1,3,2-dioxaborolane (1.5 eq) and cesium carbonate (2.0 eq) in dioxane (23.0 vol) and water (5.75 vol) was sparged with argon for 15 min. Pd(PPh3)4(0.05 eq) was added and reaction mixture was stirred overnight at 100 °C. DCM and water were added. Layers were separated and aqueous layer was extracted with DCM. Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified by automated flash column chromatography over silica gel. 6-[2- (Trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one (1) as a white solid. UPLC-MS (254 nm, 3 min): RT= 1.95 min; 98% purity; ESI(+)[M+H]+= 239.85. Step 2: 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6-[2- (trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one (Example 287) Sodium hydride (60% in mineral oil, 1.2 eq) was added to the solution of 6-[2- (trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one (1) (1.0 eq) in anhydrous DMF (26.7 vol). The resulting suspension was stirred at room temperature for 30 min and then 2-[4- (bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole1(1.25 eq) was added. After stirring overnight at room temperature, reaction mixture was quenched with 2M HCl and diluted with EtOAc. Organic layer was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material as a mixture of O- and N-alkylated products (2:1 ratio). Crude material was purified by automated flash column chromatography over silica gel. Collected material was repurified via preparative TLC.1-({4-[5- (Difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6-[2-(trifluoromethyl) phenyl]-1,2-dihydropyridin-2-one (Example 287) was obtained as an off-white solid.1synthesis of 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole was described in Example 278.1H NMR (300 MHz, DMSO-d6): δ 7.93 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.68 – 7.24 (m, 4H), 7.10 (d, J = 8.1 Hz, 2H), 6.64 (dd, J = 9.2, 1.4 Hz, 1H), 6.22 (dd, J = 6.8, 1.4 Hz, 1H), 5.35 (d, J = 16.1 Hz, 1H), 4.57 (d, J = 16.1 Hz, 1H). LCMS (205 nm, 6 min): RT= 2.53 min; 98.32% purity; ESI(+)[M+H]+= 448.08. Example 288: Synthesis toward 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,6- dihydro-[2,2'-bipyridin]-6-one.

[0029] Step 1: 4-methylbenzohydrazide (1) Methyl 4-methylbenzoate (1.0 eq) was dissolved in ethanol (10.0 vol), hydrazine monohydrate (5.0 eq) was added at room temperature. Then, the reaction mixture was stirred overnight under reflux. Almost full consumption of the starting material was observed according to UPLC-MS analysis. Solvent was partially removed under reduced pressure, water was added and the precipitate was filtered off and dried under reduced pressure to give 4-methylbenzohydrazide (1) as an off-white solid.1H NMR (300 MHz, DMSO-d6): δ 9.67 (s, 1H), 7.76 – 7.68 (m, 2H), 7.28 – 7.21 (m, 2H), 4.43 (d, J = 4.0 Hz, 2H), 2.34 (s, 3H). UPLC-MS (254 nm, 3 min): RT = 1.436 min, 97% purity, ESI(+)[M+H]+= 150.90. Step 2: 2-(difluoromethyl)-5-(4-methylphenyl)-1,3,4-oxadiazole (2) 4-Methylbenzohydrazide (1) (1.0 eq) and imidazole (3.0 eq) were dissolved in anhydrous DCM (16.0 vol) and difluoroacetic anhydride (3.0 eq) was added at 0 °C. Reaction mixture was stirred overnight under reflux. Full consumption of starting material was observed according to UPLC- MS analysis. The reaction mixture was quenched with water and DCM was added. Layers were separated and water layer was extracted with DCM (2 times). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and solvent was removed under reduced pressure to give crude as an off-white solid. Crude was purified by automated flash column chromatography over silica gel. 2-(Difluoromethyl)-5-(4-methylphenyl)-1,3,4-oxadiazole (2) was obtained as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.00 – 7.91 (m, 2H), 7.73 – 7.35 (m, 3H), 2.42 (s, 3H). UPLC- MS (254 nm, 3 min): RT = 2.229 min, 98% purity, ESI(+)[M+H = 211.20. Step 3: 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (3) 2-(Difluoromethyl)-5-(4-methylphenyl)-1,3,4-oxadiazole (2) (1.0 eq) was dissolved in 1,2-dichloroethane (10.0 vol), AIBN (0.05 eq) and NBS (1.3 eq) were added at room temperature and reaction mixture was stirred under reflux. Full consumption was observed according to UPLC- MS analysis after 4 hours. Water and DCM were added, layers were separated, and the water layer was extracted with DCM (2 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered and solvent was removed under reduced pressure. The crude was purified by automated flash column chromatography over silica gel. Purification via FCC was repeated 4 times. 2-[4-(Bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (3) was obtained as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.10 – 8.03 (m, 2H), 7.74 – 7.37 (m, 3H), 4.81 (s, 2H). UPLC- MS (254 nm, 3 min): RT= 2.285 min; 98% purity; ESI(+)[M+H]+= 331.90. Step 4: 6-bromo-1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,2- dihydropyridin-2-one (4) To a solution of 2-bromo-6-hydroxypyridine (0.9 eq) and Cs2CO3 (1.35 eq) in anhydrous DMF (20.0 vol), 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (3) (1.0 eq) was added and RM was stirred overnight at room temperature. After that time, full consumption of starting material was observed and formation of O- and N-alkylated products were observed (O- alkylated product was formed in majority). The reaction mixture was filtered and filtrate was diluted with EtOAc. The organic layer was washed with water (2 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Obtained crude was purified by automated flash column chromatography over silica gel. Two fractions were collected, O-alkylated product 2-bromo-6-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methoxy)pyridine (1.82 g, 69% yield, obtained as a white solid) and N-alkylated product 6-bromo-1-({4-[5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,2-dihydropyridin-2-one (4) (0.419 g, 16% yield, obtained as a white solid).1H NMR (300 MHz, DMSO-d6): δ 8.09 – 8.03 (m, 2H), 7.73 – 7.37 (m, 4H), 6.73 (dd, J = 7.2, 1.2 Hz, 1H), 6.55 (dd, J = 9.2, 1.2 Hz, 1H), 5.53 (s, 2H). UPLC-MS (254 nm, 3 min): RT= 2.18 min; 97% purity; ESI(+)[M+H]+= 383.65. Step 5: 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,6-dihydro-[2,2'- bipyridin]-6-one To a solution of 6-bromo-1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,2- dihydropyridin-2-one (4) (1.0 eq) in anhydrous dioxane (30.0 vol), 2-(tributylstannyl)pyridine (2.2 eq) and CuI (0.04 eq) were added and mixture was sparged with argon for 15 minutes. After that time, PdCl2(PPh3)2(0.02 eq) was added and the mixture was sparged with argon for additional 10 minutes. Next, a glass tube was sealed and reaction mixture was stirred overnight at 100 °C. After this time, UPLC-MS analysis confirmed the formation of the desired product. The reaction mixture was filtered through celite pad (washed with EtOAc) and filtrate was concentrated to give dark brown crude material which was purified by automated flash column chromatography over silica gel. The collected material was re-purified via preparative TLC to give 1-({4-[5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl]phenyl}methyl)-1,6-dihydro-[2,2'-bipyridin]-6-one (Example 288) as an off-white solid.1H NMR (300 MHz, DMSO-d6): δ 8.64 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.89 – 7.86 (m, 2H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.66 – 7.39 (m, 4H), 7.09 (d, J = 8.3 Hz, 2H), 6.63 (dd, J = 9.2, 1.3 Hz, 1H), 6.36 (dd, J = 6.8, 1.4 Hz, 1H), 5.45 (s, 2H). LCMS (205 nm, 6 min): RT= 2.397 min; 99.73% purity; ESI(+)[M+H]+= 381.18. Example 289: Synthesis toward 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6- (pyrimidin-2-yl)-1,2-dihydropyridin-2-one. Step 1: 6-(Pyrimidin-2-yl)-1,2-dihydropyridin-2-one (1) A mixture of 2-bromo-6-hydroxypyridine (1.0 eq), 2-(tributylstannyl)pyrimidine (2.2 eq) and CuI (0.05 eq) in anhydrous dioxane (30.0 vol) was sparged with argon for 20 minutes. Then, PdCl2(PPh3)2(0.02 eq) was added and reaction mixture was stirred overnight at 120 °C. After that time, UPLC-MS analysis confirmed formation of DP. RM was cooled to RT and filtered over celite pad (washed with EtOAc). The filtrate was concentrated and purified by automated flash column chromatography over silica gel. 6-(Pyrimidin-2-yl)-1,2-dihydropyridin-2-one (1) was obtained as a yellow solid.1H NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.98 (d, J = 4.8 Hz, 2H), 7.66–7.58 (m, 2H), 7.30 (dd, J = 6.9, 1.1 Hz, 1H), 6.59 (dd, J = 9.1, 1.1 Hz, 1H). UPLC-MS (254 nm, 3 min): RT= 1.33 min; 99% purity; ESI(+)[M+H]+= 173.85. Step 2: 1-({4-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6-(pyrimidin-2-yl)- 1,2-dihydropyridin-2-one Sodium hydride (60% in mineral oil, 1.2 eq) was added to the solution of 6-[2- (trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one (1) (1.0 eq) in anhydrous DMF (26.7 vol). The resulting suspension was stirred at room temperature for 30 min and then 2-[4- (bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole1(1.25 eq) was added. The reaction mixture was stirred overnight at room temperature. After that time, reaction mixture was quenched with 2M HCl and diluted with EtOAc. The layers were separated and the organic layer was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude as a mixture of O- and N-alkylated products (in ca.2:1 ratio). The crude material was purified by automated flash column chromatography over silica gel to give 1-({4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}methyl)-6-[2-(trifluoromethyl)phenyl]- 1,2-dihydropyridin-2-one (Example 289) as a pale grey solid.1synthesis of 2-[4-(bromomethyl)phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole was described in Example 278.1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J = 5.0 Hz, 2H), 7.91–7.86 (m, 2H), 7.68–7.49 (m, 3H), 7.13 (d, J = 8.3 Hz, 2H), 6.69 (dd, J = 9.2, 1.4 Hz, 1H), 6.62 (dd, J = 6.9, 1.4 Hz, 1H), 5.58 (s, 2H). LCMS (205 nm, 6 min): RT= 2.683 min; 98.53% purity; ESI(+)[M+H]+= 382.14. Example 290: 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-4- yl)pyrimidin-4(3H)-one

[0030] 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-4-yl)pyrimidin-4(3H)-one: To a stirred solution of 2-chloro-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin- 4(3H)-one (1.2 g, 3.5 mmol, 1.0 equiv.) and pyridin-4-ylboronic acid (0.5 g, 4.2 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL) and H2O (2.5 mL) were added K2CO3 (1.5 g, 10.6 mmol, 3.0 equiv.) and Pd(dppf)Cl2(0.3 g, 0.3 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 50% gradient in 35 min; detector, UV 254 nm.) to give the crude product (400 mg, 66% purity) as a brown solid. The crude product (400 mg) was purified by prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column 130, 5 µm, 30 mm × 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1% NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 30% B in 10min; Wave Length: 254 / 220 nm; RT1(min): 8.43) to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2- (pyridin-4-yl)pyrimidin-4(3H)-one (Example 290) (171.5 mg, 12.7% yield, 99.2% purity) as a light yellow solid. The reaction was repeated one more batch (SM: 1.0 g), and a total of 337.2 mg of product was obtained. LCMS (ESI): [M+H]+: 382.0.1H NMR (400 MHz, DMSO-d6) δ 8.68 – 8.61 (m, 2H), 8.12 (d, J = 6.5 Hz, 1H), 8.02 – 7.91 (m, 2H), 7.70 – 7.38 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 6.6 Hz, 1H), 5.18 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -120.71. Example 291: 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(4- (trifluoromethyl)phenyl)pyrimidin-4(3H)-one

[0031] 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(4- (trifluoromethyl)phenyl)pyrimidin-4(3H)-one: To a stirred solution of 2-chloro-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin- 4(3H)-one (400 mg, 1.2 mmol, 1.0 equiv.) and (4-(trifluoromethyl)phenyl)boronic acid (270 mg, 1.4 mmol, 1.2 equiv.) in 1,4-dioxane (6 mL) and H2O (1.5 mL) were added K2CO3 (480 mg, 3.5 mmol, 3.0 equiv.) and Pd(dppf)Cl2 (96 mg, 0.2 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The mixture was cooled down to room temperature and diluted with H2O (200 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)benzyl)-2-(4-(trifluoromethyl)phenyl)pyrimidin-4(3H)-one (Example 291) (323.2 mg, 61.0% yield, 99.0% purity) as an off-white solid. LCMS (ESI): [M+H]+: 449.1.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 6.6 Hz, 1H), 7.99 – 7.90 (m, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.70 – 7.39 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 6.6 Hz, 1H), 5.18 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -61.37, -120.72. Example 292: 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(3- (trifluoromethyl)phenyl)pyrimidin-4(3H)-one

[0032] 4-methylbenzohydrazide: A mixture of 4-methylbenzoic acid (41.0 g, 273.0 mmol, 1.0 equiv.) and hydrazine monohydrate (102.5 g, 1.6 mol, 6.0 equiv., 80% aqueous) in EtOH (500 mL) was stirred at 80 °C for 14 h. The mixture was evaporated to remove EtOH. The residual oil was diluted by water (400 mL) and extracted by EtOAc (3 × 300 mL). The combined organic layers were washed by brine (3 × 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 4-methylbenzohydrazide (45.8 g) as a white solid. LCMS (ESI): [M+H]+: 151.0.

[0033] 2-(difluoromethyl)-5-(p-tolyl)-1,3,4-oxadiazole: A mixture of 4-methylbenzohydrazide (45.7 g, 304.3 mmol, 1.0 equiv.), 2,2-difluoroacetyl 2,2- difluoroacetate (105.9 g, 608.6 mmol, 2.0 equiv.) and Burgess Reagent (145.0 g, 608.6 mmol, 2.0 equiv.) in THF (900 mL) was stirred at 70 °C for 14 h under nitrogen atmosphere. The solvent was removed under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (1 × 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford 2-(difluoromethyl)-5-(p-tolyl)-1,3,4-oxadiazole (40.3 g, 63.0% yield, 92.0% purity) as a white solid. LCMS (ESI): [M+H]+: 211.1. 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole: A mixture of 2-(difluoromethyl)-5-(p-tolyl)-1,3,4-oxadiazole (28.6 g, 136.2 mmol, 1.0 equiv.), NBS (26.6 g, 149.7 mmol, 1.1 equiv.) and BPO (9.7 g, 30.0 mmol, 0.2 equiv., 75%) in CCl4(600 mL) was stirred at 80 °C for 4 h. The mixture was cooled down to room temperature and quenched by water (800 mL). The organic layer was separated and the aqueous layer was extracted by DCM (3 × 500 mL). The combined organic layers were washed by brine (3 × 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purifed by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to afford 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (24.1 g, 61.3% yield, 95.0% purity) as an off-white solid. LCMS (ESI): [M+H]+: 289.0. 2-chloro-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin-4(3H)-one: A mixture of 2-chloropyrimidin-4-ol (3.2 g, 24.5 mmol, 1.0 equiv.), 2-(4-(bromomethyl)phenyl)- 5-(difluoromethyl)-1,3,4-oxadiazole (8.6 g, 29.8 mmol, 1.2 equiv.) and K2CO3 (7.0 g, 50.6 mmol, 2.0 equiv.) in DMF (64 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 2-chloro-3-(4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin-4(3H)-one (3.0 g, 36.1% yield, 95.0% purity) as a white solid. LCMS (ESI): [M+H]+: 339.0.

[0034] 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(3- (trifluoromethyl)phenyl)pyrimidin-4(3H)-one: To a stirred solution of 2-chloro-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin- 4(3H)-one (600 mg, 1.8 mmol, 1.0 equiv.) and (3-(trifluoromethyl)phenyl)boronic acid (404 mg, 2.1 mmol, 1.2 equiv.) in 1,4-dioxane (6 mL) and H2O (1.5 mL) were added K2CO3 (735 mg, 5.3 mmol, 3.0 equiv.) and Pd(dppf)Cl2 (145 mg, 0.2 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford 3-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)benzyl)-2-(3-(trifluoromethyl)phenyl)pyrimidin-4(3H)-one (Example 292) (323.5 mg, 40.7% yield, 99.5% purity) as a light yellow solid. 449.1.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 6.5 Hz, 1H), 7.97 – 7.90 (m, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.70 – 7.40 (m, 3H), 7.18 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 6.5 Hz, 1H), 5.17 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -61.46, -12 0.75. Example 293: 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-3- yl)pyrimidin-4(3H)-one

[0035] 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-3-yl)pyrimidin-4(3H)-one: To a stirred solution of 2-chloro-3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)pyrimidin- 4(3H)-one (1.2 g, 3.5 mmol, 1.0 equiv.) and pyridin-3-ylboronic acid (540 mg, 4.4 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL) and H2O (2.5 mL) were added K2CO3(984 mg, 7.1 mmol, 2.0 equiv.) and Pd(dppf)Cl2(289 mg, 0.4 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% NH3•H2O), 0% to 50% gradient in 35 min; detector, UV 254 nm.) to give a crude product (450 mg, 80% purity) as a light yellow solid. The crude product (450 mg) was further purified by prep- HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column 130, 5 µm, 30 mm × 150 mm; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1% NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 30% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.22) to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-2-(pyridin-3- yl)pyrimidin-4(3H)-one (190.2 mg, 14.1% yield, 99.3% purity) as a white solid. The reaction was repeated one more batch (SM: 700 mg), and a total of 321.7 mg of product was obtained. LCMS (ESI): [M+H]+: 382.1.1H NMR (400 MHz, DMSO-d6) δ 8.67 (dd, J = 4.9, 1.6 Hz, 1H), 8. 58 (dd, J = 2.3, 0.9 Hz, 1H), 8.12 (d, J = 6.5 Hz, 1H), 8.01 – 7.91 (m, 2H), 7.86 (dt, J = 7.9, 2.0 H z, 1H), 7.69 – 7.39 (m, 2H), 7.23 – 7.12 (m, 2H), 6.63 (d, J = 6.6 Hz, 1H), 5.22 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -120.71. Example 294, Example 295, and Example 296: Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6- phenylpyrimidin-4(3H)-one (Example 294): Synthesis of 3-fluoro-4-methylbenzohydrazide (2): To a stirred solution of ethyl 3-fluoro-4-methylbenzoate 1 (5.0 g, 27.44 mmol) in EtOH (500 mL) was added hydrazine hydrate (11.43 mL, 274.44 mmol) dropwise at rt under inert atmosphere. The reaction mixture was further stirred at 100°C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was allowed to cool to rt and concentrated under reduced pressure to get the crude. The crude was treated with diethyl ether (3 x 100 mL), filtered and dried under reduced pressure to afford 3-fluoro-4-methylbenzohydrazide 2 (4.7 g) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 9.79 (bs, 1H), 7.57 (t, J = 9.6 Hz, 2H), 7.37 (t, J = 8.0 Hz,1H), 4.49 (b s, 2H) and 2.27 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C8H10FN2O 169.07; found 169.09, Purity: 93%. Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-methylphenyl)-1,3,4-oxadiazole (4): To an ice cold stirred solution of 3-fluoro-4-methylbenzohydrazide 2 (4.7 g, 27.95 mmol) in DCM (500 mL) was added imidazole (5.74 g, 83.84 mmol) and difluoroacetic anhydride 3 (9.5 mL, 83.84 mmol) dropwise under inert atmosphere. The reaction mixture was stirred at 50°C for 16 h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was allowed to cool to rt and quenched with water (200 mL) followed by extraction with DCM (3 x 250 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography over (40 g snap, silica gel) by using eluents 5% EtOAc in heptanes to afford 2-(difluoromethyl)-5-(3-fluoro-4-methylphenyl)-1,3,4-oxadiazole 4 (6.0 g, 95% over 2 steps) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 9.79 (bs, 1H), 7.57 (t, J = 9.6 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 4.49 (d, J = 3.2 Hz, 2H) and 2.27 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C10H8F3N2O 229.05; found 229.06, Purity = 95.20% Synthesis of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (5): To an ice cold stirred solution of 2-(difluoromethyl)-5-(3-fluoro-4-methylphenyl)-1,3,4- oxadiazole 4 (2.3 g, 10.08 mmol) in DCM (100 mL) was added AIBN (0.331 g, 2.02 mmol) and NBS (1.8 g, 10.08 mmol) portionwise under inert atmosphere. The reaction mixture was stirred at 95°C for 8h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, cooled the reaction mixture and quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with aqueous NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 40 g silica column, eluting with 20% EtOAc in heptanes to afford 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 5 (2.1 g, 62%) as white solid.1H NMR (400 MHz, DMSO-d6): δ 7.90-7.93 (m, 2H), 7.80-7.86 (m, 1H), 7.56 (t, J = 51.2 Hz, 1H) and 4.79 (s, 2H). LCMS (ESI): m / z [M-H]+calc’d for C10H7BrF3N2O 306.96; found 307.01, Purity = 97.15% Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-6- phenylpyrimidin-4(3H)-one (Example 294): To a stirred solution of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 5 (0.3 g , 0.976 mmol) and 6-phenylpyrimidin-4(3H)-one 6 (0.201 g, 1.17 mmol) in acetone (20 mL) were added KI (0.032 g, 0.195 mmol) and K2CO3(0.404 g, , 2.93 mmol) at rt uner inert atmosphere at rt. The resulting reaction mixture was stirred at rt for 16h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was quenched with water (50 mL) followed by extraction with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 12 g silica column, eluting with 70% ethyl acetate in heptanes to afford 3-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-6-phenylpyrimidin-4(3H)-one Example 294 (251 mg, 64%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.08-8.10 (m, 2H), 7.87-7.92 (m, 2H), 7.42-7.68 (m, 5H), 7.03 (s, 1H) and 5.28 (s, 2H). LCMS (ESI): m / z [M+H]+calc’d for C20H14F3N4O2399.10; found 399.15, Purity = 98.52% Scheme 2: Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2- methyl-6-phenylpyrimidin-4(3H)-one (Example 295): Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl acetate (7): To a stirred solution of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 5 (1.0 g, 3.25 mmol) in CH3CN (20 mL) was added KOAc (0.634 g, 6.5 mmol) dropwise at rt under inert atmosphere. The reaction mixture was stirred at 100°C for 2h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was allowed to cool to rt and concentrated under reduced pressuret o get the crude residue. The crude residue was flash column chromatography over (40g snap, silica gel) by using eluents 10% EtOAc in heptanes to afford 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl acetate 7 (0.8 g, 85%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.81 (dd, J = 1.6, 10.2 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 51.2 Hz, 1H), 5.26 (s, 2H) and 2.16 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C12H10F3N2O3287.06; found 287.12, Purity = 96.21% Synthesis of (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)methanol (8): To a stirred solution of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl acetate 7 (0.8 g, 2.79 mmol) in MeOH (20 mL) was added K2CO3(1.16 g, 8.39 mmol) into the reaction mixture under inert atmosphere at rt. The resulting reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled and concentrated under reduced pressure to get the crude residue. The crude residue was flash column chromatography over (40g snap, silica gel) by using eluents 20% EtOAc in heptanes to afford (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)methanol 8 (0.6 g, 88%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.81 (dd, J = 1.6, 10.2 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.56 (t, = 51.2 Hz, 1H), 5.52 (t, J =11.2 Hz, 1H) and 4.65 (d, J = 5.6 Hz, 2H). LCMS (ESI): m / z [M+H]+calc’d for C10H8F3N2O2245.05; found 254.07, Purity = 99.37% Synthesis of 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2-methyl-6- phenylpyrimidin-4(3H)-one (Example 295): To a stirred solution of 2-methyl-6-phenylpyrimidin-4(3H)-one 9 (0.4 g, 2.15 mmol) and (4-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)methanol 8 (0.630 g, 2.58 mmol) in DCM (10 mL) was added Ph3P (0.815 g, 3.25 mmol) followed by addition of DIAD (0.64 mL, 3.25 mmol) dropwise at 45°C. The resulting reaction mixture was stirred at 45°C for 1h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The crude residue was purified by flash column chromatography over (40g snap, silica gel) by using eluents 50% EtOAc in heptanes to afford 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-2-methyl-6- phenylpyrimidin-4(3H)-one Example 295 (233 mg, 21%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 8.11-8.14 (m, 2H), 7.94 (dd, J = 1.2, 10.4 Hz, 1H), 7.87 (dd, J = 1.2, 8.2 Hz, 1H), 7.56 (t, J = 51.2 Hz, 1H), 7.29-7.52 (m, 3H), 7.56 (t, J = 7.6 Hz, 1H) 7.01 (s, 1H), 5.42 (s, 2H), and 2.58 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C21H16F3N4O2413.11; found 413.22, Purity = 98.80% Scheme 3: Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 6-phenylpyrimidin-4(3H)-one (Example 296): Synthesis of 6-methylnicotinohydrazide (11): To a stirred solution of ethyl 6-methylnicotinate 10 (5.0 g, 30.27 mmol) in EtOH (500 mL) was added hydrazine hydrate (12.5 mL, 302.7 mmol) dropwise at rt under inert atmosphere. The reaction mixture was stirred at 100°C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled and concentrated under reduced pressure to get the crude. The crude was treated with diethyl ether (3 x 100 mL), filtered to afford 6-methylnicotinohydrazide 11 (5.0 g) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 9.87 (br s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 2.0, 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.53 (br s, 2H) and 2.51 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C7H10N3O152.07; found 152.09, Purity = 93.02% Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (12): To an ice cold stirred solution of 6-methylnicotinohydrazide 11 (5.0 g, 33.07 mmol) in DCM (250 mL) was added imidazole (6.76 g, 99.22 mmol) and difluoroacetic anhydride 3 (11.22 mL, 99.22 mmol) dropwise uner inert atmosphere. The reaction mixture was stirred at 50°C for 16 h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was colled to rt, and quenched with water (100 mL) followed by extraction with DCM (2 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography over (40 g snap, silica gel) by using eluents 70% EtOAc in heptanes to afford 2- (difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole 12 (6.3 g, 98% over 2 steps) as an off- white solid.1H NMR (400 MHz, DMSO-d6): δ 9.08 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 2.2, 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 6.30 (t, J = 53.4 Hz, 1H) and 2.60 (s, 3H). LCMS (ESI): m / z [M+H]+calc’d for C9H8F2N3O 212.06; found 212.01, Purity = 95.50% Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (13): To an ice cold stirred solution of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole 12 (4.0 g, 18.94 mmol) in DCE (200 mL) was added AIBN (0.622 g, 3.78 mmol) and NBS (3.37 g, 18.94 mmol) portionwise under inert atmosphere. The reaction mixture was stirred at 95°C for 8 h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was allowed to cool to rt, quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with aqueous NaHCO3(100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 40 g silica column, eluting with 20% ethylacetate in heptanes to afford 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole 13 (1.1 g, 27% based on SM recovery) as brown solid along with 500 mg SM recoverd back.1H NMR (400 MHz, DMSO-d6): δ 9.20 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 2.4, 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 51.2 Hz, 1H) and 4.81 (s, 2H). LCMS (ESI): m / z [M+H]+calc’d for C9H7BrF2N3O 289.97; found 290.07, Purity = 99.03% Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6- phenylpyrimidin-4(3H)-one (Example 296): To a stirred solution of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 13 (0.3 g, 1.04 mmol) and 6-phenylpyrimidin-4(3H)-one 6 (0.213 g, 1.24 mmol) in acetone (20 mL) was added KI (0.035 g, 0.208 mmol) and K2CO3(0.432 g, 3.12 mmol) at rt uner inert atmosphere. The resulting reaction mixture was stirred at rt for next 16 h. The reaction progress was monitored by TLC and LCMS analysis. Upon completion, the reaction mixture was quenched with water (50 mL) followed by extraction with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 12 g silica column, eluting with 15% ethyl acetate in heptanes to afford 3-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methyl)-6-phenylpyrimidin-4(3H)-one Example 296 (237 mg, 60%) as an off white solid.1H NMR (400 MHz, DMSO-d6 at HT): δ 9.13 (d, J = 1.6 Hz, 1H), 8.76 (s, 1H), 8.44 (dd, J = 2.4, 8.4 Hz, 1H), 8.07-8.12 (m, 2H), 7.69-7.44 (m, 5H), 7.01 (s, 1H) and 5.37 (s, 2H). LCMS (ESI): m / z [M+H]+calc’d for C19H14F2N5O2382.10; found 382.19, Purity = 98.97% Example 297, Example 298, and Example 299:

[0036] To a solution of methyl 3-fluoro-4-methyl-benzoate (20.0 g, 118.93 mmol) in EtOH (300 mL) was added NH2NH2-H2O (35.02 g, 594.66 mmol). The mixture was stirred at 90 °C for 16 hr. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE at 20 °C for 2 hr. Compound 1-2 (18.0 g, crude) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.81 (br s, 1H), 7.64 - 7.53 (m, 2H), 7.37 (s, 1H), 4.51 (br s, 2H), 2.27 (s, 3H) To a solution of compound 1-2 (15.0 g, 89.20 mmol), 4Å MS (30.0 g) and Imidazole (30.36 g, 445.98 mmol) in DCM (1000 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (62.10 g, 356.79 mmol). The mixture was stirred at 50 °C for 16 hr. LC-MS showed compound 1-2 was consumed completely and desired mass was detected. To the reaction mixture was added H2O (1000 mL), and then the mixture was extracted with DCM (500 mL * 3). The combined organic layers were washed with brine (500 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 1-3 (16.0 g, crude) as a white solid.1H NMR: (400 MHz, CHLOROFORM-d) δ 7.81 (dd, J = 1.5, 7.7 Hz, 1H), 7.75 (dd, J = 1.4, 9.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 51.7 Hz, 1H), 2.39 (d, J = 1.8 Hz, 3H). To a solution of compound 1-3 (5.00 g, 21.91 mmol) and NBS (4.29 g, 24.10 mmol) in DCM (50 mL) was added AIBN (359.83 mg, 2.19 mmol). The mixture was stirred at 50 °C for 16 hr. LC- MS showed several new peaks were found. The reaction mixture was 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% Ethyl acetate / Petroleum ether gradient at 100 mL / min). Compound 1-4 (5.00 g, 16.12 mmol, 73.56% yield) was obtained as a yellow solid. To a solution of compound 1-4 (4.20 g, 13.68 mmol) and 1H-pyrimidin-6-one (1.71 g, 17.78 mmol) in DMF (20 mL) was added K2CO3 (3.78 g, 27.36 mmol). The mixture was stirred at 70 °C for 2 hr. LC-MS showed several new peaks were found. The reaction mixture was 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 0~40% Ethyl acetate / Petroleum ether gradient at 80 mL / min). Compound 1-5 (2.10 g, 6.52 mmol, 47.65% yield) was obtained as a yellow solid. A mixture of compound 1-5 (2.00 g, 6.21 mmol), iodobenzene (3.17 g, 15.53 mmol), Pd(OAc)2(139.34 mg, 620.65 μmol), PPh3(488.34 mg, 1.86 mmol), DBU (1.13 g, 7.45 mmol) and CuI (2.36 g, 12.41 mmol) in DMF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 135 °C for 16 hr under N2 atmosphere. The reaction mixture was 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 at 40 mL / min). Example 297 (507.17 mg, 1.27 mmol, 20.51% yield) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.6 Hz, 1H), 7.80 (dd, J = 8.1, 1.4 Hz, 1H), 7.75 (dd, J = 10.4, 1.3 Hz, 1H), 7.37-7.68 (m, 6H), 7.27 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 6.6 Hz, 1H), 5.20 (s, 2H) To a solution of methyl 5-fluoro-6-methyl-pyridine-3-carboxylate (5.00 g, 29.56 mmol) in EtOH (50 mL) was added NH2NH2-H2O (8.70 g, 147.80 mmol). The mixture was stirred at 70 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE at 20 °C for 2 hr. Compound 3-2 (4.30 g, crude) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.98 (br s, 1H), 8.73 (s, 1H), 7.95 (dd, J = 1.6, 10.3 Hz, 1H), 4.58 (s, 2H), 2.49 (d, J = 3.0 Hz, 3H). To a solution of compound 3-2 (4.00 g, 23.65 mmol) and Imidazole (4.83 g, 70.94 mmol) in DCM (200 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (12.35 g, 70.94 mmol). The mixture was stirred at 50 °C for 16 hr. LC-MS showed compound 3-2 was consumed completely and desired mass was detected. H2O (200 mL) was added to the reaction mixture, and then the mixture was extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3-3 (5.00 g, crude) as a yellow solid. To a solution of compound 3-3 (5.00 g, 21.82 mmol) and NBS (4.66 g, 26.18 mmol) in DCE (50 mL) was added AIBN (358.28 mg, 2.18 mmol,). The mixture was stirred at 90 °C for 2 hr. LC- MS showed several new peaks were found. The reaction mixture was 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 0~20% Ethyl acetate / Petroleum ether gradient at 80 mL / min). Compound 3-4 (12.0 g, 12.98 mmol, 43.68% yield) was obtained as a red solid. To a solution of compound 3-4 (4.00 g, 12.98 mmol) in DMF (50 mL) was added 1H-pyrimidin- 6-one (1.50 g, 15.58 mmol) and K2CO3(3.59 g, 25.97 mmol). The mixture was stirred at 70 °C for 2 hr. LC-MS showed compound 3-4 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 flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient at 80 mL / min). Compound 3-5 (2.00 g, 6.19 mmol, 47.65% yield) was obtained as a white solid. A mixture of compound 3-5 (2.00 g, 6.19 mmol), iodobenzene (3.79 g, 18.56 mmol), Pd(OAc)2(277.83 mg, 1.24 mmol), PPh3 (811.45 mg, 3.09 mmol), DBU (1.13 g, 7.43mmol) and CuI (2.36 g, 12.38 mmol) in DMF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 135 °C for 16 hr under N2 atmosphere. The reaction mixture was 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 at 40 mL / min). Example 298 (143.87 mg, 360.28 μmol, 5.82% yield) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.30 (dd, J = 9.9, 1.6 Hz, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.32-7.78 (m, 6H), 6.49 (d, J = 6.5 Hz, 1H), 5.31 (s, 2H) To a solution of ethyl 2-methylthiazole-5-carboxylate (20.0 g, 116.81 mmol) in EtOH (200 mL) was added NH2NH2-H2O (34.4 g, 584.06 mmol). The mixture was stirred at 90 °C for 5 hr. LC- MS showed starting material 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 triturated with MTBE at 20 °C for 2 hr. Compound 4-2 (10.0 g, crude) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.84 (br dd, J = 2.6, 4.4 Hz, 1H), 8.14 (s, 1H), 4.67 - 4.36 (m, 2H), 2.66 (s, 3H) To a solution of compound 4-2 (11.0 g, 69.98 mmol), 4Å MS (20.00 g) and Imidazole (23.82 g, 349.89 mmol) in DCM (500 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (48.72 g, 279.91 mmol). The mixture was stirred at 50 °C for 16 hr. LC-MS showed compound 4-2 was consumed completely and desired mass was detected. To the reaction mixture was added H2O (500 mL), and then the mixture was extracted with DCM (200 mL * 3). The combined organic layers were washed with brine (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 4-3 (12.0 g, crude) as a yellow solid. To a solution of compound 2-3 (5.00 g, 23.02 mmol) and NBS (4.92 g, 27.62 mmol) in DCE (50 mL) was added AIBN (378.02 mg, 2.30 mmol). The mixture was stirred at 90 °C for 4 hr. LC-MS showed several new peaks were found. The reaction mixture was 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% Ethyl acetate / Petroleum ether gradient at 100 mL / min). Compound 2-4 (3.50 g, 11.82 mmol, 51.35% yield) was obtained as a yellow solid.1H) To a solution of compound 4-4 (2.60 g, 8.78 mmol) and 2-methylsulfanyl-1H-pyrimidin-6-one (1.37 g, 9.66 mmol) in DMF (10 mL) was added Cs2CO3 (5.72 g, 17.56 mmol). The mixture was stirred at 70 °C for 2 hr. LC-MS showed several new peaks were found. The reaction mixture was 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 0~30% Ethyl acetate / Petroleum ether gradient at 60 mL / min). Compound 4-5A (0.90 g, 2.52 mmol, 28.68% yield) was obtained as a yellow solid. A mixture of compound 4-5A (900.0 mg, 2.52 mmol), phenylboronic acid (614.15 mg, 5.04 mmol), Pd(PPh3)4 (291.03 g, 0.25 mmol) and thiophene-2-carbonyloxycopper (1.06 g, 5.54 mmol) in THF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 70 °C for 2 hr under N2 atmosphere. The reaction mixture was 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 at 40 mL / min). Example 299 (288.65 mg, 0.75 mmol, 29.59% yield) was obtained as a white solid.1 ) δ 8.50 (s, 1H), 8.08 (d, J = 6.6 Hz, 1H), 7.33-7.75 (m, 6H), 6.56 (d, J = 6.6 Hz, 1H), 5.41 (s, 2H) Example 300:

[0037] Step 1 To a solution of E190-1 (511.00 mg, 1.66 mmol) in ACN (10 mL) was added K2CO3(459.30 mg, 3.33 mmol) and E190-1’ (341.87 mg, 2.00 mmol). The reaction mixture was stirred at 70°C for 10 h. The mixture was filtered and washed with DCM and EA. The filtrate was concentrated and purified by MPLC to give Example 300 (540 mg, 1.36 mmol, 81.66% yield, 100.00% purity) as a white solid. LCMS (E+) m / z: 398.0 [M+H]+., NMR (600 MHz, Chloroform-d) δ 7.91 – 7.83 (m, 2H), 7.71 – 7.64 (m, 2H), 7.62 (s, 1H), 7.45 – 7.38 (m, 4H), 7.37 – 7.31 (m, 1H), 6.91 (t, J = 51.7 Hz, 1H), 6.71 (d, J = 9.4 Hz, 1H), 5.31 (s, 2H). Example 301: Step 1 To a solution of E191-1’ (489.85 mg, 2.61 mmol) in DMF (10 mL) under N2was added LiBr (452.54 mg, 5.21 mmol) and NaH (68.78 mg, 2.87 mmol). The reaction mixture was stirred 20 min at room temperature, then E191-1 (800 mg, 2.61 mmol) was added, and the reaction mixture was heated to 70°C for 2 h. After cooled to room temperature, the mixture was quenched with ice- cooled water (100 mL), extracted with DCM (100 mL*3). The combined organic layer was wash with brine (100 mL), dried over Na2SO4, and then concentrated. The residue was purified by column chromatography on silica gel (PE:EA=1:1) to give E191-2 (416 mg, 1.00 mmol, 38.55% yield) as a white solid. Step 2 To a solution of E191-2 (767 mg, 1.85 mmol) in 1,4-Dioxane (20 mL) and H2O (10 mL) were added Na2CO3(490.75 mg, 4.63 mmol), E191-2’ (338.70 mg, 2.78 mmol) and Pd(dppf)Cl2(135.50 mg, 185.19 μmol). The reaction mixture was stirred at 70°C under N2 for 1 h. After cooled to room temperature, the mixture was quenched with water (200 mL), extracted with DCM (200 mL*3). The combined organic layer was then washed with brine (100 mL), dried over Na2SO4, concentrated. The residue was purified by column chromatography on silica gel (EA:PE=1:1) to give Example 301 (600 mg, 1.46 mmol, 78.76% yield, 98.82% purity) as a solid. LCMS (E+) m / z: 412.3 [M+H]+.,1H NMR (600 MHz, Chloroform-d) δ 7.89 – 7.82 (m, 2H), 7.44 – 7.37 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.26 – 7.19 (m, 3H), 6.92 (t, J = 51.7 Hz, 1H), 6.65 (d, J = 9.4 Hz, 1H), 5.55 (s, 2H), 2.24 (s, 3H). Example 302: Step 1 To a stirred solution of E192-1 (684 mg, 3.99 mmol) in DMF (10 mL) was added NaH (42.16 mg, 4.39 mmol) at 0°C. After being stirred at 0°C for 0.5 h, KBr (238 mg, 7.89 mmol) and E192-1’ (303.45 mg, 4.19 mmol) were added. The mixture was then stirred at 65 °C for 2 h until LCMS indicated the SM was consumed. The mixture was then cooled to room temperature and purified by MPLC to provide Example 302 (1.19 g, 1.41 mmol, 35.43% yield). LCMS (E+) m / z: 381.3 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 9.15 (dd, J = 2.3, 0.8 Hz, 1H), 8.42 (dd, J = 8.3, 2.2 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 9.4, 2.7 Hz, 1H), 7.71-7.27 (m, 7H), 6.55 (d, J = 9.5 Hz, 1H), 5.40 (s, 2H). Example 303: Step 1: To a solution of methyl 2-methyloxazole-5-carboxylate (5.00 g, 35.43 mmol) and AIBN (1.16 g, 7.09 mmol) in CCl4(300 mL) was added NBS (12.61 g, 70.86 mmol) in portion at 25 °C. The mixture was allowed to stir at 80 °C for 16 hr under nitrogen. After complete consumption of starting material (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to provide E151-2 (4.00 g, 18.18 mmol, 51.31% yield) as a solid. LCMS: 219.9 [M+H]+; 94.27%; RT = 1.262 Step 2: To a solution of E151-2 (4.20 g, 19.09 mmol) and lithium carbonate (2.82 g, 38.18 mmol) in DMF (15 ml) was added 2-chloro-4-hydroxypyrimidine (1.87 g, 14.32 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 hr. After complete consumption of starting material (monitored by LCMS), the reaction mixture was filtered and the filtrate was purified by flash column chromatography to provide E151-3 (1.15 g, 4.26 mmol, 22.34% yield) as a solid. LCMS: 270.1 [M+H]+; 92.06%; RT = 0.8451H NMR: (600 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.92 (d, J = 6.4 Hz, 1H), 6.57 (d, J = 6.5 Hz, 1H), 5.57 (s, 2H), 3.85 (s, 3H). Step 3:

[0038] To a solution of E151-3 (1.15 g, 4.26 mmol), phenylboronic acid (1.04 g, 8.53 mmol) and sodium carbonate (1.36 g, 12.79 mmol) in dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium (246.42 mg, 213.25 μmol) at 25 °C. The mixture was degassed with N2 and then stirred at 90 °C for 2 hr. After complete consumption of starting material (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to provide E151-4 (546.00 mg, 1.75 mmol, 41.13% yield) as a solid. LCMS: 312.3 [M+H]+; 84.43%; RT = 1.084 Step 4: To a stirred solution of E151-4 (546.00 mg, 1.75 mmol) in methanol (17.5 mL) was added hydrazine hydrate (0.87 mL, 80% purity in water) at 25 °C. The mixture was stirred at 25 °C for 2 hr. After complete consumption of the starting material (monitored by TLC), trifluoroacetic acid (1.50 mL) was added to the mixture to adjust the pH to 6~7. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to E151-5 (475.00 mg, 1.53 mmol, 87.00% yield) as a solid. LCMS: 312.1 [M+H]+; 78.34%; RT = 1.082. Step 6: To a mixture of E151-5 (465.00 mg, 1.49 mmol) and TEA (604.61 mg, 5.98 mmol) in THF (15 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (311.99 mg, 1.79 mmol). The mixture was stirred at 25 °C for 1 hr. After complete consumption of the starting material (monitored by LCMS), TEA (906.92 mg, 8.96 mmol) was added to the mixture followed by tosyl chloride (854.34 mg, 4.48 mmol). The mixture was allowed to heated to 60 °C for 2 hr. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to provide Example 303 (60.00 mg, 161.60 μmol, 10.82% yield) as a solid. 1 Step 1:

[0039] To a solution of 3-bromo-6-hydroxy-2-methylpyridine (1.56 g, 8.27 mmol) in DMF (21 mL) under N2was added LiBr (1.20 g, 13.79 mmol) and NaH (182.03 mg, 7.58 mmol). The mixture was stirred for 20 min at room temperature, then E193-1 (2.0 g, 6.90 mmol) was added. The reaction mixture was heated to 70°C for 2 hr. After cooled to room temperature, the mixture was quenched with water (200 mL), extracted with DCM (150 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, and then concentrated. The residue was purified by column chromatography to give E193-2 (1.21 g, 3.05 mmol, 44.18% yield) as a white solid. LCMS: 369.9 [M+H]+; 93.23%; RT = 2.065 S To a solution of E193-2 (1.20 g, 3.02 mmol) in a mixture solution of 1, 4-dioxane / H2O=2:1 (48 mL) Na2CO3(800.66 mg, 7.55 mmol), phenylboronic acid (552.59 mg, 4.53 mmol) and Pd(dppf)Cl2(221.07 mg, 302.13 μmol) were added. The reaction mixture was stirred at 70°C under N2 for 0.5 hr. After cooled to room temperature, the mixture was quenched with water (200 mL), extracted with DCM (150 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, and then concentrated. The residue was then purified by column chromatography to give Example 304 (404 mg, 1.02 mmol, 33.91% yield, 98.53% purity) as a white solid. LCMS: 395.4 [M+H]+; 100.00%; RT = 2.423.1H NMR: (600 MHz, Chloroform-d) δ 9.26 (d, J = 2.1 Hz, 1H), 8.36 (dd, J = 8.2, 2.3 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 6.9 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.26 – 7.22 (m, 2H), 6.94 (t, J = 51.7 Hz, 1H), 6.61 (d, J = 9.3 Hz, 1H), 5.60 (s, 2H), 2.36 (s, 3H). Example 305: Step 1: To a bottle charged with 4-bromopyridin-2(1H)-one (10.00 g, 57.47 mmol), phenylboronic acid (10.51 g, 86.21 mmol), Na2CO3 (15.23 g, 143.68 mmol) in 1,4-dioxane (120 mL) and H2O (40 mL) was added Pd(dppf)Cl2(2.94 g, 4.02 mmol). After degassed with N2for three times, the mixture was allowed to heat to 80 °C for 4 hr under N2 atmosphere until LCMS indicated starting material was almost consumed. The mixture was filtered, and the cake was washed with MeCN (60 mL x 2). The combined organic filtrate was concentrated and then purified by MPLC to afford E245-2 (7.00 g, 40.89 mmol, 71.15% yield). Step 2: To a stirred solution of E245-2 (0.55 g, 3.21 mmol) in DMF (5 mL) were added NaH (141.37 mg, 3.53 mmol, 60% purity) and LiBr (558.05 mg, 6.43 mmol). After being stirred at 25 °C for 10 min, the solution of E245-2 (746.61 mg, 3.05 mmol) in DMF (2 mL) was added. Then, the mixture was allowed to heat to 70 °C for 2 hr until LCMS showed the starting material was consumed. The mixture was cooled to room temperature and quenched by water (50 mL). The suspension was extracted with EA (50 ml x 3). The combined organic layer was washed with water (50 ml x 2) and brine (50 ml x 2). The organic phase was dried over Na2SO4and then filtered. The filtrate was concentrated, and the residue was purified by MPLC to afford Example 305 (0.68 g, 1.78 mmol, 55.52% yield, 99.51% purity) as a white solid. LCMS: 380.4 [M+H]+; 98.81%; RT =2.532.1H NMR: 1H NMR (400 MHz, DMSO-d6) δ 8.12 – 8.01 (m, 2H), 7.95 (d, J = 7.1 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.69 – 7.39 (m, 6H), 6.75 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 7.1, 2.1 Hz, 1H), 5.25 (s, 2H). Example 306: Step 1:

[0040] To a solution of E246-1 (400.00 mg, 1.38 mmol) and E246-1’ (354.12 mg, 2.06 mmol) in DMF (5 mL) was added K2CO3(380.60 mg, 2.76 mmol). The mixture was heated to 70 °C for 4 hr. Then, the reaction mixture was cooled and filtered. The filtrate was concentrated and purified by MPLC to afford Example 306 (241.00 mg, 634.21 μmol, 45.96% yield) as a solid. LCMS: 381.3 [M+H]+; 96.53%; RT =2.300.1H NMR: 1H NMR (600 MHz, Methanol-d4) δ 9.22 – 9.18 (m, 1H), 8.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.91 – 7.86 (m, 1H), 7.72 – 7.66 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 – 7.43 (m, 3H), 7.23 (t, J = 51.6 Hz, 1H), 6.80 (d, J = 6.4 Hz, 2H), 5.42 (s, 2H). Example 307:

[0041] To a solution of methyl 5-fluoro-6-methylnicotinate (4.00 g, 23.65 mmol) in MeOH (260 mL) was added hydrazine hydrate (11.84 g, 236.47 mmol, 11 mL). The mixture was then stirred at 25 °C for 1 hr. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure and purified by silica gel to provide E247-2 (2.9 g, 17.14 mmol, 72.50% yield) as a solid. LCMS: 169.9 [M+H]+; 95.08%; RT = 0.696 Step 2:

[0042] To a solution of E247-2 (2.70 g, 15.96 mmol) and TEA (12.92 g, 127.69 mmol, 17.81 mL) in THF (80 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (6.67 g, 38.31 mmol) at 25 °C. After being stirred at 25 °C for 3 hr., 4-methylbenzenesulfonyl chloride (9.13 g, 47.88 mmol) was added. The mixture was then stirred at 60 °C for another 3 hr. The reaction mixture was concentrated under reduced pressure. The mixture was diluted in water (80 mL) and extracted with DCM (80 mL) 3 times. The organic layer was concentrated under reduced pressure and purified by silica gel to provide E247-3 (1.10 g, 4.80 mmol, 30.07% yield). LCMS: LCMS: 230.0 [M+H]+; 89.01%; RT = 1.066 Step 3: To a solution of E247-3 (1.00 g, 4.36 mmol) in THF (20 mL) was added NBS (2.33 g, 13.09 mmol) and AIBN (358.29 mg, 2.18 mmol). The mixture was stirred at 80 °C for 16 hr under N2. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted in water (20 mL) and extracted with DCM (20 mL) 3 times. The organic layer was concentrated under reduced pressure and purified by MPLC to provide E247-4 (845 mg, 2.74 mmol, 62.86% yield). LCMS: 307.8 [M+H]+; 80.25%; RT = 1.405 Step 4:

[0043] To a solution of 4-phenyl-1H-pyridin-2-one (264.63 mg, 1.55 mmol) in DMF (16 mL) were added NaH (68.02 mg, 1.70 mmol, 60% purity) and LiBr (268.51 mg, 3.09 mmol). After being stirred at 25 °C for 15 min, E247-4 (845 mg, 2.74 mmol) was added. The mixture was stirred at 70 °C for 2 hr. After monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and extracted with EA (20 mL) 3 times. The organic layer was concentrated under reduced pressure and purified by silica gel to provide Example 307 (414 mg, 1.04 mmol, 67.24% yield). LCMS: 399.0 [M+H]+; 96.93%; RT = 2.4791H NMR: 1H NMR (400 MHz, Methanol-d4) δ 9.03 – 8.94 (m, 1H), 8.28 (dd, J = 9.7, 1.8 Hz, 1H), 7.87 (dd, J = 7.0, 0.7 Hz, 1H), 7.74 – 7.63 (m, 2H), 7.55 – 7.42 (m, 3H), 7.23 (t, J = 51.6 Hz, 1H), 6.83 – 6.72 (m, 2H), 5.49 (d, J = 1.5 Hz, 2H). Example 308:

[0044] To a stirred solution of benzamidine hydrochloride (20.00 g, 127.70 mmol) in EtOH (400 mL) were added K2CO3(17.62 g, 127.70 mmol) and ethyl propiolate (10.74 g, 127.70 mmol) under N2. The reaction mixture was stirred at 80℃for 20 hr until LCMS showed starting material was almost consumed. After it cooled to room temperature, the mixture was filtered. The filtrate was concentrated under vacuum and the residue was dissolved in water (200 mL). The solution was acidified with HCl aqueous solution (6 M) until pH = 3. The precipitate was filtered and the cake was washed with water (100 mL). The crude product was purified by column chromatography on silica gel to give E280-2 (10.70 g, 62.14 mmol, 48.66% yield). LCMS: 172.9 [M+H]+; 98.93%; RT = 1.183 Step 2: To a stirred solution of E280-2 (2.00 g, 11.62 mmol) in acetic acid (40 mL) was added NCS (1.55 g, 11.62 mmol) in portions. The reaction mixture was stirred at 90℃for 2 hr until LCMS showed starting material was consumed completely. The solvent was removed under reduced pressure and then EA (10 mL) was added. After stirred at room temperature for 0.5 hr, the suspension was filtered to give E280-3 (1.67 g, 8.08 mmol, 69.58% yield). LCMS: 207.2 [M+H]+; 97.34%; RT = 1.5221 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 7.7 Hz, 2H), 7.68 – 7.42 (m, 3H). Step 3: To a stirred solution of E280-3 (300.00 mg, 1.45 mmol) in DME (15 mL) were added NaH (87.11 mg, 2.18 mmol, 60% suspension in mineral oil) and LiBr (252.19 mg, 2.90 mmol) carefully. After stirred at room temperature for 20 min, E280-3 (421.14 mg, 1.45 mmol) was added. The reaction mixture was then heated to 85°C for 32 hr until LCMS showed starting material was almost consumed. The mixture was cooled and quenched by adding 2 mL water, and the resulting solution was concentrated under reduced pressure. The residue was purified directly by column chromatography on silica gel to give Example 308 (150.00 mg, 360.77 μmol, 24.85% yield, 96.70% purity). LCMS: 415.9 [M+H]+; 97.67%; RT = 2.005.1H NMR: (600 MHz, Chloroform-d) δ 9.26 – 9.17 (m, 1H), 8.35 (dd, J = 8.2, 2.2 Hz, 1H), 8.23 (s, 1H), 7.61 – 7.52 (m, 2H), 7.52 – 7.46 (m, 1H), 7.44 – 7.37 (m, 3H), 6.94 (t, J = 51.6 Hz, 1H), 5.34 (s, 2H). Example 309 Step 1: To a stirred solution of E280-2 (6.60 g, 38.33 mmol) in acetic acid (133 mL) was added NBS (6.82 g, 38.33 mmol) in portions. The reaction mixture was stirred at 90℃for 2 hr until LCMS showed starting material was consumed completely. The reaction solvent was removed under vacuum and then EA (20 mL) was added. The suspension was stirred at room temperature for 0.5 hr and filtered to give E281-2 (9.00 g, 35.85 mmol, 93.51% yield) as a white solid. LCMS: 251.2 [M+H]+; 98.09%; RT = 1.630.1H NMR: (400 MHz, DMSO-d6) δ1H NMR (600 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.46 (s, 1H), 8.09 (d, J = 7.7 Hz, 2H), 7.63 – 7.58 (m, 1H), 7.54 (dd, J = 8.4, 7.0 Hz, 2H). Step 2: A solution of E281-2 (9.00 g, 35.85 mmol), potassium vinyltrifluoroborate (14.40 g, 107.54 mmol) K2CO3 (14.84 g, 107.54 mmol) and Pd(PPh3)2Cl2 (1.26 g, 1.79 mmol) in dioxane (150 mL) and H2O (30 mL) was stirred at 95 °C under N2. After stirred for 16 hr, LCMS showed starting material was almost consumed. The mixture was cooled and poured into water (150 mL). The suspension was extracted with EA (150 mL x 3). The combined organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel to give E281-3 (7.00 g, 35.31 mmol, 98.52% yield). LCMS: 199.1 [M+H]+; 96.78%; RT = 1.167 Step 3: To a solution of E281-3 (4.00 g, 20.18 mmol) in MeOH (400 mL) was added Pd / C (400.00 mg, 50% purity). After degassed under vacuum and purged with H2several times, the mixture was stirred at room temperature for 3 hr until LCMS showed starting material was consumed completely. The suspension was filtered through a pad of celite and the pad was washed with MeOH (100 mL). The combined filtrates were concentrated to dryness. The crude compound was purified by column chromatography on silica gel to give E281-4 (1.60 g, 7.99 mmol, 39.60% yield). LCMS: 201.3 [M+H]+; 98.77%; RT = 1.414 Step 4: To a stirred solution of E281-4 (500.00 mg, 2.50 mmol) in DME (20 mL) were added NaH (109.87 mg, 2.75 mmol, 60% suspention in mineral oil) and LiBr (433.74 mg, 4.99 mmol) carefully. After stirred at room temperature for 20 min, E281-4’ (724.31 mg, 2.50 mmol) was added. The reaction mixture was heated to 85°C for 16 hr until LCMS showed SM was almost consumed. The reaction solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to give Example 309 (258.00 mg, 630.21 μmol, 25.24% yield, 98.77% purity). LCMS: 410.0 [M+H]+; 99.54%; RT =2.379.1H NMR: (600 MHz, Methanol-d4) δ 9.14 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 8.3, 2.2 Hz, 1H), 7.94 (s, 1H), 7.54 – 7.46 (m, 3H), 7.46 – 7.39 (m, 3H), 7.23 (t, J = 51.6 Hz, 1H), 5.35 (s, 2H), 2.59 – 2.51 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H). Example 310: Step 1: To a stirred solution of 4-dimethylaminopyridine (5.33 g, 43.65 mmol) in acetonitrile (66 mL) was added 2,4-dinitro-1-(trifluoromethoxy)benzene (22.01 g, 87.31 mmol) at 0-10 °C. After stirred for 10 min, benzyl bromoacetate (5.00 g, 21.83 mmol) was added. The reaction mixture was then allowed to warm to 40 °C for another 20 hr until HNMR showed target product was > 30%. The reaction solvent was removed under vacuum and the residue purified by column chromatography on silica gel to give E282-2 (2.70 g, 11.53 mmol, 52.82% yield). 1H NMR: (400 MHz, DMSO-d6) δ 7.50 – 7.30 (m, 5H), 5.25 (s, 2H), 4.52 (s, 2H). Step 2: To a stirred solution of NaH (691.80 mg, 17.30 mmol, 60% suspention in mineral oil) in THF (30 mL) was added ethyl formate (1.71 g, 23.06 mmol) and E282-2 (2.7 g, 11.53 mmol). The reaction mixture was stirred at room temperature for 16 hr until TLC showed target product was almost consumed. The mixture was concentrated, and the residue was directly used for the next step with no further purification. Step 4:

[0045] To a stirred solution of E282-3 (crude) in EtOH (30 mL) were added benzamidine hydrochloride (2.69 g, 17.16 mmol) and EtONa (2.33 g, 34.33 mmol). The reaction mixture was stirred at room temperature for 16 hr until LCMS showed product was ~ 19%. The reaction solvent was removed by vacuum and adjusted the pH to 5 with 1N HCl. Then the mixture was poured into water (30 mL) and extracted with EA (30 mL×5). The organic extracts were dried using sodium sulfate, filter and concentrated under reduced pressure, then purified by column chromatography on silica gel to give E282-4 (500 mg, 1.95 mmol, 17.06% yield of 2 steps). LCMS: 256.9 [M+H]+; 89.16%; RT = 2.109 Step 3: To a stirred solution of E282-4 (480.00 mg,1.87 mmol) in DME (50 mL) were added NaH (149.89 mg, 3.75 mmol, 60% suspention in mineral oil) and LiBr (325.46 mg, 3.75 mmol). After stirred at room temperature for 20 min, E282-4’ (570.66 mg, 1.97 mmol) was added. The suspension was heated to 85°C for 32 hr until LCMS showed ~ 50% purity of target product was found. The reaction solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to give Example 310 (270.00 mg, 580.23 μmol, 30.97% yield, 95.28% purity). LCMS: 465.9 [M+H]+; 97.02%; RT = 2.762.1 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.70 – 7.39 (m, 7H), 5.32 (s, 2H). Example 311: Step 1:

[0046] To a solution of 5-bromo-2-methoxy-4-methylpyridine (3.00 g, 14.85 mmol) in DME (20 mL) and H2O (2 mL) were added phenylboronic acid (2.17 g, 17.82 mmol), Pd(dppf)Cl2(1.09 g, 1.48 mmol) and K2CO3(4.10 g, 29.70 mmol). After degassed with N2three times, the reaction mixture was stirred at 100°C for 16 hr under N2. The reaction mixture was concentrated and then purified by prep-HPLC to give E283-2 (2.80 g, 14.05 mmol, 94.65% yield). LCMS: 200.0 [M+H]+; 90.24%; RT = 2.305 Step 2: A solution of E283-2 (2.50 g, 12.55 mmol) in HBr (40 wt% in H2O, 110 mL) was stirred at 100°C overnight. After cooled to room temperature, the mixture was extracted with DCM (100 mL×3). The combined organic layer was washed with brine (100 mL×2). The mixture was dried over Na2SO4and then concentrated. The residue was purified by prep-HPLC to give E283-3 (1.96 g, 10.58 mmol, 84.34% yield). LCMS: 186.3 [M+H]+; 90.72%; RT = 1.066 Step 3:

[0047] To a solution of E283-3 (300.0 mg, 1.62 mmol) in DMF (8 mL) was added LiBr (281.3 mg, 3.24 mmol) and NaH (71.2 mg, 1.78 mmol, 60% suspention in mineral oil). After stirred at 25°C for 10 min, E283-3’ (493.30 mg, 1.70 mmol) was added. The suspension was then stirred at 70°C for 2 hr. The reaction mixture was quenched by addition of H2O (30 mL) and extracted with DCM (30 mL×3). The combined organic was dried over Na2SO4. The solution was concentrated and the residue purified by column chromatography on silica gel (PE:EA = 10:1) to give Example 311 (336.0 mg, 0.84 mmol, 51.77% yield, 98.41% purity). LCMS: 395.4 [ Methanol-d4) δ 9.17 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 8.2, 2.3 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.39 – 7.32 (m, 3H), 7.23 (t, J = 51.6 Hz, 1H), 6.51 (s, 1H), 5.38 (s, 2H), 2.16 (s, 3H). Example 312:

[0048] Step 1: To a solution of 2-bromo-3-methylpyridine (5.00 g, 29.06 mmol), phenylboronic acid (4.61 g, 37.78 mmol), XPhos (2.77 g, 5.81 mmol) and Potassium phosphate (18.51 g, 87.18 mmol) in Dioxane / H2O=3:1 (104 mL) was added Pd2(dba)3 (2.66 g, 2.91 mmol) under N2 atmosphere. The mixture was stirred at 100℃ for 16 hr. After it cooled to room temperature, the mixture was diluted with water (100 mL). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (hexane / ethyl acetate = 100:1 to 10:1) to provide E284-2 (4.25 g, 25.11 mmol, 86.43% yield). LCMS: 169.9 [M+H]+; 86.00%; RT = 0.922.1 NMR: (400 MHz, Chloroform-d) δ 8.53 (dd, J = 4.9, 1.6 Hz, 1H), 7.59 (m, 1H), 7.54 – 7.48 (m, 2H), 7.48 – 7.35 (m, 3H), 7.19 (dd, J = 7.7, 4.8 Hz, 1H), 2.36 (s, 3H). Step 2: To a solution of E284-2 (4.25 g, 25.11 mmol) in anhydrous DCM (80 mL) was added m-CPBA (26.91 g, 37.67 mmol) in small portions at 0℃. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was carefully adjusted to pH > 7 with the aqueous NaOH solution (2 M) under 0-10 °C. And then the saturated aqueous solution of sodium thiosulphate was added slowly. The mixture was stirred for another 30 minutes until the organic layer was separated. The organic phase was washed with water (20 mL) and then dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to provide E284-3 (3.7 g, crude, about 93% purity) which was used for the next step without further purification. LCMS: 186.0 [M+H]+;87.53% ; RT = 1.481.1H NMR: (400 MHz, Chloroform-d) δ 8.23 (dd, J = 6.1, 1.6 Hz, 1H), 7.58 – 7.41 (m, 3H), 7.37 – 7.31 (m, 2H), 7.21 – 7.09 (m, 2H), 2.11 (s, 3H). Step 3: To a tube were added E284-3 (1.20 g, 6.48 mmol) and acetic anhydride (12 ml), and then the mixture was irradiated in a microwave oven at 175°C for 45 minutes. The mixture was concentrated under reduced pressure to dryness. 7M ammonia in MeOH (60 ml) was added and the mixture was allowed to stirred overnight. The resulted solution was concentrated, and the residue was purified by MPLC to give E284-4 (490.00 mg, 2.65 mmol, 40.83% yield). LCMS: 185.9 [M+H]+; 91.11% ; RT = 1.153.1H NMR: (400 MHz, Chloroform-d) δ 10.83 (s, 1H), 7.51 – 7.39 (m, 5H), 7.32 (d, J = 9.3 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 2.06 (s, 3H). Step 4: To a stirred solution of E284-4 (490.00 mg, 2.65 mmol) in anhydrous DMF (15 mL) were added NaH (159.20 mg, 3.98 mmol, 60% mw) and LiBr (460.31 mg, 5.30 mmol). After being stirred for 20 min, E284-4’ (768.69 mg, 2.65 mmol) was added. The mixture was then heated to 70 °C for another 30 min until LCMS indicated the starting material was almost consumed. After cooled to room temperature, the mixture was quenched by water (100 mL). The suspension was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4and then filtered. The filtrate was concentrated, and the residue was purified by column chromatography (hexane / ethyl acetate = 10:1 to 1:3) to provide Example 312 (357.50 mg, 0.91 mmol, 34.28% yield). LCMS: 395.2 [M+H]+; 98.96%; RT = 3.209.1 NMR: (400 MHz, Chloroform-d) δ 9.13 (dd, J = 2.2, 0.8 Hz, 1H), 8.25 (dd, J = 8.2, 2.2 Hz, 1H), 7.41 – 7.29 (m, 4H), 7.18 (dd, J = 8.2, 0.9 Hz, 1H), 7.08 (m, 2H), 6.92 (t, J = 51.7 Hz, 1H), 6.66 (d, J = 9.3 Hz, 1H), 5.19 (s, 2H), 1.80 (s, 3H). Example 313: Step 1:

[0049] To a sealed tube were charged with 5-bromo-6-methylpyridin-2-ol (10.00 g, 53.19 mmol), phenylboronic acid (9.73 g, 79.78 mmol), Pd(dppf)Cl2.CH2Cl2 (868.06 mg, 1.06 mmol), K3PO4 (33.83 g, 159.56 mmol), dimethoxyethane (200 mL) and water (20 mL). After degassed with N2 three times, the mixture was allowed to heat to 85 °C for 5 hr until LCMS showed the starting material was almost consumed. The mixture was concentrated and the residue was purified by flash column chromatography to give E285-2 (3.10 g, 16.74 mmol, 31.47% yield) as a brown solid. LCMS: 186.0 [M+H]+; 90.61%; RT =1.190 Step 2: To a stirred solution of E285-2 (2.10 g, 11.34 mmol) in CHCl3 (100 mL) was added N- Bromosuccinimide (2.02 g, 11.34 mmol) in one portion. The mixture was then stirred at room temperature for 1 hr until LCMS showed the complete consumption of E285-2. The mixture was then concentrated and the residue was purified by flash column chromatography to afford E285-3 (2.70 g, 10.22 mmol, 90.12% yield) as a yellow solid. LCMS: 263.9 [M+H]+; 94.73%; RT = 1.231 Step 3:

[0050] To a stirred solution of E285-3 (2.00 g, 7.57 mmol) in dry DMF (20 mL) was added NaH (363.20 mg of a 60% suspension in mineral oil, 9.08 mmol) at 0 °C under N2. After being stirred for 25 min, a solution of benzyl bromide (1.68 g, 9.84 mmol) in dry DMF (5 mL) was added dropwise. The mixture was stirred at room temperature for another 2 hr until LCMS showed the complete consumption of E285-3. The mixture was quenched by addition of 2 mL water and then directly purified by flash column chromatography to afford E285-4 (2.20 g, 6.21 mmol, 82.04% yield) as a white solid. LCMS: 354.3 [M+H]+; 64.29 %; RT =1.470 & 1.742 Step 4: A solution of E285-4 (2.00 g, 5.65 mmol), methylboronic acid (1.01 g, 16.95 mmol), Pd(dppf)Cl2.CH2Cl2(457.31 mg, 0.56 mmol) and Cs2CO3(3.68 g, 11.30 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 2 hr under N2 until LC-MS showed the complete consumption of E285-4. The mixture was then purified by flash column chromatography to give crude E285-5 (875.00 mg, 3.02 mmol, 53.52 % yield) as a brown oil. LCMS: 290.0 [M+H]+; NA; RT =3.155 & 4.035 (the LCMS of reaction mixture) Step 5: To a solution of E285-5 (855.00 mg, 2.95 mmol) in MeOH (80 ml) was added 10% palladium on carbon (400.00 mg). After degassed with H2three times, the mixture was stirred under an atmosphere of hydrogen (60 psi) at 40 °C for 16 hr. The mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to give E285-6 (265.00 mg, 1.33 mmol, 45.08% yield) as a white solid. LCMS: 200.2 [M+H]+; 95.94 %; RT = 1.045 Step 6: To a stirred solution of E285-6 (254.00 mg, 1.27 mmol) and LiBr (220.57 mg, 2.54 mmol) in dry DMF (15 mL) was added NaH (56.00 mg of a 60% suspension in mineral oil, 1.40 mmol) at room temperature under N2. After being stirred for 0.5 hr, a solution of E285-6’ (385.79 mg, 1.33 mmol) in dry DMF (5 mL) was added. The mixture was stirred at 70 °C for another 2 hr until LC-MS showed the complete consumption of E285-6. The mixture was quenched by adding water (4 mL) and then purified by flash column chromatography to give Example 313 (210.00 mg, 0.51 mmol, 40.49 % yield) as a gray solid. LCMS: 409.5 [M+H]+; 95.02%; RT = 2.712.1 δ 9.15 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 8.2, 2.3 Hz, 1H), 7.67 – 7.48 (m, 2H), 7.47 – 7.48 (m, J = 7.6 Hz, 2H), 7.37 – 7.29 (m, 4H), 5.56 (s, 2H), 2.26 (s, 3H), 2.05 (s, 3H). Example 314: A solution of E286-1 (2.00 g, 5.65 mmol, prepared by 3 steps shown as E285-4), cyclopropylboronic acid (1.46 g, 16.95 mmol), Pd(dppf)Cl2.CH2Cl2 (457.31 mg, 0.56 mmol) and Cs2CO3 (3.68 g, 11.30 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 2 hr under N2 until LCMS showed the starting material was almost consumed. The mixture was concentrated and the residue was purified by flash column chromatography to give E286-2 (1.40 g, 4.44 mmol, 78.56 % yield) as a brown oil. LCMS: 316.4 [M+H]+; P1: 82.22 %, RT = 1.434 ; P2: 98.19 %, RT = 1.866 Step 2: To a solution of E286-2 (1.40 g, 4.44 mmol) in MeOH (80 mL) was added Pd / C (700.00 mg, 50% purity) carefully. Then the mixture was degassed with H2 three times. The mixture was allowed to heat at 40 °C for 2 hr. The suspension was then filtered through a pad of celite and washed with MeOH (150 mL). The combined filtrate was then concentrated. The residue was purified by flash column chromatography to afford E286-3 (375.90mg, 1.67 mmol, 37.58 % yield) as a white solid. LCMS: 226.2 [M+H]+; 92.38%; RT = 1.130 Step 3:

[0051] To a stirred solution of E286-3 (353.40 mg, 1.57 mmol) and LiBr (272.68 mg, 3.14 mmol) in DMF (10 mL) was added NaH (68.80 mg, 1.72 mmol, 60% suspension in mineral oil) carefully. Afterstirred at room temperature for 20 min, E286-3’ (478.62 mg, 1.65 mmol) was added. The mixturewas then heated at 70 °C for 2 hr until LCMS indicated starting material was almost consumed. The mixture was cooled and quenched by adding 4 mL water. The resulting solution was then concentrated to dryness and the residue was purified by flash column chromatography to give Example 314 (414.60 mg, 0.95 mmol, 60.51 % yield) as a gray solid. LCMS: 435.0 [M+H]+; 95.62%; RT =3.015.1H NMR: (600 MHz, DMSO-d6) δ 9.16 (d, J = 2.3 Hz, 1H), 8.44 (dd, J = 8.3, 2.3 Hz, 1H), 7.68 – 7.49 (m, 2H), 7.47 – 7.41 (m, 2H), 7.37 – 7.28 (m, 3H), 6.93 (s, 1H), 5.57 (s, 2H), 2.26 (s, 3H), 2.08 – 1.99 (m, 1H), 0.92 – 0.79 (m, 2H), 0.74 – 0.62 (m, 2H). Example 315:

[0052] Step 1: To a stirred solution of 5-bromo-3-methoxy-6-methylpyridin-2-amine (2.20 g, 10.14 mmol) in H2O (3 mL) was added dropwise con.H2SO4 (4.4 ml) at 0-10 °C. After stirred for 10 min, A solution of NaNO2 (1.40 g, 20.28 mmol) in water (3 mL) was added. The mixture was allowed to warm to 25 °C and stirred for another 1 hr before icy-water (50 ml) was added. The resulting suspension was filtered, and the cake was washed with water (50 ml) and then dried to afford E287-2 (1.41 g, 6.47 mmol, 63.81 % yield) as a white solid. LCMS: 217.0 [M+H]+; 65.44%; RT = 1.084 Step 2: A solution of E287-2 (1.41 g, 6.47 mmol), phenylboronic acid (1.18 g, 9.71 mmol), Pd(dppf)Cl2.CH2Cl2(106.08 mg, 0.13 mmol) and K3PO4(4.12 g, 19.41 mmol) in 1,2- dimethoxyethane (20 mL) and water (2 ml) was stirred at 85 °C for 2 hr under N2. The mixture was cooled and concentrated. The residue was purified by column chromatography to give E287- 3 (510.00 mg, 2.37 mmol, 36.62 % yield) as a white solid. LCMS: 215.9 [M+H]+; 88.79%; RT = 1.219 Step 3: To a stirred solution of E287-3 (301.00 mg, 1.40 mmol) and LiBr (243.15 mg, 2.80 mmol) in DMF (8 mL) was added NaH (61.60 mg, 1.54 mmol, 60% suspension in mineral oil). After stirring at room temperature for 20 min, E287-3’ (426.40 mg, 1.47 mmol) was added. The mixture was heated at 70 °C for 2 hr until LCMS indicate starting material was almost consumed. The mixture was cooled and quenched by addition of water (4 mL). The mixture was directly purified by flash column chromatography to give Example 315 (210.00 mg, 0.49 mmol, 35.34 % yield) as a gray solid. LCMS: 425.1 [M+H]+; 100.00%; RT = 2.418.1H NMR: (600 MHz, DMSO-d6) δ 9.15 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 8.3, 2.3 Hz, 1H), 7.67 – 7.41 (m, 4H), 7.39 – 7.33 (m, 3H), 6.82 (s, 1H), 5.57 (s, 2H), 3.75 (s, 3H), 2.21 (s, 3H). Example 316: Step 1: To a solution of 5-bromo-6-methylpyrimidin-4-ol (8.00 g, 42.33 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) were added K2CO3 (17.52 g, 126.98 mmol), phenylboronic acid (6.19 g, 50.80 mmol) and Pd(dppf)Cl2.CH2Cl2(3.45 g, 4.23 mmol) under N2. The mixture was stirred at 80 °C for 1 hr until LCMS indicated the SM was consumed completely. Then the reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EA (100 ml x 3). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solution was concentrated and the residue was purified by prep-HPLC to provide E290-2 (1.50 g, 7.25 mmol, 17.13% yield) as a white solid. LCMS: 187.0 [M+H]+; 94.00%; RT = 0.816 Step 2: To a stirred solution of E290-2 (514.00 mg, 2.76 mmol) in DMF (2.00 mL) and DME (8.00 mL) were added LiBr (240.0 mg, 2.76 mmol) and NaH (61.0 mg, 1.52 mmol, 60% purity). The mixture was stirred at room temperature for 1 h, and then E290-2’ (400.0 mg, 1.38 mmol) was added. The mixture was stirred at 70 °C for another 1 hr. After cooled to room temperature, the mixture was diluted with water (50 mL) and extracted with EA (50 ml x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. The mixture was concentrated to afford the crude product, which was purified by prep-HPLC to provide Example 316 (366.20 mg, 889.19 μmol, 64.48% yield) as an off-white solid. LCMS: 396.2 [M+H]+; 95.91%; RT = 2.142.1H NMR: (600 MHz, DMSO-d6) δ 9.16 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.68 – 7.48 (m, 2H), 7.42 – 7.37 (m, 2H), 7.35 – 7.30 (m, 1H), 7.26 – 7.21 (m, 2H), 5.34 (s, 2H), 2.14 (s, 3H). Example 317:

[0053] Step 1: To a stirred solution of methyl-3-hydroxy-2-phenylacrylate (5.00 g, 26.01 mmol) and cyclopropane-1-carboximidamide hydrochloride (4.70 g, 39.02 mmol) in EtOH (60 mL) was added EtONa (4.42 g, 65.03 mmol). The mixture was stirred at room temperature for 16 hr. The reaction mixture was quenched by the addition of saturated NH4Cl aqueous solution (100 mL) and extracted with CH2Cl2 (60 mL x 3). The combined organic layer was washed with brine (60 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by gel chromatography eluted with the PE / EA mixture solution (10% -50%) to give E291-2 (780.00 mg, 3.67 mmol, 14.13% yield) as a yellow solid. LCMS: 213.2 [M+H]+; 97.72%, RT = 1.105 Step 2: To a stirred solution of E291-2 (430.00 mg, 2.03 mmol) in DMF (1 mL) and DME (4 mL) were added LiBr (351.91 mg, 4.05 mmol) and NaH (97.25 mg, 2.43 mmol, 60% purity). After stirred atroom temperature for 30 min, E291-2’ (587.65 mg, 2.03 mmol) was added. The reactiontemperature was then warmed to 70 °C and stirred for another 1 hr until TLC indicate starting material was almost consumed. The mixture was cooled and quenched by the addition of saturated NH4Cl aqueous solution (10 mL). The mixture was extracted with EA (30 mL x 3) and the combined organic layer was washed with brine (30 mL). The mixture was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by gel chromatography eluted with the PE / EA mixture solution (10% to 60%) and pre-HPLC to give Example 317 (305.00 mg, 723.78 μmol, 35.73% yield) as a white solid. LCMS: 422.0 [M+H]+; 98.50%; RT =2.744.1H NMR: (600 MHz, Chloroform-d) δ 9.27 (d, J = 2.0 Hz, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 8.01 (s, 1H), 7.69 – 7.64 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.43 – 7.38 (dd, m, 2H), 7.37 – 7.32 (m, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.74 (s, 2H), 2.29 – 2.22 (m, 1H), 1.30 – 1.22 (m, 2H), 1.11 – 1.13 (m, 2H). Example 318:

[0054] To a stirred solution of methyl-3-hydroxy-2-phenylacrylate (3.50 g, 18.21 mmol) and o- methylisourea hemisulfate (3.36 g, 13.66 mmol) in EtOH (60 mL) was added EtONa (3.10 g, 45.52 mmol). The mixture was stirred at room temperature for 16 hr. The reaction mixture was quenched by the addition of saturated NH4Cl aqueous solution (100 mL). The resultant mixture was extracted with CH2Cl2 (60 mL × 3) and the combined organic layer was washed with brine (60 mL). The mixture was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by gel chromatography eluted with the mixture solution of PE / EA (10%- 50%) to give E292-2 (800.00 mg, 3.96 mmol, 21.73% yield) as a yellow solid. LCMS: 203.2 [M+H]+; 85.36%; RT = 0.985 Step 2:

[0055] To a stirred solution of E292-2 (470.00 mg, 2.32 mmol) in DMF (1 mL) and DME (4 mL) were added LiBr (403.74 mg, 4.65 mmol) and NaH (111.57 mg, 2.79 mmol, 60% purity). After stirredat room temperature for 30 min, E292-2’ (674.20 mg, 2.32 mmol) was added. The reactiontemperature was then warmed to 70 °C and stirred for another 1 hr until LCMS indicated starting material was almost consumed. The mixture was cooled and quenched by addition of saturated NH4Cl (10 mL). The resultant mixture was extracted with EA (30 mL × 3) and the combined organic layer was washed with brine (30 mL). The solution was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by gel chromatography eluted with the mixture solution of PE / EA (10% to 60%) and pre-HPLC to give Example 318 (166.80 mg, 405.48 μmol, 17.45% yield) as a white solid. LCMS: 411.9 [M+H]+; 94.00%; RT = 2.435.1H NMR: (600 MHz, Chloroform-d) δ 9.23 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 8.3, 2.2 Hz, 1H), 7.53 – 7.47 (m, 3H), 7.42 – 7.36 (m, 3H), 7.35 – 7.30 (m, 1H), 6.92 (t, J = 51.7 Hz, 1H), 5.45 (s, 2H), 3.53 (s, 3H). Example 319: Step 1:

[0056] To a solution of methyl 6-methylnicotinate (25 g, 165 mmol) in EtOH (175 mL) was added NH2NH2-H2O (40.6 mL, 827 mmol) at rt. The resulting reaction mixture was stirred at 90 °C for 16 hr. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude residue was stirred with heptanes (100 mL) at rt for 1 hr. The solid obtained was filtered, washed with heptanes (50 mL) and dried under reduced pressure. Compound 1-2 (23.0 g, crude) was obtained as a light yellow solid. LCMS: 152.01 [M+H]+; 98.00%; RT = 0.54.1H NMR: (400 MHz, DMSO-d6) δ 9.87 (br s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 2.4, 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.53 (br s, 2H), 2.51 (s, 3H). Step 2: To a solution of compound 1-2 (12 g, 79.4 mmol) and imidazole (16.2 g, 238 mmol) in DCM (250 mL) was added 2,2-difluoroacetyl difluoroacetate (27.6 mL, 238 mmol) at rt drop wise. The resulting reaction mixture was further stirred at 45 °C for 16 hr. LC-MS showed compound 1-2 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (100 mL) and extracted with DCM (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~30% Ethyl acetate / heptanes gradient). Compound 1-3 (13 g, 61.6 mmol, 75.55% yield) was obtained as a light yellow solid. LCMS: LCMS: 212.08 [M+H]+; 99.00%; RT = 1.321 δ 9.09 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 2.0, 8.0 Hz, 1H), 7.44- 7.50 (m, 2H), 2.60 (s, 3H). Step 2:

[0057] To a solution of compound 1-3 (6.5 g, 30.8 mmol) in DCE (120 mL) were added NBS (5.48 g, 30.8 mmol) and AIBN (2.53 g,15.4 mmol) at rt . The reaction mixture was stirred at 90 °C for 8 hr. LC-MS showed compound 1-3 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (200 mL) and extracted with DCM (200 mL x 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~12% Ethyl acetate / heptanes gradient). Compound 1-4 (2.4, 8.27 mmol, 26.88% yield) was obtained as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 9.19 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 2.4, 8.4 Hz, 1H), 7.82 d, J = 8.0 Hz, 1H), 7.59 (t, J = 51.2 Hz, 1H), 4.82 (s, 2H). Step 3: To a stirred solution of compound 1-5 (415 mg, 2.01 mmol) and compound 1-4 (757 mg, 2.61 mmol) in DMF (10 mL) was added CsF (915 mg, 6.03 mmol) at rt. The reaction mixture was stirred at rt for 16 h. LC-MS showed starting materials were consumed completely and desired mass was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with water (50 mL x 3), brine (70 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was purified by prep HPLC. Compound Example 319 (379 mg, 0.912 mmol, 42.39% yield) was obtained as an off white solid. LCMS: 416.10 [M+H]+; 99.14%; RT = 6.09.1H NMR: (400 MHz, MeOD) δ 9.22 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 8.49 (dd, J = 2.0, 8.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.64-7.67 (m, 1H), 7.52- 7.56 (m, 1H), 7.41-7.50 (m, 2H), 7.11-7.37 (m, 1H), 6.75 (s, 1H), 5.44 (s, 2H). Example 320: Step 1: A mixture of 6-chloropyrimidin-4(3H)-one (2.0 g, 15.3 mmol), (4-chlorophenyl)boronic acid (2.4 g, 15.3 mmol) and Na2CO3(3.25 g, 30.6 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was degassed and purged with N2for 20 min followed by addition of Pd(PPh3)4(885 mg, 0.766 mmol) at rt. The reaction mixture was again purged with N2 for 5 min and further stirred at 100 °C for 16 hr. LC-MS showed starting materials were consumed completely and desired product mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (50 mL) and extracted with 10% MeOH in DCM (50 mL * 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was diluted with Et2O (50 mL) and stirred for 15 min. The solid precipitated was filtered, washed with Et2O (25 mL) and dried under reduced pressure. Compound 3-1 (160 mg, 0.774 mmol, 5.05% yield) was obtained as an off white solid. LCMS: 207.00 [M+H]+; 96.05%; RT = 1.43.1H NMR: (400 MHz, DMSO-d6) δ 12.59 (br s, 1H), 8.29 (s, 1H), 8.08 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 6.93 (s.1H). Step 2:

[0058] To a s solution of compound 3-1 (620 mg, 3 mmol) and compound 1-4 (1.13 g, 3.9 mmol) in DMF (10 mL) was added CsF (1.37 g, 9 mmol) at rt. The reaction mixture was stirred at rt for 16 hr. LC-MS showed starting materials were consumed completely and desired product mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with water (50 mL * 3), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was purified by prep HPLC. Compound Example 320 (265 mg, 0.637 mmol, 21.24% yield) was obtained as an off white solid. LCMS: 416.3 [M+H]+; 99.77%; RT = 6.03.1 2.0 Hz, 1H), 8.77 (s, 1H), 8.46 (dd, J = 2.4, 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.43-7.71 (m, 4H), 7.06 (s, 1H), 5.38 (s, 2H). Example 321:

[0059] Step 1: A mixture of 6-chloropyrimidin-4(3H)-one (2.0 g, 15.3 mmol), (3-chlorophenyl)boronic acid (2.4 g, 15.3 mmol) and Na2CO3 (3.25 g, , 30.6 mmol) in 1,2-dimethoxyethane (28 mL) and water (12 mL) was degassed and purged with N2for 20 min followed by addition of Pd(PPh3)4(885 mg, 0.766 mmol) at rt. The reaction mixture was again purged with N2for 5 min and further stirred at 100 °C for 16 hr. LC-MS showed starting materials were consumed completely and desired product mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (50 mL) and extracted with 10% MeOH in DCM (50 mL * 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was diluted with Et2O (50 mL) and stirred for 15 min. The solid precipitated was filtered, washed with Et2O (25 mL) and dried under reduced pressure. Compound 2-1 (450 mg, crude) was obtained as an off white solid. LCMS: 207.06 [M+H]+: 54.15%; RT = 1.45 Step 2: To a solution of compound 2-1 (360 mg, 1.74 mmol) and compound 1-4 (657 mg, 2.26 mmol) in DMF (10 mL) was added CsF (794 mg, 5.23 mmol) at rt. The reaction mixture was stirred at rt for 16 hr. LC-MS showed starting materials were consumed completely and desired product mass was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with water (50 mL * 3), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was purified by prep HPLC. Compound Example 321 (253 mg, 0.608 mmol, 34.93% yield) was obtained as an off white solid. LCMS: 416.3 [M+H]+; 99.30%; RT = 6.02.1H NMR: (400 MHz, DMSO-d6) δ 9.14 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.46 (dd, J = 2.0, 8.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.44-7.72 (m, 4H), 7.12 (s, 1H), 5.39 (s, 2H). Example 322: To a solution of ethyl 6-methylnicotinate (5.0 g, 30.3 mmol) in EtOH (50 mL) was added NH2NH2-H2O (7.58g, 151 mmol) at rt. The resulting reaction mixture was stirred at 90 °C for 12 hr. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude residue was stirred in cold Et2O (100 mL) at rt for 15 min. The solid obtained was filtered and dried under reduced pressure. Compound 1-2 (4.6 g, crude) was obtained as an off white solid. LCMS: 152.01 [M+H]+; 98.00%; RT = 0.54.1H NMR: (400 MHz, DMSO-d6) δ 9.87 (br s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 2.4, 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.53 (br s, 2H), 2.51 (s, 3H). Step 2: To a solution of compound 1-2 (4.5 g, 29.8 mmol) and imidazole (3.04 g, 44.7 mmol) in DCM (80 mL) was added 2,2-difluoroacetyl difluoroacetate (10.4 g, 59.5 mmol) at rt drop wise. The resulting reaction mixture was further stirred at 50 °C for 8 hr. LC-MS showed compound 1-2 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (100 mL) and extracted with DCM (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~40% Ethyl acetate / heptanes gradient). Compound 1-3 (6.4 g, 29.7 mmol, quantitative) was obtained as an off white solid. LCMS: LCMS: 212.08 [M+H]+; 99.00%; RT = 1.32.1H NMR: (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 2.0, 8.0 Hz, 1H), 7.44-7.50 (m, 2H), 2.60 (s, 3H). Step 3:

[0060] To a solution of compound 1-3 (6.39 g, 30.3 mmol) in DCM (200 mL) were added NBS (5.49 g, 30.3 mmol) and AIBN (497 mg, 3.03 mmol) at 0oC . The reaction mixture was stirred at 50 °C for 8 hr. LC-MS showed compound 1-3 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with ice-cold water (200 mL) and extracted with DCM (200 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~20% Ethyl acetate / heptanes gradient). Compound 1-4 (2.4g, 8.11 mmol, 26.79% yield) was obtained as an off white solid.1.4 Hz, 1H), 7.82 To a stirred solution of compound 1-4 (2.0 g, 6.89 mmol) in acetone (50 mL) was added KOAc (11.9 g, 121 mmol) at rt under inert atmosphere. The reaction mixture was stirred at 50 °C for 8 hr. LC-MS showed compound 1-4 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~20% Ethyl acetate / heptanes gradient). Compound 1-5 (2.4g, 8.11 mmol, 14.73% yield) was obtained as a brown solid LCMS: LCMS: 270.12 [M+H]+; 94.84%; RT = 1.45.1H NMR: (400 MHz, DMSO-d6) δ 9.19 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 2.4, 8.2 Hz, 2H), 7.58 (t, J = 51.2 Hz, 1H), 5.26 (s, 2H), 2.16 (s, 3H). Step 5: To a stirred solution of compound 1-5 (1.8 g, 6.69 mmol) in MeOH (20 mL) was added K2CO3 (2.77 g, 20.1 mmol) at rt under inert atmosphere. The reaction mixture was further stirred at rt for 2h hr. LC-MS showed compound 1-5 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~20% Ethyl acetate / heptanes gradient). Compound 1-6 (1.0 g, 4.4 mmol, 65.84% yield) was obtained as an off white solid. LCMS: LCMS: 228.15 [M+H]+; 99.10%; RT = 1.22.1H NMR: (400 MHz, DMSO-d6) δ 9.13 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 2.4, 8.2 Hz, 1H), 7.73 = 8.2H z, 1H), 7.58 (t, J = 51.2 Hz, 1H), 5.67 (d, J = 12 H z, 1H), 4.68 6.0 Hz, 2H). Step 6: To a solution of 2-methyl-6-phenylpyrimidin-4(3H)-one (1.0 g, 4.4 mmol) and compound 1-6 (656 mg, 4.4 mmol) in DCM (15 mL) was added PPh3(1.73g, 6.6 mmol) followed by addition of DIAD (1.34 g, 6.6 mmol) dropwise at 0oC. The reaction mixture was further stirred at stirred 50oC for 0.5 h. LC-MS showed compound 1-6 was consumed completely and desired product mass was detected. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure to afford crude residue. The crude residue was purified by purified through RP-HPLC purification using eluent as 5mM Ammonium Bicarbonate in Water / Acetonitrile and column using X Bridge Shield RP18 (19*250) 10µ). Compound Example 322 (306 mg 0.774 mmol, 17.58% yield) was obtained as an off white solid. LCMS: LCMS: 396.18 [M+H]+; 98.31%; RT = 7.92.1H NMR: (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 2.0, 8.0 Hz, 1H), 8.10 (dd, J = 2.0, 6.8 Hz, 2H), 7.63 (t, J = 51.2 Hz, 1H), 7.49-7.68 (m, 4H), 6.93 (s, 1H), 5.50 (s, 2H), 2.59 (s, 3H). Example 323:

[0061] To a solution of methyl 6-methylnicotinate (25 g, 165 mmol) in EtOH (175 mL) was added NH2NH2-H2O (40.6 mL, 827 mmol) at rt. The resulting reaction mixture was stirred at 90 °C for 16 hr. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude residue was stirred with heptanes (100 mL) at rt for 1 hr. The solid obtained was filtered, washed with heptanes (50 mL) and dried under reduced pressure. Compound 1-2 (23.0 g, crude) was obtained as a light yellow solid. LCMS: 152.01 [M+H]+; 98.00%; RT = 0.54.1H NMR: (400 MHz, DMSO-d6) δ 9.87 (br s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 2.4, 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.53 (br s, 2H), 2.51 (s, 3H). Step 2: To a solution of compound 1-2 (12 g, 79.4 mmol) and imidazole (16.2 g, 238 mmol) in DCM (250 mL) was added 2,2-difluoroacetyl difluoroacetate (27.6 mL, 238 mmol) at rt drop wise. The resulting reaction mixture was further stirred at 45 °C for 16 hr. LC-MS showed compound 1-2 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (100 mL) and extracted with DCM (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~30% Ethyl acetate / heptanes gradient). Compound 1-3 (13 g, 61.6 mmol, 75.55% yield) was obtained as a light yellow solid. LCMS: LCMS: 212.08 [M+H]+; 99.00%; RT = 1.32.1H NMR: (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 2.0, 8.0 Hz, 1H), 7.44-7.50 (m, 2H), 2.60 (s, 3H). Step 3:

[0062] To a solution of compound 1-3 (6.5 g, 30.8 mmol) in DCE (120 mL) were added NBS (5.48 g, 30.8 mmol) and AIBN (2.53 g,15.4 mmol) at rt . The reaction mixture was stirred at 90 °C for 8 hr. LC-MS showed compound 1-3 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (200 mL) and extracted with DCM (200 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~12% Ethyl acetate / heptanes gradient). Compound 1-4 (2.4, 8.27 mmol, 26.88% yield) was obtained as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 9.19 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 2.4, 8.4 Hz, 1H), 7.82 d, J = 8.0 Hz, 1H), 7.61 (t, J = 51.2 Hz, 1H), 4.82 (s, 2H). Step 4: To a solution of compound 1-4 (2.4 g, 8.27 mmol) and 6-methyl-2-(methylthio)-4(1H)- pyrimidinone (1.29 g, 8.27 mmol) in ACN (50 mL) were added K2CO3(3.43 g, 24.8 mmol) and KI (137 mg, 0.827 mmol) at rt. The reaction mixture was stirred at 70 °C for 16 hr. The crude LC- MS showed formation of compound 1-5 (~14%). The reaction mixture was allowed to cool to rt, diluted with water (50 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~50% Ethyl acetate / heptanes gradient). Compound 1-5 (560 mg, 1.53 mmol, 18.52% yield) was obtained as a colorless waxy solid. LCMS: 366.12 [M+H]+; 89.61%; RT = 1.53. Step 5: A solution of compound 1-5 (550 mg, 1.51 mmol) and phenylboronic acid (551 mg, 4.52 mmol) in THF (30 mL) was degassed and purged with N2for 10 min. followed by addition of CuTC (574 mg, 3.01 mmol) and Pd(PPh3)4(87 mg, 0.076.mmol) to it at rt. The reaction mixture was again purged with N2 for 5 min and further stirred at 75 °C for 16 hr. LC-MS showed compound 1-5 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by prep HPLC using ammonium bicarbonate buffer. Compound Example 323 (410 mg, 1.04 mmol, 68.89% yield) was obtained as an off white solid. LCMS: 396.18 [M+H]+; 99.49%; RT = 5.33.1 δ 9.09 (d, J = 1.6 Hz, 1H), 8.32 (dd, J = 2.0, 8 Hz, 1H), 7.36-7.70 (m, 7H), 6.34 (s, 1H), 5.21 (s, 2H) 2.28 (s, 3H). Example 324: Step 1:

[0063] To a stirred solution of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 32 mmol) and thiourea (2.44 g, 32 mmol) in EtOH (40 mL) was added KOH (1.8 g, 32 mmol) at rt. The reaction mixture was stirred at 90 °C for 16 hr. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt. The solid precipitation was observed. The precipitated solid was filtered, washed with EtOH (50 mL) and dried under reduced pressure. Compound 2-1 (1.5g, crude) was obtained as an off white solid. LCMS: 169.01 [M+H]+; 99.23%; RT = 0.72.1 ) δ 9.99 (s, 1H), 5.39 (br s, 1H), 1.47-1.55 (m, 1H), 0.77-0.83 (m, 2H), 0.66-0.70 (m, 2H), Step 2: To a solution of Compound 2-1 (1.5 g, 8.92 mmol) in EtOH (10 mL) and H2O (10 mL) were added NaOH (1.07 g, 26.8 mmol) and dimethyl sulphate (1.35 g , 10.7 mmol) at rt. The reaction mixture was further stirred at rt for 5 hr. LC-MS showed compound 2-1 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure, diluted with H2O (25 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 2-2 (1.2g, crude) was obtained as a white solid. LCMS: 183.01 [M+H]+; 91.47%; RT = 1.33 Step 3: To a solution of compound 1-4 (1.91 g, 6.58 mmol) and compound 2-2 (1.0 g, 5.49 mmol) in ACN (20 mL) were added K2CO3 (2.27 g, 16.5 mmol) and KI (91.1 mg, 0.549 mmol) at rt. The reaction mixture was stirred at 70 °C for 16 hr. LC-MS showed starting materials was completely consumed. The reaction mixture was allowed to cool to rt, diluted with H2O (50 mL) and extracted with EtOAC (50 mL * 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~50% Ethyl acetate / heptanes gradient). Compound 2-3 (900 mg, 2.3 mmol, 41.91% yield) was obtained as a light yellow solid. LCMS: 391.99 [M+H]+; 94.42%; RT = 1.75.1H NMR: (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 2.0, 8.0 Hz, 1H), 7.45-7.71 (m, 2H), 6.24 (s, 1H), 5.39 (s, 2H), 2.44 (s, 3H), 1.88-1.96 (m, 1H), 1.02-1.09 (m, 2H), 0.84-0.98 (m, 2H). Step 4:

[0064] A solution of compound 2-3 (900 mg, 2.3 mmol) and phenylboronic acid (841 mg, 6.9 mmol) in THF (25 mL) was degassed and purged with N2for 10 min followed by addition of CuTC (877 mg, 4.6 mmol) and Pd(PPh3)4 (133 mg, 0.115 mmol) in to it at rt. The reaction mixture was again purged with N2for 5 min and further stirred at 70 °C for 16 hr. LC-MS showed compound 2-3 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (70mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was purified by prep HPLC using ammonium bicarbonate buffer. Compound Example 324 (425 mg, 1.01 mmol, 43.86% yield) was obtained as an off white solid. LCMS: 422.21 [M+H]+; 98.88%; RT = 5.85.1H NMR: (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 2.4, 8.4 Hz, 1H), 7.34-7.70 (m, 7H), 6.42 (s, 1H), 5.19 (s, 2H), 1.93-1.98 (m, 1H), 0.93-0.99 (m, 4H). Example 325:

[0065] Step 1: To a mixture of 3,5-difluoro-4-methylbenzoic acid (5.0 g, 29 mmol) in DCM (70 mL) and DMF (0.3 mL) was added oxalyl dichloride (6.23 mL, 72.6 mmol) at 0 °C dropwise. The reaction mixture was allowed to warm to rt and further stirred at 45 °C for 3h. TLC showed starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to afford crude residue. The crude residue obtained above was dissolved in DCM (40 mL) and added to a mixture of tert-butyl hydrazinecarboxylate (4.61 g, 34.9 mmol) and Et3N (12.1 mL, 87.1 mmol) in DCM (70 mL) at 0 °C dropwise. The resulting reaction mixture was further stirred at 0oC-rt for 16 h. LC-MS showed starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure, diluted with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was diluted with pentane (70 mL) and stirred for 0.5 h. The precipitated solid was filtered, washed with with pentane (30 mL * 2) and dried under reduced pressure. Compound 3-1 (7.7 g, crude) was obtained as an off white solid. LCMS: 285.19 [M-H]+; 99.74%; RT = 1.67.1 10.34 (br s, 1H), 9.01 (br s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.43 (s, 9H). Step 2: To a solution of compound 3-1 (7.7 g, 26.9 mmol) in DCM (50 mL) was added 4.0 N HCl in dioxane (50 mL) at rt. The reaction mixture was further stirred at rt for 16 h. LC-MS showed compound 3-1 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to afford residue. Compound 3-2 (4.8 g, crude) was obtained as an off white solid. LCMS: 185.13 [M-H]+; 95.69%; RT = 1.24.1H NMR: (400 MHz, DMSO-d6) δ 11.92 (br s, 1H), 10.44 (br s, 2H), 7.67 (d, J = 7.2 Hz, 2H), 2.23 (s, 3H). Step 3: To a stirred solution of compound 3-2 (4.8 g, 25.8 mmol) in DCM (200 mL) were added imidazole (5.27 g, 77.4 mmol) and 2,2-difluoroacetic anhydride (8.69 mL, 77.4 mmol) at 0 °C dropwise. The reaction mixture allowed to warm to rt and further stirred at 45 °C for 16 hr. LC-MS showed compound 3-2 was consumed completely and desired mass was detected. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~30% Ethyl acetate / heptanes gradient). Compound 3-3 (5.8 g, 23.6 mmol, 91.38% yield) was obtained as a light-yellow solid LCMS: 246.98 [M+H]+; 99.45%; RT = 1.87.1H NMR: (400 MHz, DMSO-d6) δ 7.74-7.78 (m, 2H), 7.56 (t, J = 51.2 Hz, 1H), 2.26 (s, 3H). Step 4: To a solution of compound 3-3 (5.8 g, 23.6 mmol) in DCE (200 mL) were added NBS (4.19 g, 23.6 mmol) and AIBN (1.55 g, 9.42 mmol) at rt. The reaction mixture was stirred at 100 °C for 8 hr. LC-MS showed compound 3-3 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / heptanes gradient). Compound 3-4 (4.5 g, 13.8 mmol, 58.76% yield) was obtained as an off white solid.1H). To a solution of compound 3-4 (4.54 g, 14 mmol) and 2-(methylthio)-4(1H)-pyrimidinone (1.6 g, 11.3 mmol) in ACN (70 mL) were added K2CO3 (4.67, 33.8 mmol) and KI (187 mg, 1.13 mmol) at rt. The reaction mixture was stirred at 80 °C for 16 h. LC-MS showed starting materials were completely consumed. The reaction mixture was allowed to cool to rt, diluted with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~50% Ethyl acetate / heptanes gradient). Compound 3-5 (210 mg, 11.3 mmol, 4.83% yield) was obtained as a colorless waxy solid. LCMS: 387.12 [M+H]+; 90.83%; RT = 1.73.1H NMR: (400 MHz, DMSO-d6) δ 7.88 (d, J = 6.4 Hz, 1H), 7.77-7.83 (m, 2H), 7.43-7.69 (m, 1H), 6.25 (d, J = 6.4 Hz, 1H), 5.41 (s, 2H), 2.54 (s, 3H). Step 6: A solution of compound 3-5 (210 mg, 0.544 mmol) and phenylboronic acid (199 mg, 1.63 mmol) in THF (15 mL) was degassed and purged with N2for 10 min followed by addition of CuTC (207 mg, 1.09 mmol) and Pd(PPh3)4 (31.4 mg, 0.027 mmol) to it at rt. The reaction mixture was again purged with N2 for 5 min and further stirred at 70 °C for 16 hr. LC-MS showed compound 3-5 was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to rt, diluted with water (20 mL) and extracted with EtOAc (20 mL * 3). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude residue. The crude was purified by prep HPLC using ammonium bicarbonate buffer. Compound Example 325 (178 mg, 0.428 mmol, 78.65% yield) was obtained as an off white solid. LCMS: 417.40 [M+H]+; 99.70%; RT = 5.88.1H NMR: (400 MHz, DMSO-d6) δ 8.01 (d, J = 6.4 Hz, 1H), 7.40-7.66 (m, 8H), 6.44 (d, J = 6.4 Hz, 1H), 5.32 (s, 2H). Example 326, Example 327, and Example 328:

[0066] Step 1:

[0067] To a stirred solution of 4-bromopyridin-2(1H)-one 1 (10 g, 57.8 mmol) and in ACN (200 mL) was added 2-(6-(bromomethyl) pyridin-3-yl)-5-(difluoro methyl)-1,3,4-oxadiazole 1-2 (16.71 g, 57.8 mmol) and the reaction mixture was stirred for at 90 °C 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate (100 mL). The filterate was concentrated under reduced pressure to get the crude product. The crude product was purified by the GRACE FLASH column chromatography and eluted with 15% ethyl acetate in pet-ether to get the 4-bromo-1-((5-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)pyridin-2(1H)-one 1-3 (6 g, 45.4%) as a pale yellow solid. LCMS: 44.03%, m / z [M+H]+= 383.20. LCMS: 44.03%, m / z [M+H]+= 383.20. RT = 1.46 Example 326:

[0068] To a stirred solution of 4-bromo-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)pyridin-2(1H)-one 1-3 (2.0 g, 5.23 mmol) in 1,4-dioaxne (20 mL) was added 2- (tributylstannyl)pyridine 1-4 (2.31 g, 6.28 mmol) at rt. The reaction mixture was de-gassed by argon for 10 mins. Then added PdCl2(PPh3)2(0.36 g, 0.52 mmol) into the reaction mixture and stirred for 4 h at 90 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite pad, washed with ethyl acetate (80 mL). The filterate layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified reverse phase prep HPLC (X-SELECT CSH PHENYL HEXYL (250*19), 5µm Mobile phase (A):- 10mM NH₄HCO₃, Mobile phase (B): - 100% ACN Gradient (T / % of B) to get 1'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-[2,4'-bipyridin]-2'(1'H)-one (Example 326) (0.24 g, 12%) as a pale-yellow solid. LCMS: 97.66%, m / z 382.28 [M+H]+; HPLC Purity: 98.17%. Example 326:1H NMR (400 MHz, DMSO-d6) δ: 9.15 (d, J = 1.6 Hz, 1H), 8.74–8.72 (m, 1H ), 8.42 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.98–7.92 (m, 2H), 7.70–7.44 (m, 3H), 7.13 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.0 Hz, 7.2 Hz, 1H), 5.36 (s, 2H). Example 327:

[0069] To stirred solution of 4-bromo-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)pyridin-2(1H)-one 1-3 (2.0 g, 5.23 mmol) in 1,4-dioaxne (20 mL) and water (05 mL) were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1-5 (1.07 g, 5.23 mmol), potassium phosphate tribasic (2.21 g, 104.7 mmol), and X-Phos (0.49 g, 1.04 mmol) at rt. Then reaction mixture was de-gassed by argon for 10 mins. Then Pd2(dba)3 (0.47 g, 0.52 mmol) was added into the reaction mixture and stirred for 12 h at 100 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite pad, washed with ethyl acetate (80 mL). The filtrate layer was dried over anhydrous sodium sulphate and concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by the GRACE FLASH column chromatography and eluted with 5% methanol in DCM to get 1'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-[3,4'-bipyridin]-2'(1'H)-one (Example 327) (0.115 g, 5%) as an off white solid. LCMS: 95.68%, m / z 382.2 [M+H]+; HPLC Purity: 95.76%. Example 327:1H NMR (400 MHz, DMSO-d6) δ: 9.15 (d d, J = 2.0 Hz, 0.8 Hz, 1H), 8.98 (d, J = 1.6 Hz, 1H ), 8.67 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.43 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 8.19–8.16 (m, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.70– 7.44 (m, 3H), 6.83 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 5.36 (s, 2H). Example 328:

[0070] To stirred solution of 4-bromo-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyridin-2- yl)methyl)pyridin-2(1H)-one 3 (2.0 g, 5.23 mmol) in 1,4-dioaxne (20 mL) was added 4- (tributylstannyl)pyridine 6 (2.31 g, 6.28 mmol) at rt. The reaction mixture was de-gassed by argon for 10 mins. Then PdCl2(PPh3)2(0.36 g, 0.52 mmol) was added into the reaction mixture and stirred for 4 h at 90 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite pad, washed with ethyl acetate (80 mL). The filtrate layer was concentrated and dried under reduced pressure to get the crude compound. The crude compound was purified by the GRACE FLASH column chromatography and eluted with 5% methanol in DCM to get 1-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methyl)-[4,4'-bipyridin]-2(1H)-one (Example 328) (0.13 g, 6%) as a pale-yellow solid. LCMS: 95.07%, m / z [M+H]+= 382.28;HPLC Purity: 95.30%. Example 328:1H NMR (400 MHz, DMSO-d6) δ: 9.15 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 6.0 Hz, 2H), 8.43 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 6.0 Hz, 2H), 7.69–7.44 (m, 2H), 6.89 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 5.37 (s, 2H). Example 329, Example 330, and Example 331:

[0071] Step 1:

[0072] To a stirred solution of 6-chloropyrimidin-4(3H)-one 1 (2.0 g, 15.32 mmol) in acetonitrile (40 mL) was added cesium carbonate (5.9 g, 22.06 mmol) followed by 2-(6-(bromomethyl) pyridin-3-yl)- 5-(difluoro methyl)-1,3,4-oxadiazole 1-2 (4.4 g, 15.32 mmol) at rt. The resulting reaction mixture was heated at 85 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude compound. The crude compound was purified by using flash column chromatography with 45% ethyl acetate in pet ether as an eluent to get 6-chloro-3- ((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl) pyrimidin-4(3H)-one 1-3 (3.2 g, 61.53%) as off white solid. LCMS: 82.15%; m / z [M+H]+= 340.08. The structure was confirmed by NOE and HSQC. LCMS: 82%, m / z [M+H]+= 340.08. RT = 0.96 Example 329:

[0073] To a stirred solution of 6-chloro-3-((5-(5-(difluoro methyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) pyrimidin-4(3H)-one 1-3 (1.1 g, 3.23 mmol) in 1,4-dioxane (20 mL) under argon atmosphere was added 4-(tributyltin) pyrimidine 1-4 (1.43 g, 3.87 mmol) and bis(triphenylphosphine)palladium chloride (0.22 g, 0.323 mmol) in a sealed tube. After addition, the reaction mixture was stirred at 120 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude as brown liquid. The crude was purified by using reverse phase prep HPLC to get 1-((5-(5-(difluoro methyl)-1,3,4- oxadiazol-2-yl) pyridin-2-yl) methyl)-[4,4'-bipyrimidin]-6(1H)-one (Example 329) (0.176 g, 14.66 %) as off white solid. HPLC: 99.45%. Example 329:1H NMR (400 MHz, DMSO-d6) δ: 9.34 (d, J =1.2 Hz, 1H), 9.13 (d, J =1.6 Hz, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.88 (s, 1H), 8.45 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 8.30 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 51.2 Hz, 1H), 7.38 (s, 1H), 5.43 (s, 2H). Step 2:

[0074] To a stirred solution of 6-chloro-3-((5-(5-(difluoro methyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) pyrimidin-4(3H)-one 1-3 (1.0 g, 2.94 mmol) in 1,4-dioxane (20 mL) under argon atmosphere in a sealed tube were added 2-(tributyltin) pyrazine 1-5 (1.3 g, 3.52 mmol) and bis(triphenylphosphine)palladium chloride (0.22 g, 0.323 mmol). After addition, the reaction mixture was stirred at 120 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude compound as brown liquid. The crude compound was purified by using reverse phase prep HPLC to get 3-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(pyrazin-2-yl)pyrimidin-4(3H)-one (Example 330) (169 mg, 15.0 %) as an off white solid. LCMS: 99.12%, m / z 384.151 HPLC purity: 99.12%. Example 330: H NMR (400 MHz, DMSO-d6) δ: 9.46 (d, J = 1.2 Hz, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.87 (s, 1H), 8.82–8.80 (m, 2H), 8.45 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.73–7.44 (m, 2H), 7.27 (s, 1H), 5.43 (s, 2H). Example 331:

[0075] To a stirred solution of 6-chloro-3-((5-(5-(difluoro methyl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) pyrimidin-4(3H)-one 3 (1.1 g, 3.23 mmol) in 1,4-dioxane (20 mL) under argon atmosphere wereadded 5-(tributyltin) pyrimidine 6 (1.43 g, 3.87 mmol) and bis(triphenylphosphine)palladium chloride (0.22 g, 0.323 mmol) in a sealed tube. After the addition, the reaction mixture was stirred at 120 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude compound as brown liquid. The crude compound was purified by using reverse phase prep HPLC to get 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)-[4,5'-bipyrimidin]-6(1H)-one (Example 331) (0.144 g, 11.66 %) as an off white solid LCMS: 99.45%; m / z [M+H]+= 384.25. HPLC: 99.71%; Example 331:1H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 2H), 9.31 (s, 1H), 9.14 (d, J = 1.6 Hz, 1H), 8.85 (s, 1H), 8.45 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.73–7.44 (m, 2H), 7.29 (s, 1H), 5.41 (s, 2H). Example 332, Example 333, and Example 334

[0076] To a stirred solution of 5-bromo-2-methylpyrimidin-4(3H)-one 1 (2 g, 10.58 mmol) and 2-(6- (bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 1-2 (3.06 g, 0.58 mmol) in acetonitrile (20 mL) was added cesium carbonate (5.17 g, 15.8 mmol) at 25°C. Then the reaction mixture was stirred at 85 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated and diluted with ice water (50 mL) and extracted with ethyl acetate (2 x 75 mL). Organic layer was concentrated and dried under reduced pressure to get crude compound as yellowish semisolid. The obtained crude compound was purified by 100-200 silica gel column chromatography by eluting the product in 50% ethyl acetate in pet ether to get 5-bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)-2-methylpyrimidin-4(3H)-one 1-3 (3.8 g, 90.19%) as brownish solid. LCMS: 83%; m / z [M+H]+ 399.21. RT-0.98 Example 332: To a stirred solution of 5-bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-2-methylpyrimidin-4(3H)-one 1-3 (1 g, 2.51 mmol) and 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1-4 (1.100 g, 5.03 mmol) in 1,4-dioxane (10 mL) and water (3.0 mL) was added cesium carbonate (2.45 g, 7.53 mmol) and degassed for 10 min by nitrogen gas at rt. Then PdCl2(dppf). DCM (0.092 g, 0.126 mmol) was added into the reaction mixture and again degassed for 5 min. Then the resulting reaction mixture was heated at 100 °C for 6 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filter on celite pad and pad washed with ethyl acetate (50 mL). Filtrate was diluted with ice water (50 mL) and extracted with ethyl acetate (3 x 50 mL). Organic layer was dried and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by 100-200 silica gel column chromatography by eluting the product in 70% ethyl acetate in pet ether to get a compound as brownish semisolid. This compound was submitted to reverse phase prep-HPLC to get 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)-2-methyl-5-(2-methylpyridin-3-yl)pyrimidin-4(3H)-one (Example 332) (43 mg, 4.17%), as an off white solid. LCMS: 98.10%, m / z [M+H]+= 411.30. HPLC Purity: 97.83%; Example 332;1H NMR (400 MHz, DMSO-d6) δ: 9.13 (d, J = 1.6 Hz, 1H), 8.46–8.43 (m, 1H), 7.95 (s, 1H), 7.71–7.44 (m, 3H), 7.25 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 5.55 (s, 2H), 2.59 (s, 3H), 2.30 (s, 3H), 3.31 (s, 3H). Example 333: To a stirred solution of 5-bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-2-methylpyrimidin-4(3H)-one 1-3 (0.50 g, 1.25 mmol) and (3-methylpyridin-4- yl)boronic acid 5 (343.9 mg, 2.51 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL) was added caesium carbonate (1.22 g, 3.76 mmol) and degassed for 10 min by nitrogen gas at rt. Then PdCl2(dppf). DCM (45.94 mg, 0.063 mmol) was added into the reaction mixture and again degassed for 5 min. Then the resulting reaction mixture was heated at 100 °C for 6 h. Progress of the reaction monitored by TLC and LCMS. After completion of the reaction, reaction mixture was filter on celite pad and pad washed with ethyl acetate (50 mL). Filtrate was dilute with ice water (30 mL) and extracted with ethyl acetate (3 x 50 mL). Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by reverse phase prep-HPLC to get a compound 3-((5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2-methyl-5-(3-methylpyridin-4-yl)pyrimidin-4(3H)- one (Example 333) (235 mg, 45.60%) as a white solid. LC-MS: 97.80%, m / z [M+H]+= 411.30. HPLC Purity: 97.38%; Example 333:1H NMR (400 MHz, DMSO-d6) δ: 9.13 (d, J = 1.6 Hz, 1H), 8.46–8.40 (m, 3H), 7.96 (s, 1H), 7.72–7.44 (m, 2H), 7.22 (d, J = 4.8 Hz, 1H), 5.55 (s, 2H), 2.59 (s, 3H), 2.12 (s, 3H). Example 334: To a stirred solution of 5-bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2- yl)methyl)-2-methylpyrimidin-4(3H)-one 3 (0.50 g, 1.25 mmol) and o-tolyl boronic acid 6 (341.45 mg, 2.512 mmol) in 1,4-dioxane (5.0 mL) and water (1.5 mL) was added cesium carbonate (1.227 g, 3.76 mmol) and degassed for 10 min by nitrogen gas. Then PdCl2(dppf). DCM (45.94 mg, 0.063 mmol) was added into the reaction mixture and again degassed for 5 min. Then ...

Claims

CLAIMS 1. A compound of Formula (VI):or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1is N or CR1or CR2; Y1 is N, N+-O-, S, O, CR3, or CH; Y2is N, N+-O-, S, O, or CR3; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or one instance of R1 and one instance of R2 are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3 is H or halogen; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturatedheterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

2. A compound of Formula (VI’):or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: n is 0 or 1; X1 is N or CR1; Y1 is N, N+-O-, S, O, or CR3; Y2is N, N+-O-, S, O, or CR3; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted phenyl, and 5-6 membered heteroaryl wherein heteroatoms in said heteroaryl are N and optionally substituted C3-C6 cycloalkyl; or R1 and R2 are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is H or halogen; andR is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

3. The compound of claim 1 or 2, wherein Y1is N.

4. The compound of claim 1 or 2, wherein Y1 is CR3.

5. The compound of claim 3, wherein Y1is CH.

6. The compound of claim 1 or 2, wherein X1 is N.

7. The compound of any one of claims 1-6, wherein X1is CR3.

8. The compound of claim 7, wherein X1 is CH.

9. The compound of claim 1 or 2, wherein n is 0.

10. , The compound of claim 9, whereinY2 is N, O, or S.

11. The compound of claim 10, wherein Y2 is N.

12. The compound of claim 10, wherein Y2is O.

13. The compound of claim 10, wherein Y2 is S.

14. The compound of claim 9, whereinY1is N, O, or S.

15. The compound of claim 14, wherein Y1 is N.

16. The compound of claim 10, wherein Y1 is O.

17. The compound of claim 10, wherein Y1is S.

18. The compound of claim 1 or 2, wherein when n is 1.

19. The compound of claim 18, wherein Y2is CR1.

20. The compound of claim 19, wherein Y2 is CH.

21. The compound of any one of claims 1-20, wherein R3is H.

22. The compound of any one of claims 1-20, wherein R3is halogen.

23. The compound of claim 22, wherein R3 is F.

24. The compound of any one of claims 1-23, wherein R1or R2are independently selected from the group consisting of H, methyl, optionally substituted phenyl, pyridine, pyrimidine, and cyclopropyl.

25. The compound of claim 24, wherein R1or R2are independently H or methyl.

26. The compound of claim 24, wherein at least one of R1 or R2 is optionally substituted phenyl.

27. The compound of claim 24, wherein at least one of R1or R2is phenyl-CF3.

28. The compound of any one of claims 1-23, wherein R1 or R2 is -C(O)OH or -C(O)NH2.

29. The compound of any one of claims 1-23, wherein R1or R2is -CH3,-CH2CH3, isopropyl, -30. The compound of any one of claims 1-23, wherein R1or R2is optionally substituted phenyl.

32. The compound of claim 30, wherein R1 or R2 is phenyl.

33. The compound of any one of claims 1-23, wherein R1 or R2 is -OH, -OCH3, -OCF3, -34. The compound of any one of claims 1-23, wherein R1 or R2 is -NH2 or -N(CH3)2.

35. The compound of any one of claims 1-23, wherein R1or R2is optionally substituted azetidine.

36. The compound of claim 35, wherein37. The compound of claim 35, wherein R1 or R2 is azetidine..

39. The compound of any one of claims 1-23, wherein R1or R2is optionally substituted pyridine.

40. The compound of claim 39, wherein.

41. The compound of claim 39, wherein R1or R2is pyridine.

42. The compound of claim 39, wherein R1 or R2 is.

43. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted pyrimidine.

44. The compound of claim 43, wherein R1 or R2 is is pyrimidine.

45. The compound of claim 43, wherein R1 or R2 is46. The compound of any one of claims 1-23, wherein R1 or R2 is halogen.

47. The compound of claim 46, wherein R1or R2is Cl.

48. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted piperidine.

49. The compound of claim 48, wherein50. The compound of claim 48, wherein R1 or R2 is is piperidine.

51. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted piperazine.

52. The compound of claim 51, wherein R53. The compound of claim 51, wherein R1or R2is is piperazine.

54. The compound of claim 51, wherein R1 or R2 is .

55. The compound of any one of claims 1-23, wherein R1or R2is optionally substituted morpholine.

56. The compound of claim 55, wherein R1or R2is morpholine.

57. The compound of claim 55, wherein.

58. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted thiomorpholine.

59. The compound of claim 58, wherein.

60. The compound of claim 58, wherein R1or R2is thiomorpholine.

61. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted oxetane.

62. The compound of claim 61, wherein R1or R2is oxetane.

63. The compound of claim 61, wherein R1or R2is.

64. The compound of any one of claims 1-23, wherein R1or R2is optionally substituted pyridazine.

65. The compound of claim 64, wherein R1or R2is pyridazine.

66. The compound of any one of claim 64, wherein.

67. The compound of any one of claims 1-23, wherein R1 or R2 is optionally substituted pyrazine.

68. The compound of claim 67, wherein R1or R2is pyrazine.

69. The compound of claim 67, wherein R1 or R2 is is.

70. The compound of any one of claims 1-23, wherein at least one of R1or R2is pyridine.

71. The compound of any one of claims 1-23, wherein at least one of R1 or R2 is pyrimidine.

72. The compound of any one of claims 1-23, wherein at least one of R1 or R2 is cyclopropyl.

73. A compound selected from the group consisting of:or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

75. A compound of Formula (VIa):or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 X2, X3, are independently N, CR1or CR2;; Y1is N, N+-O-, CR3or CR4; Y2 is N, N+-O-, CR3, or CR4;L1is a single bond or C1-C4alkyl; A is an optionally substituted phenyl, an optionally substituted 5-7 membered cycloalkyl ring, and optionally substituted aryl, an optionally substituted 4-6 membered heterocycloalkyl ring, or an optionally substituted 5-6 membered heteroaryl ring, wherein said heterocycloalkyl ring includes N, S, or O as heteroatoms, and said heteroaryl ring includes N as heteroatom; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3and R4are independently selected from the group consisting of H or halogen; R5is H or F; and R is H, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted monocyclic 4-7 membered saturated or partially unsaturated heterocyclic ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

76. A compound Formula (VIa’):or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 X2, X3, and X4 are independently N, or CR1or CR2; Y1is N, N+-O-, CR3or CR4; Y2is N, N+-O-, CR3or CR4; L1 is a single bond or C1-C4 alkyl; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1and R2are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6cycloalkyl; or R1and R2are taken together!with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 is H or F; R3 and R4 are independently selected from the group consisting of H or halogen; and R5is H or F.

77. A compound of Formula (VIb):or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X1 is NCR1or CR2; Y1 is N or CR3; Y2isN or CR3; A is an optionally substituted 5-7 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl rings include N or O as heteroatoms, and the optional substitutions are selected from the group consisting of H, C1-C6alkyl, partially or completely halogenated C1-C6alkyl, or halogen; R1 and R2 are independently selected from H, halogen, -CN, -OR, -N(R)2, -C(O)OR, C(O)N(R)2, -C(R)2C(O)OR, -C(R)2C(O)N(R)2, optionally substituted C1-C6alkyl, optionally substituted 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 4-6 membered aryl or heteroaryl wherein heteroatoms in said heteroaryl are N, and optionally substituted C3-C6 cycloalkyl; or R1 and R2 are taken together! with their intervening to form an optionally substituted 5-membered partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5is H or F; and R3and R4are independently selected from the group consisting of H or halogen.

78. The compound of any one o claims 75-77, wherein Y1is N.

79. The compound of any one o claims 75-77, wherein Y1 is CR3.

80. The compound of claim 79, wherein Y2is CH.

81. The compound of any one o claims 75-80, wherein X1 is N.

82. The compound of any one o claims 75-80, wherein X1 is CH.

83. The compound of claims any one o claims 75-77, wherein R3 or R4 are independently selected from the group consisting of H and halogen.

84. The compound of claim 83, wherein, R3 and R4 are both H.

85. The compound of claim 83, wherein R3and R4are both F.

86. The compound of claim 83, wherein R3is F and R4is H.

87. The compound of any one of claim 75-86, wherein R1is selected from the group consisting of H, methyl, isopropyl and -OCH3.

88. The compound of claim 87, wherein R1is cyclopropyl.

89. The compound of any one of claims 75-88, wherein X1and X3are CR1or CR2and X2is N.

90. The compound of any one of claims 75-88, wherein X1and X2are CR1or CR2and X3is N.

91. The compound of any one of claims 75-88, wherein X2 and X3 are CR1or CR2and X1 is N.

92. The compound of any one of claims 75-91, wherein A is optionally substituted 6- membered aryl or heteroaryl, wherein the heteroaryl comprises N as heteroatom.

93. The compound of claim 92, wherein A is selected from group consisting of optionally substituted phenyl, pyridine, and pyrimidine.

94. The compound of claim 92, wherein, A is optionally substituted phenyl.

95. The compound of claim 92, wherein A is optionally substituted pyridine.

96. The compound of claim 92, wherein A optionally substituted pyrimidine.

97. The compound of claim 96, wherein the one or more optional substitutions on A are selected from the group consisting of C1-C3 alkyl, partially halogenated C1-C3-alkyl, and halogen.

98. The compound of claim 97, wherein one or more substitutions on A is -CF3.

99. The compound of any one of claims 75-91, wherein A is optionally substituted phenyl.

100. The compound of claim 99, wherein101. The compound of claim 99, wherein A is phenyl.

102. The compound of any one of claims 75-91, wherein A is optionally substituted pyridine.

103. The compound of claim 102, wherein.

104. The compound of claim 102, wherein A is pyridine.

105. The compound of claim 102, wherein106. The compound of any one of claims 75-91, wherein A is optionally substituted pyrimidine.

107. The compound of claim 106, wherein A is pyrimidine.

108. The compound of claim 106, wherein109. The compound of any one of claims 75-91, wherein A is optionally substituted piperidine.

110. The compound of claim 109, wherein111. The compound of claim 109, wherein A is piperidine.

112. The compound of any one of claims 75-91, wherein A is optionally substituted piperazine.1 . The compound of claim 112, wherein A is.

114. The compound of claim 112, wherein A is piperazine.

115. The compound of claim 112, wherein116. The compound of any one of claims 75-91, wherein A is optionally substituted morpholine.

117. The compound of claim 116, wherein A is morpholine.

118. The compound of any one of claims 75-91, wherein A is .

119. The compound of any one of claims 75-91, wherein A is optionally substituted thiomorpholine.

120. The compound of claim 119, wherein121. The compound of claim 119, wherein A is thiomorpholine.

122. The compound of any one of claims 75-91, wherein A is optionally substituted oxetane.

123. The compound of claim 122, wherein A is oxetane.

124. The compound of claim 122, wherein A is.

125. The compound of any one of claims 75-91, wherein A is optionally substituted azetidine.

126. The compound of claim 125, wherein127. The compound of claim 125, wherein A is azetidine.

128. The compound of claim 125, wherein A is.

129. The compound of any one of claim 75-128, wherein at least one of R1or R2is cyclopropyl.or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof.

131. A pharmaceutical composition comprising a compound of any one of claims 1-130.

132. A method of inhibiting HDAC6 in a patient, comprising administering an effective amount of a compound of any one of claims 1-130 or a pharmaceutical composition of claim 131.

133. 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 1-130 or a pharmaceutical composition of claim 131.

134. Use of a compound of any one of claims 1-130 or a pharmaceutical composition of claim 131 in the manufacture of a medicament for inhibiting HDAC6 in a patient.

135. Use of a compound of any one of claims 1-130 or a pharmaceutical composition of claim 131 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.

136. A compound of any one of claims 1-130 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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