Oxadiazole HDAC6 inhibitors and their uses

Abstract

Provided herein are compounds that selectively inhibit HDAC6, a protein whose activity is associated with various diseases (e.g., cancer, neurological diseases). Also provided are pharmaceutical compositions and kits that include the compounds, as well as methods of treating HDAC6-associated diseases and disorders (e.g., Alzheimer's disease, cancer) in a subject with the compounds by administering the compounds and / or compositions described herein.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Application USSN 63 / 329,143, filed April 8, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Histone deacetylases (HDACs) are classified into four classes based on sequence homology. HDAC6, a class IIb HDAC, is a cytoplasmic microtubule-associated enzyme. HDAC6 has unique features among HDAC paralogs. Unlike other HDACs, HDAC6 contains two deacetylase domains and a ubiquitin-binding domain, allowing HDAC6 to function in different cell signaling pathways involved in protein acetylation and ubiquitination, respectively. Importantly, it does not deacetylate histones. HDAC6 deacetylates tubulin, tau, Hsp90, cortactin, and other novel targets. HDAC6 deacetylase function is involved in microtubule-based cargo transport, protein degradation / recycling, and stress-induced glucocorticoid receptor signaling. HDAC6 deacetylase function is also involved in cell morphology, motility, and migration, as well as cell growth and survival. In addition to its deacetylase function, HDAC6 forms complexes with partner proteins that are associated with ubiquitin-dependent functions and affect protein aggregation, trafficking, and degradation via the aggresome pathway. HDAC6 expression has been shown to be elevated in postmortem brain samples from Alzheimer's disease patients. Small molecule compounds that inhibit HDAC6 are being developed as potential treatments for Alzheimer's disease patients. Summary of the Invention

[0003] HDAC6's cytoplasmic location, distinct substrates, and structure are unique among HDAC paralogs, and HDAC6-selective treatment regimens show promise for avoiding many of the side effects of first-generation pan-HDAC inhibitors. However, paralog selectivity is difficult to obtain. The present disclosure arises from the recognition that the unique structure and function of HDAC6 among HDAC paralogs provides an opportunity for the design of selective HDAC6 inhibitors. The present disclosure also recognizes that targeting HDAC6-mediated pathways may provide improved treatment of neurological diseases. In the context of neurodegeneration, HDAC6 (1) deacetylates tubulin, impairing microtubule function and causing defects in axonal and mitochondrial transport; (2) deacetylates tau, promoting tau aggregation, leading to pathological tau phosphorylation and formation of neurofibrillary tangles; and (3) deacetylates HSP90, preventing degradation of HSP90 client proteins, including misfolded tau, and stabilizing chaperone complexes associated with protein folding / recycling. Thus, the present disclosure provides brain-penetrant, selective HDAC6 inhibitors. These compounds provide new compositions and methods for treating diseases associated with HDAC6 activity, such as Alzheimer's disease and other tauopathies, neurological disorders such as amyotrophic lateral sclerosis, and cancer.

[0004] In one aspect, provided is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X is CR 1 or N, Y is CR 1 or N, where at least one of X and Y is N; R a and R b are each independently hydrogen or halogen; L is a bond or C optionally substituted with one or more halogens. 1~4 is alkylene; A is aryl, heteroaryl, carbocyclyl, or heterocyclyl, where A is one or more substituents R 2 Optionally replaced by; R 1 is hydrogen or a halogen; R 2 each occurrence is independently halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R 2 two occurrences of are joined with intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0005] In certain embodiments of the compounds of formula (I), R a and R b are each independently hydrogen or fluoro; L is a bond or -CH-; R 1 is hydrogen or fluoro; A is a bicyclic ring containing a C6 monocyclic aryl, a 6-membered heteroaryl fused to a C6 aryl or C6 carbocyclyl, or a 6-membered heterocyclyl containing a nitrogen, oxygen, or sulfur heteroatom; C 10 bicyclic aryl, 5-6 membered monocyclic heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, 9-10 membered bicyclic heteroaryl containing one or more nitrogen or oxygen heteroatoms (e.g., 5,6-bicyclic heteroaryl or 6,6-bicyclic heteroaryl groups), C 4~10 Carbocyclyl (e.g., C 4~7 Monocyclic carbocyclyl or C 4~7bridged polycyclic ring system), or 6-10 membered heterocyclyl (e.g., a 6- to 7-membered monocyclic heterocyclyl ring having one or more nitrogen, oxygen, or sulfur heteroatoms, or a fused or bridged 7- to 10-membered polycyclic ring system), where A is one or more substituents R 2 Optionally, each R 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 It is a haloalkyl, acyl, amido, or a 5- to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur heteroatoms.

[0006] In certain embodiments of the compounds of formula (I), R a and R bは are hydrogen; L is a bond, and R 1 is hydrogen or fluoro; A is one or more substituents R 2 C replaced with 5~6 is a monocyclic aryl; 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 It is a haloalkyl, acyl, amido, or a 5- to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur heteroatoms.

[0007] In certain embodiments of the compounds of formula (I), R a and R b are each independently hydrogen or fluoro; L is a bond; R 1 is hydrogen or fluoro; A is one or more substituents R 2 and each R is a 6,6-bicyclic aryl ring system, a 5,6-bicyclic heteroaryl ring system, or a 6,6-bicyclic heteroaryl ring system optionally substituted by 2 are independently chloro, fluoro, and C 1~4 Alkyl, or C 1~4A 6,6-bicyclic aryl ring system (or group), a 5,6-bicyclic heteroaryl ring system (or group), and a 6,6-bicyclic heteroaryl ring system (or group) refer to fused ring systems (e.g., 5,6 means a 5-membered ring fused to a 6-membered ring).

[0008] In certain embodiments of the compounds of formula (I), R a and R b are hydrogen; L is a bond; R 1 is hydrogen; A is a bicyclic ring containing a 6-membered heteroaryl or a 6-membered heterocyclyl containing a nitrogen, oxygen or sulfur heteroatom fused to a C6 aryl or C6 carbocyclyl, where A is selected from the group consisting of one or more substituents R 2 Optionally, each R 2 are independently chloro, fluoro, and C 1~4 Alkyl, or C 1~4 It is haloalkyl.

[0009] In certain embodiments of the compounds of formula (I), R a and R b are each hydrogen; L is a bond or -CH2-; R 1 is hydrogen or fluoro; A is C 4~7 Monocyclic carbocyclyl, C 4~7 A is a bridged polycyclic ring system, a 6- to 7-membered monocyclic heterocyclyl ring having one or more nitrogen, oxygen or sulfur heteroatoms, or a fused or bridged 7- to 10-membered polycyclic ring system, where A is one or more substituents R 2 Optionally, each R 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 It is a haloalkyl, acyl, amido, or a 5- to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur heteroatoms.

[0010] In certain embodiments of the compound of formula (I), X is N; R 1 is hydrogen or fluoro; R a and Rb are each independently hydrogen; L is a bond; A is a 5- to 11-membered heteroaryl; C 6~14 Aryl, C 3~10 cycloalkyl, or 4- to 11-membered heterocyclyl, where A is one to three independent substituents R 2 Optionally replaced by R 2 Each occurrence of is independently a halogen, cyano, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 alkynyl, where each C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 Alkynyl is optionally substituted with one or more halogen or cyano. In certain embodiments of the compound of formula (I), A is one to three independent substituents R 2 and each R is a 5,6-bicyclic heteroaryl optionally substituted by 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In certain embodiments of the compounds of formula (I), A is a 5,6-bicyclic heteroaryl ring system containing one or more nitrogen or oxygen heteroatoms. In certain embodiments of the compounds of formula (I), A is unsubstituted or a single R 2 In certain embodiments of the compounds of formula (I), R 2 is C 1~4 In certain embodiments of the compounds of formula (I), R 2 is methyl. In certain embodiments of the compound of formula (I), A is [ka] In certain embodiments of the compound of Formula (I), A is unsubstituted.

[0011] In certain embodiments of the compounds of Formula (I), Y is CR 1 and R 1 is hydrogen or fluorine, or Y is N.

[0012] In another aspect, provided is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable excipient.

[0013] In another aspect, provided is a method of treating a neurological or peripheral disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I). In certain embodiments, the neurological disease or disorder treated using the compounds or compositions described herein is a neurodegenerative disease, a neurodevelopmental disease, a neuropsychiatric disease, or a neuropathic disease. In certain embodiments, the neurological disease or disorder is Alzheimer's disease, fragile X syndrome, Charcot-Marie-Tooth disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Rett syndrome, major depressive disorder, chemotherapy-induced cognitive impairment, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), brain tumor, or a tauopathy, such as, for example, frontotemporal dementia, progressive supranuclear palsy, or corticobasal degeneration. In certain embodiments, the peripheral disease or disorder is chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, diabetic retinopathy, obesity, autosomal dominant polycystic kidney disease, cardiomyopathy, an autoimmune disease such as systemic lupus erythematosus (SLE), or cancer.

[0014] In another aspect, provided is a method for inhibiting the activity of HDAC6, comprising contacting HDAC6 with a compound of formula (I), or a pharma- ceutically acceptable salt thereof.In certain embodiments, inhibiting the activity of HDAC6 comprises selectively inhibiting the activity of HDAC6 over the activity of HDAC8.In certain embodiments, HDAC6 is in a cell (e.g., a human cell).In certain embodiments, inhibiting the activity of HDAC6 occurs in vitro.In certain embodiments, inhibiting the activity of HDAC6 occurs in vivo.

[0015] In another aspect, provided is a kit comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the kit further comprises instructions for administration (e.g., administration to a human).

[0016] Details of certain aspects of the invention are set forth in the detailed description set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Provided herein are compounds that are HDAC inhibitors (e.g., HDAC6 inhibitors). The compounds described herein have advantageous properties, such as selective inhibition of HDAC6 and / or ability to cross the blood-brain barrier, making them useful as therapeutic agents. In one aspect, provided are HDAC6 inhibitors compounds of formula (I), as well as their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-labeled derivatives, prodrugs, and pharmaceutical compositions. Thus, the compounds are useful for treating and / or preventing diseases and disorders associated with HDAC6 activity (e.g., neurological disorders or diseases, or peripheral diseases or disorders) in subjects in need thereof.

[0018] The compounds described herein interact with HDAC6. As described herein, the therapeutic effect may be the result of the inhibition, regulation, binding, and / or modification of HDAC6 by the compounds described herein. The compounds may be provided for use in any of the compositions, kits, or methods described herein as their pharma- ceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0019] Compounds of formula (I) In one aspect, disclosed is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein X is CR 1 or N, Y is CR 1 or N, where at least one of X and Y is N; R a and R b are each independently hydrogen or halogen; L is a bond or C optionally substituted with one or more halogens. 1~4 is alkylene; A is aryl, heteroaryl, carbocyclyl, or heterocyclyl, where A is one or more substituents R 2 Optionally replaced by; R 1 is hydrogen or a halogen; R 2each occurrence is independently halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R 2 two occurrences of are joined with intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0020] In one aspect, disclosed is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein X is CR 1 or N, Y is CR 1 or N, where at least one of X and Y is N; R a and R b are each independently hydrogen or halogen; L is a bond or C optionally substituted with one or more halogens. 1~4 is alkylene; A is aryl, heteroaryl, carbocyclyl, or heterocyclyl, where A is one or more substituents R 2 Optionally replaced by; R 1 is hydrogen or a halogen; R 2each occurrence is independently halogen, amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R 2 two occurrences of are joined with intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0021] In certain embodiments, the compound of formula (I) is 1 or N and Y is CR 1 or N, with the proviso that at least one of X and Y is N; and L is a bond or -(CH2)-.

[0022] In certain embodiments, the compound of formula (I) is 1 or N and Y is CR 1 or N, with the proviso that at least one of X and Y is N; L is a bond or -(CH)-; R a and R bは Each independently is hydrogen or fluoro.

[0023] In certain embodiments, the compound of formula (I) is 1 or 1 and Y is CR 1 or 1, with the proviso that at least one of X and Y is N; L is a bond or -(CH)-; R a and R b are each independently hydrogen or fluoro; A is a C6 monocyclic aryl, a 6-membered heteroaryl fused to a C6 aryl or C6 carbocyclyl, or a bicyclic ring containing a 6-membered heterocyclyl containing a nitrogen, oxygen, or sulfur heteroatom; C 10bicyclic aryl, 5-6 membered monocyclic heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, 9-10 membered bicyclic heteroaryl containing one or more nitrogen or oxygen heteroatoms (e.g., 5,6-bicyclic heteroaryl or 6,6-bicyclic heteroaryl groups), C 4~10 Carbocyclyl (e.g., C 4~7 Monocyclic carbocyclyl or C 4~7 bridged polycyclic ring system), or 6-10 membered heterocyclyl (e.g., a 6- to 7-membered monocyclic heterocyclyl ring having one or more nitrogen, oxygen, or sulfur heteroatoms, or a fused or bridged 7- to 10-membered polycyclic ring system), where A is one or more substituents R 2 Optionally, each R 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Compounds that are haloalkyl, acyl, amido, or 5- to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur heteroatoms.

[0024] In certain embodiments, the compound of formula (I) is R a and R b are each independently hydrogen; L is a bond; R 1 is hydrogen or fluoro; A is one or more substituents R 2 is a C6 monocyclic aryl substituted with 2 are independently chloro, fluoro, -CN, -CHCN, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Compounds that are haloalkyl, acyl, amido, or 5- to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur heteroatoms.

[0025] X and Y As used herein, X is CR 1 or N, Y is CR 1 or N, with the proviso that at least one of X and Y is N; R 1is hydrogen or a halogen.

[0026] In certain embodiments, X is N. In certain embodiments, X is CR 1 In certain embodiments, X is CR 1 and R 1 In certain embodiments, X is CR 1 and R 1 In certain embodiments, X is hydrogen or fluoro. In certain embodiments, X is CH or CF. In certain embodiments, X is CH. In certain embodiments, X is CF.

[0027] In certain embodiments, Y is N. In certain embodiments, Y is CR 1 In certain embodiments, Y is CR 1 and R 1 In certain embodiments, Y is CR 1 and R 1 In certain embodiments, Y is hydrogen or fluoro. In certain embodiments, Y is CH or CF. In certain embodiments, Y is CH. In certain embodiments, Y is CF.

[0028] In certain embodiments, at least one of X and Y is N. In certain embodiments, at least one of X and Y is N. In certain embodiments, X is N and Y is CR 1 In certain embodiments, X is N and Y is CH. In certain embodiments, X is N and Y is CF. In certain embodiments, X is N and Y is N.

[0029] In certain embodiments, Y is N and X is CR 1 In certain embodiments, X is N and Y is CH. In certain embodiments, Y is N and X is CF. In certain embodiments, Y is N and X is N.

[0030] R 1 As described herein, R 1is hydrogen or halogen. In certain embodiments, R 1 is hydrogen or fluoro. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is fluoro.

[0031] R a and R b As described herein, R a and R b are each independently hydrogen or halogen. a and R b are each independently halogen. In certain embodiments, R a and R b are each independently hydrogen or fluoro. a and R b Each is hydrogen. In certain embodiments, R a and R b are each fluoro.

[0032] In certain embodiments, R a is hydrogen or halogen, and R b is halogen. In certain embodiments, R a is hydrogen or halogen, and R b is hydrogen. In certain embodiments, R a is hydrogen, and R b is halogen. In certain embodiments, R a is hydrogen, and R b is hydrogen or halogen. In certain embodiments, R a is a halogen, and R b is hydrogen or halogen. In certain embodiments, R a is a halogen, and R b is hydrogen.

[0033] In certain embodiments, R a is hydrogen or fluoro, and R b is fluoro. In certain embodiments, R ais hydrogen or fluoro, and R b is hydrogen. In certain embodiments, R a is hydrogen, and R b is hydrogen or fluoro. In certain embodiments, R a is fluoro and R b is hydrogen or fluoro.

[0034] In certain embodiments, R a is hydrogen, and R b is fluoro. In certain embodiments, R a is fluoro and R b is hydrogen. In certain embodiments, R a is fluoro and R b is hydrogen.

[0035] L As described herein, L is a bond or C optionally substituted with one or more halogens. 1~4 In certain embodiments, L is a bond or a C optionally substituted with one or more halogens. 1~3 In certain embodiments, L is a bond or a C optionally substituted with one or more halogens. 1~2 In certain embodiments, L is an alkylene. In certain embodiments, L is a bond. In certain embodiments, L is unsubstituted methylene. In certain embodiments, L is methylene optionally substituted with one or more halogens. In certain embodiments, L is ethylene optionally substituted with one or more halogens. In certain embodiments, L is n-propylene optionally substituted with one or more halogens. In certain embodiments, L is a bond or C optionally substituted with one or more fluoro. 1~2 In certain embodiments, L is a bond or an unsubstituted C 1~3 In certain embodiments, L is a bond or an unsubstituted C 1~2In certain embodiments, L is an alkylene. In certain embodiments, L is a bond or -CH2-. In certain embodiments, L is -CH2-. In certain embodiments, when A is a substituted or unsubstituted aryl or heteroaryl, L is a bond. In certain embodiments, when A is a substituted or unsubstituted carbocyclyl or heterocyclyl, L is unsubstituted methylene.

[0036] A As described herein, A is aryl, heteroaryl, carbocyclyl, or heterocyclyl, where A is selected from one or more substituents R 2 is optionally replaced by

[0037] In certain embodiments, A is C 6~14 Aryl, 5-11 membered heteroaryl, C 3~10 cycloalkyl, or 4- to 11-membered heterocyclyl, where A is one to three independent substituents R 2 is optionally replaced by

[0038] In certain embodiments, A is phenyl, C 9~14 A is a fused bicyclic aryl, a 5- to 6-membered heteroaryl, or a 9- to 14-membered fused bicyclic heteroaryl, where A is one to three independent substituents R 2 is optionally replaced by

[0039] In certain embodiments, A is a phenyl fused to a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or C 4~6 A is a 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, or C 4~6 A is a carbocyclic ring, where A is one to three independent substituents R 2 In certain embodiments, A is a 4-6 membered heterocyclyl fused phenyl or C 4~6 A is a carbocycle, or A is a 5-6 membered heteroaryl fused to a 4-6 membered heterocyclyl or C 4~6A is a carbocyclic ring, where A is one to three independent substituents R 2 is optionally replaced by

[0040] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is aryl optionally substituted by 1 to 3 independent substituents R 2 C optionally replaced by 6~14 In certain embodiments, A is phenyl or C 9~14 A is a fused bicyclic aryl, where A is one to three independent substituents R 2 In certain embodiments, A is phenyl or naphthyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is phenyl optionally substituted by one to three independent substituents R 2 is phenyl substituted by

[0041] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 phenyl substituted with, where R 2 Each occurrence is independently fluoro, chloro, cyano, cyclopropyl, C 2~4 Alkynyl or C optionally substituted by one or more fluoro, cyano, or alkynyl 1~4 In certain embodiments, A is selected from 1 to 3 independent substituents R 2 phenyl substituted with, where R 2 Each occurrence of is independently fluoro, chloro, cyano, methyl optionally substituted with one or more fluoro, or methyl optionally substituted with cyano. In certain embodiments, A is selected from 1 to 3 independent substituents R 2 phenyl substituted with, where R 2Each occurrence of is independently fluoro, chloro, cyano, methyl optionally substituted with one or more fluoro, or methyl optionally substituted with cyano.

[0042] In certain embodiments, A is selected from 1 to 2 independent substituents R 2 phenyl substituted with, where R 2 Each occurrence is independently fluoro, chloro, cyano, cyclopropyl, C 2~4 Alkynyl or C optionally substituted by one or more fluoro, cyano, or alkynyl 1~4 In certain embodiments, A is selected from 1 to 2 independent substituents R 2 phenyl substituted with, where R 2 Each occurrence of is independently fluoro, chloro, cyano, methyl optionally substituted with one or more fluoro, or methyl optionally substituted with cyano. In certain embodiments, A is selected from 1 to 2 independent substituents R 2 phenyl substituted with, where R 2 Each occurrence of is independently fluoro, chloro, cyano, methyl optionally substituted with one or more fluoro, or methyl optionally substituted with cyano.

[0043] In certain embodiments, A is [ka] where p is 0, 1, 2, or 3. In certain embodiments, A is [ka] where p is 1, 2, or 3. In certain embodiments, A is [ka] where p is 1 or 2. In certain embodiments, A is [ka] where p is 1. In certain embodiments, A is [ka] where p is 2. In certain embodiments, A is [ka] where p is 3.

[0044] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0045] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0046] In certain embodiments, A is [ka] [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0047] In certain embodiments, A is C 9~14 A is a fused bicyclic aryl, where A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0048] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is heteroaryl optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a 5-11 membered heteroaryl optionally substituted by 1-3 independent substituents R 2In certain embodiments, A is a monocyclic or bicyclic heteroaryl, optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a bicyclic heteroaryl optionally substituted by 1 to 3 independent substituents R 2 one to three independent substituents R fused to another 5-membered monocyclic heteroaryl optionally substituted by 2 In certain embodiments, A is a 5-membered monocyclic heteroaryl optionally substituted by 1-3 independent substituents R 2 1 to 3 independent substituents R fused to a 6-membered monocyclic heteroaryl optionally substituted by 2 In certain embodiments, A is a 5-membered monocyclic heteroaryl optionally substituted with one to three independent substituents R 2 1 to 3 independent substituents R fused to a 5-membered monocyclic heteroaryl optionally substituted by 2 In certain embodiments, A is a 6-membered monocyclic heteroaryl optionally substituted with one to three independent substituents R 2 one to three independent substituents R fused to another 6-membered monocyclic heteroaryl optionally substituted by 2 is a 6-membered monocyclic heteroaryl optionally substituted by

[0049] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is a monocyclic heteroaryl optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a 5-6 membered monocyclic heteroaryl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 5-membered monocyclic heteroaryl optionally substituted by R2In certain embodiments, A is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, or oxadiazolyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is pyridyl or pyrimidinyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is 2-pyridyl, 3-pyridyl, or 4-pyridyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1 to 3 independent substituents R 2 is 2-pyridyl or 3-pyridyl optionally substituted by

[0050] In certain embodiments, A is [ka] where p is 0, 1, 2, or 3. In certain embodiments, A is [ka] where p is 0, 1, 2, or 3. In certain embodiments, A is [ka] where p is 0, 1, 2, or 3. In certain embodiments, A is [ka] where p is 0 or 1. In certain embodiments, A is [ka] where p is 0 or 1. In certain embodiments, A is [ka] where p is 0 or 1.

[0051] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is pyrimidinyl optionally substituted by 1 to 2 independent substituents R 2 In certain embodiments, A is pyrimidinyl optionally substituted by one substituent R 2 is pyrimidinyl optionally substituted by

[0052] In certain embodiments, A is [ka] It is.

[0053] In certain embodiments, A is [ka] It is.

[0054] In certain embodiments, A is [ka] It is.

[0055] In certain embodiments, A is selected from 1 to 3 independent substituents R 2In certain embodiments, A is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiophenyl, or oxadiazolyl optionally substituted by [ka] It is.

[0056] In certain embodiments, A is [ka] It is.

[0057] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 is a 9-14 membered fused bicyclic heteroaryl optionally substituted by

[0058] In certain embodiments, A is a phenyl fused to a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or C 4~6 A is a carbocyclyl ring, or A is a 5- to 6-membered heteroaryl fused to a phenyl, a 5- to 6-membered heteroaryl, a 4- to 6-membered heterocyclyl, or C 4~6 A is a carbocyclyl ring, where A is one to three independent substituents R 2 In certain embodiments, A is a phenyl fused to a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or C 4~6 A is a 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, or C 4~6 A is a carbocyclyl ring, where A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by 4-6 membered heterocyclyl or C 4~6 A is a phenyl fused to a carbocyclyl ring, or A is a 4- to 6-membered heterocyclyl or C 4~6 A is a 5-6 membered heteroaryl fused to a carbocycle, where A is one to three independent substituents R 2In certain embodiments, A is phenyl fused to a 5-6 membered heteroaryl, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is phenyl fused to a 4-6 membered heterocyclyl, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is phenyl fused to a 4-6 carbon ring, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is a 5-6 membered heteroaryl fused to a phenyl, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is a 5-6 membered heteroaryl fused to a 4-6 membered heterocyclyl, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by C 4~6 A is a 5-6 membered heteroaryl fused to a carbocycle, where A is one to three independent substituents. R2 is optionally replaced by

[0059] In certain embodiments, A is benzoxazolyl, indazolyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoxazolo[4,5-c]pyridinyl, tetrahydroisoxazolo[5,4-c]pyridinyl, quinazolinyl, triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, quinolinyl, benzisoxazolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, indolyl, or quinoxalinyl; A is selected from one to three independent substituents R 2In certain embodiments, A is benzoxazolyl, indazolyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, quinolinyl, benzisoxazolyl, benzimidazolyl, or quinoxalinyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl, or benzopyrazolyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is phenyl, quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl, or benzopyrazolyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl, or benzopyrazolyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is quinazolinyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is imidazo[1,2-a]pyrazinyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is benzoisoxazolyl, where A is optionally substituted with 1 to 3 independent substituents R 2 In certain embodiments, A is benzopyrazolyl, where A is optionally substituted with 1 to 3 independent substituents R 2 is optionally replaced by

[0060] In certain embodiments, A is [ka] where R x and R yare bonded to a 5- to 6-membered heteroaryl, a 4- to 6-membered heterocyclyl, or C 4~6 A forms a carbocyclyl ring, where A is one to three independent substituents R 2 In certain embodiments, R 2 is the phenyl ring of A, or R x and R y is bonded to form a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or C 4~6 It may be linked to a carbocyclyl ring.

[0061] In certain embodiments, A is [ka] where R x and R y are bonded to a 5- to 6-membered heteroaryl, a 4- to 6-membered heterocyclyl, or C 4~6 A forms a carbocyclyl ring, where A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R y are bonded to form a 5-6 membered heteroaryl ring, and A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R y are linked to form a 4- to 6-membered heterocyclyl ring, and A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R y is combined with C 4~6 A is a group consisting of 1 to 3 independent substituents R 2 is optionally replaced by

[0062] In certain embodiments, A is [ka] where A is one to three independent substituents R 2 is optionally replaced by

[0063] In certain embodiments, A is [ka] where A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] It is.

[0064] In certain embodiments, A is [ka] where R x and R y are bonded to a 5- to 6-membered heteroaryl, a 4- to 6-membered heterocyclyl, or C 4~6 A is a group consisting of 1 to 3 independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R yare bonded to form a 5-6 membered heteroaryl ring, and A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R y are linked to form a 4- to 6-membered heterocyclyl ring, and A is one to three independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] where R x and R y is combined with C 4~6 A is a group consisting of 1 to 3 independent substituents R 2 In certain embodiments, A is optionally substituted by [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0065] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0066] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0067] In certain embodiments, A is [ka] It is.

[0068] In certain embodiments, A is carbocyclyl or heterocyclyl, where A is selected from the group consisting of one or more substituents R 2 In certain embodiments, A is optionally substituted by C 3~10 cycloalkyl or 4-11 membered heterocyclyl, where A is one to three independent substituents R 2 is optionally replaced by

[0069] In certain embodiments, A is one or more substituents R 2 In certain embodiments, A is cycloalkyl optionally substituted by one or more substituents R 2 C optionally replaced by 3~10 In certain embodiments, A is C 5~10 Bridged cycloalkyl, C 5~10 Spirocyclic cycloalkyl, or C 3~8 A is a monocyclic cycloalkyl, where A is one or more substituents R 2 In certain embodiments, A is optionally substituted by C 5~10 Bridged cycloalkyl, or C 3~8 A is a monocyclic cycloalkyl, where A is one or more substituents R 2 In certain embodiments, A is optionally substituted by one or more substituents R 2 C optionally replaced by 5~10 In certain embodiments, A is a bridged cycloalkyl. 2 In certain embodiments, A is cycloalkyl optionally substituted by one or more substituents R 2 C optionally replaced by 8~10 In certain embodiments, A is a spirocyclic cycloalkyl. 2 C optionally replaced by 3~8 In certain embodiments, A is a monocyclic cycloalkyl. 2 C optionally replaced by 3~6 It is a monocyclic cycloalkyl.

[0070] In certain embodiments, A is bicyclo[1.1.1]pentan-1-yl, tetrahydronaphthalenyl, or adamantyl, where A is one to three independent substituents. R2 In certain embodiments, A is adamantyl or bicyclo[1.1.1]pentan-1-yl, where A is optionally substituted with 1 to 3 independent substituents R 2 is optionally replaced by

[0071] In certain embodiments, A is [ka] It is.

[0072] In certain embodiments, A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is heterocyclyl optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a 4-11 membered heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-7 membered heterocyclyl, a 5-10 membered bridged heterocyclyl, or a 7-11 membered heterocyclic spiro ring system, where A is substituted with 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-7 membered heterocyclyl or a 5-10 membered bridged heterocyclyl, where A is optionally substituted with 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-7 membered heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-6 membered heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-5 membered heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 5-6 membered heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 5-10 membered bridged heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 6-10 membered bridged heterocyclyl optionally substituted by 1-3 independent substituents R 2In certain embodiments, A is an 8-10 membered bridged heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 10-membered bridged heterocyclyl optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 7-11 membered heterocyclic spiro ring system optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 7-9 membered heterocyclic spiro ring system optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 9-11 membered heterocyclic spiro ring system optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is an 8-10 membered heterocyclic spiro ring system optionally substituted by 1-3 independent substituents R 2 is a 9-membered heterocyclic spiro ring system optionally substituted by

[0073] In certain embodiments, A is azabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, quinuclidinyl, morpholinyl, or oxadamantanyl, where A is selected from 1 to 3 independent substituents R 2 In certain embodiments, A is (1r,3r,5r,7r)-2-oxadamantanyl.

[0074] In certain embodiments, A is [ka] It is.

[0075] In certain embodiments, A is phenyl, pyridinyl, quinolinyl, or naphthalenyl, where A is selected from 1 to 3 independent substituents R 2 is optionally replaced by

[0076] In certain embodiments, A is [ka] In certain embodiments, A is [ka] [ka] It is.

[0077] In certain embodiments, A is [ka] In certain embodiments, A is [ka] It is.

[0078] In some embodiments, A is [ka] In certain embodiments, A is [ka] [ka] It is.

[0079] In some embodiments, A is [ka] It is.

[0080] R 2 As described herein, R 2 each occurrence is independently halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2 Two occurrences of are linked with intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 2 each occurrence is independently halogen, amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2 Two occurrences of are linked with intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 2 Each occurrence of is independently halogen, amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 2Each occurrence is independently halogen, amido, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0081] In certain embodiments, R 2 is a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted amidoalkyl, C 1~4 Amino optionally substituted with alkyl, or C 1~4 In certain embodiments, R is an amide optionally substituted with alkyl. 2 is C 1~4 Amino or amido optionally substituted with alkyl.

[0082] In certain embodiments, R 2 Each occurrence is independently selected from halogen, cyano, -NH2, -NHCH3, -(C=O)OH, -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHPh, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted aminoalkyl, 4- to 6-membered substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 4- to 6-membered heterocyclyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 In certain embodiments, R 2 Each occurrence is independently selected from halogen, cyano, -NH2, -NHCH3, -(C=O)OH, -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHPh, C 1~6 Alkyl, aminoalkyl, 4- to 6-membered heterocyclylalkyl, substituted or unsubstituted phenyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered substituted or unsubstituted heteroaryl, C 2~6 Alkenyl, or C2~6 alkynyl, and each C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 The alkynyl is optionally substituted with one or more halogen or cyano. In certain embodiments, R 2 Each occurrence is independently halogen, cyano, -(C=O)NH2, C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 2~6 Alkenyl, or C 2~6 alkynyl, and each C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 The alkynyl is optionally substituted by one or more halogen or cyano.

[0083] In certain embodiments, R 2 Each occurrence of R is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, -(C=O)NH, cyano, cyanomethyl, ethynyl, or morpholinyl. 2 Each occurrence of is independently fluoro. In certain embodiments, R 2 Each occurrence of is independently chloro. In certain embodiments, R 2 Each occurrence of is independently methyl. In certain embodiments, R 2 Each occurrence of is independently ethyl. 2 Each occurrence of is independently isopropyl. In certain embodiments, R 2 Each occurrence of is independently trifluoromethyl. In certain embodiments, R 2 Each occurrence of is independently cyclopropyl. In certain embodiments, R 2 Each occurrence of is independently -(C=O)NH. 2 Each occurrence of is independently cyano. In certain embodiments, R 2 Each occurrence of is independently cyanomethyl. In certain embodiments, R 2Each occurrence of is independently ethynyl. In certain embodiments, R 2 Each occurrence of is independently morpholinyl.

[0084] In certain embodiments, R 2 Each occurrence of is independently a halogen. 2 Each occurrence of is independently fluoro or chloro. 2 Each occurrence of is fluoro.

[0085] In certain embodiments, R 2 Each occurrence is independently a halogen, a cyano, or a substituted or unsubstituted C 1~6 In certain embodiments, R 2 Each occurrence of is independently a halogen, a cyano, or an unsubstituted C 1~6 In certain embodiments, R 2 Each occurrence of is independently fluoro, cyano, or methyl.

[0086] In certain embodiments, A is 1 or 2 R 2 group, where R 2 Each occurrence is independently halogen, cyano, -(C=O)NH2, C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 2~6 Alkenyl, or C 2~6 alkynyl, and each C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 The alkynyl is optionally substituted by one or more halogen or cyano.

[0087] In certain embodiments, A is 1 or 2 R 2 group, where R 2 Each occurrence is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, -(C=O)NH2, cyano, cyanomethyl, ethynyl, or morpholinyl.

[0088] In certain embodiments, A is 1 to 2 R 2 group, where R 2 Each occurrence is independently fluoro, chloro, cyano, cyclopropyl, C 2~4 Alkynyl or C optionally substituted by one or more fluoro, cyano, or alkynyl 1~4 It is an alkyl.

[0089] In certain embodiments, A is 1 or 2 R 2 group, where R 2 Each occurrence of is independently halogen. In certain embodiments, A is one or two R 2 group, where R 2 Each occurrence of is independently fluoro or chloro. In certain embodiments, A is 1 or 2 R 2 group, where R 2 Each occurrence of is independently fluoro.

[0090] In certain embodiments, A is C 6~14 Aryl, 5-11 membered heteroaryl, C 3~10 cycloalkyl, or 4- to 11-membered heterocyclyl, where A is one to three independent substituents R 2 Optionally replaced by; R 1 Each occurrence is independently hydrogen, halogen, or C optionally substituted with one or more halogens or alkoxy. 1~6 R is alkyl; 2 Each occurrence of is independently a halogen, cyano, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~ 6 alkenyl, or C 2~6 alkynyl, where each C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, or C 2~6 The alkynyl is optionally substituted by one or more halogen or cyano.

[0091] In certain embodiments, R1 each occurrence is independently hydrogen, halogen, or methyl optionally substituted with one or more halogen or alkoxy; R 2 Each occurrence is independently halogen, cyano, methyl, cyclopropyl, C 2~3 Alkenyl, or C 2~3 Alkynyl, each of methyl, cyclopropyl, C 2~3 Alkenyl, or C 2~3 The alkynyl is optionally substituted by one or more halogen or cyano.

[0092] In certain embodiments, R 1 , R 2 , R a and R b is fluoro or chloro. In certain embodiments, R 1 , R 2 , R a and R b Each halogen in is fluoro.

[0093] In certain embodiments, the compound of formula (I) has formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein

[0094] In certain embodiments of formula (Ia), Y is CH, CF or N. In certain embodiments of formula (Ia), Y is CH. In certain embodiments of formula (Ia), Y is CF. In certain embodiments of formula (Ia), Y is N.

[0095] In certain embodiments of formula (Ia), A is a bicyclic fused heteroaryl containing at least two heteroatoms (e.g., S, N, O) and A is selected from one or two R 2 group, where R 2 Each occurrence is independently fluoro, cyano, or substituted or unsubstituted C 1~6In certain embodiments of formula (Ie), A is a 5,6 bicyclic fused heteroaryl containing at least two heteroatoms (e.g., S, N, O), and A is one or two R 2 group, where R 2 Each occurrence of is independently fluoro, cyano, or substituted or unsubstituted C1-6 alkyl. In certain embodiments of formula (Ia), A is a 5,6 bicyclic fused heteroaryl containing at least two heteroatoms (e.g., S, N, O), and A is selected from 1 or 2 R 2 group, where R 2 Each occurrence is independently fluoro, cyano, or substituted or unsubstituted C 1~6 In certain embodiments of formula (Ia), A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzoisoxazolyl, or benzopyrazolyl, and A is one or two R 2 group, where R 2 Each occurrence is independently fluoro, cyano, or substituted or unsubstituted C 1~6 In certain embodiments of formula (Ia), A is imidazo[1,2-a]pyrazinyl and A is one or two R 2 group, where R 2 Each occurrence is independently fluoro, cyano, or substituted or unsubstituted C 1~6 In certain embodiments of formula (Ia), A is an unsubstituted 5,6 bicyclic heteroaryl. In certain embodiments of formula (Ia), A is an unsubstituted imidazo[1,2-a]pyrazinyl.

[0096] In certain embodiments of formula (Ia), A is phenyl, pyridinyl, or pyrimidinyl and A is one or two R 2 group, where R 2Each occurrence of is independently fluoro, chloro, cyano, methyl optionally substituted with one or more fluoro, or methyl optionally substituted with cyano. In certain embodiments of formula (Ia), A is phenyl, quinazolinyl, imidazo[1,2-a]pyrazinyl, benzoisoxazolyl, or benzopyrazolyl; A is one or two R 2 group, where R 2 Each occurrence is independently fluoro, cyano, or substituted or unsubstituted C 1~6 It is an alkyl.

[0097] In certain embodiments of formula (Ia), Y is CH, CF or N and A is unsubstituted phenyl or pyridinyl. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with halogen, alkyl, amido, haloalkyl, aryl, aralkyl or heteroaryl, where amido is optionally substituted with alkyl, aryl or heteroaryl, where aryl, aralkyl or heteroaryl is optionally substituted with alkyl, cycloalkyl or heterocycloalkyl. In certain embodiments of formula (Ia), Y is CH, CF or N and A is halogen, C 1~4 Alkyl, benzyl, C 1~4 In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with one or more fluoro or chloro. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with one or two fluoro or chloro. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with fluoro. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with fluoro. In certain embodiments of formula (Ia), Y is CH, CF or N; A is C 1~4 Alkyl or C 1~4A is phenyl or pyridinyl substituted with haloalkyl. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with methyl or -CF3. In certain embodiments of formula (Ia), Y is CH, CF or N; A is pyridinyl substituted with methyl. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with -CF3. In certain embodiments of formula (Ia), Y is CH, CF or N; A is phenyl or pyridinyl substituted with alkylamido. In certain embodiments of formula (Ia), Y is CH, CF or N; A is -NHC(=O)R aa phenyl or pyridinyl substituted with R aa is C 1~4 In certain embodiments of formula (Ia), Y is CH, CF or N; A is -NR aa R bb C(=O)R cc or -C(=O)NR aa R bb phenyl or pyridinyl substituted with R aa , R bb and R cc are each independently hydrogen or C 1~4 It is an alkyl.

[0098] In certain embodiments, the compound of formula (I) is one of the following compounds or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0099] In certain embodiments, the compound of formula (I) is one of the following compounds or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka]

[0100] In certain embodiments, the compound of formula (I) is not one or more of the following compounds: 2-(difluoromethyl)-5-(2-((4-fluorophenoxy)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (1); 2-(6-((5-chloro-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (2); 2-(6-((4-chloro-2-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (3); oxadiazole (3);2-(6-((2-chloro-4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (4);2-(difluoromethyl)-5-(6-((2,4-difluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (5);2-(difluoromethyl)-5-(5-fluoro-6-((4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (6);2-(6-((2-chloro 2-(6-((4-chlorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (7); 2-(6-((4-chlorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (8); 2-(difluoromethyl)-5-(6-((3,4-difluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (9); 2-(difluoromethyl)-5-(6-((quinolin-8-yloxy)methyl)pyridin 2-(difluoromethyl)-5-(6-((naphthalen-1-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (10); 2-(difluoromethyl)-5-(6-((4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (11); 2-(difluoromethyl)-5-(6-((4-fluorophenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (12); 2-(6-(difluoro(quinolin-8-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (13);2-(6-(difluoro(naphthalen-1-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (14); and 2-(6-(difluoro(4-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (15).

[0101] In certain embodiments, provided compounds (e.g., compounds of Formula (I)) have an IC of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. 50 inhibits HDAC6.

[0102] In certain embodiments, provided compounds (e.g., compounds of Formula (I)) selectively inhibit HDAC6 over any of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, compounds selectively inhibit HDAC6 over each of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, the compound is a 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1,000-fold, or 10,000-fold more selective inhibitor of HDAC6 than any of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, the compound is a 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1,000-fold, or 10,000-fold more selective inhibitor of HDAC6 than each of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, the compound is a 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1,000-fold, or 10,000-fold more selective inhibitor of HDAC6 over HDAC8.

[0103] Pharmaceutical Compositions and Kits The present disclosure provides pharmaceutical compositions comprising a disclosed compound (e.g., a compound of formula (I)), or a pharma- ceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0104] The present disclosure provides a pharmaceutical composition comprising a compound that interacts with (e.g., inhibits) HDAC6 for use in treating a disease or disorder associated with HDAC6 in a subject in need thereof.The present disclosure provides a pharmaceutical composition comprising a compound that interacts with (e.g., inhibits) HDAC6 for use in treating a disease or disorder associated with abnormal activity of HDAC6 in a subject in need thereof.The present disclosure provides a pharmaceutical composition comprising a compound that interacts with (e.g., inhibits) HDAC6 for use in treating a disease or disorder associated with increased activity of HDAC6 in a subject in need thereof.

[0105] In certain embodiments, the composition is for use in treating a neurological or peripheral disorder, hi certain embodiments, the composition is for use in treating a neurodegenerative, neurodevelopmental, neuropsychiatric, or neuropathic disease or disorder.

[0106] The compounds or compositions as described herein may be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions may be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity, (e.g., efficacy and / or effectiveness), improve bioavailability in a subject or cell, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in treating a disease in a subject in need of disease treatment, preventing a disease in a subject in need of disease prevention, and / or reducing the risk of developing a disease in a subject in need of disease reduction. It will also be understood that the therapeutic approaches employed may achieve desired effects against the same disease and / or may achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that include the compounds described herein and the additional pharmaceutical agents exhibit synergistic effects that are not present in pharmaceutical compositions that include one of the compounds and the additional pharmaceutical agents but not both.

[0107] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parenteral injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for subcutaneous injection.

[0108] After formulation with appropriate pharma- ceutically acceptable excipients at a desired dosage, the pharmaceutical compositions of the present disclosure can be administered to humans and other animals orally, parenterally, intravesically, intraperitoneally, topically, mucosally, etc., depending on the disease or condition to be treated.

[0109] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include the step of bringing into association a composition containing a compound of formula (I) with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dosage unit.

[0110] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is approximately equal to the dosage of active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, such as, for example, half or one-third of such a dosage.

[0111] The relative amounts of active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0112] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfuming agents may also be present in the composition.

[0113] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0114] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0115] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., cellulose esters, sorbitan fatty acid ... For example, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj45), polyoxyethylene Hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol, sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate,Pluronic F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0116] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., gum arabic, sodium alginate, Chondrus crispus extract, breadwah gum, Gahatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0117] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0118] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0119] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0120] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0121] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0122] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0123] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0124] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0125] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0126] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper tar oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, lily of the valley oil, licorice oil, lavender oil, lemon juice, licorice oil, lavandin oil, lavender oil, lemon juice, lavandin oil ... oils, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0127] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents. In certain embodiments for parenteral administration, the agents of the invention are mixed with solubilizing agents such as CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0128] Injectable preparations, for example, sterile aqueous or oily injection suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, 1,3-butanediol solutions. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0129] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0130] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0131] Solid compositions of a similar type may be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings that are well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0132] The active agent may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings, which are well known in the pharmaceutical formulation art. In such solid dosage forms, the active agent may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. In accordance with conventional practices, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0133] Formulations suitable for topical administration include liquid or semi-liquid preparations, such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes, or solutions or suspensions, such as drops. Formulations for topical administration to skin surfaces can be prepared by dispersing the drug with a dermatologically acceptable carrier, such as lotions, creams, ointments, or soaps. Useful carriers can form a film or layer on the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the drug can be dispersed in a liquid tissue adhesive or other material known to enhance adsorption to tissue surfaces. For example, hydroxypropylcellulose or fibrinogen / thrombin solutions can be used to advantage. Alternatively, tissue coating solutions such as pectin-containing formulations may be used. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of drugs to the body. Such dosage forms can be made by dissolving or dispensing the drug in a suitable medium. Absorption enhancers can also be used to increase the flux of the drug across the skin. The rate can be controlled by using rate-controlling membranes or by dispersing the drug in a polymer matrix or gel.

[0134] Furthermore, the carrier for topical formulations can be in the form of hydroalcoholic systems (e.g., liquids and gels), anhydrous oil or silicone-based systems, or emulsion systems, including but not limited to oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. Emulsions can cover a wide range of consistency, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. Emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semi-solids (such as gels and sticks), and aqueous-based mousse systems.

[0135] The present disclosure also encompasses kits (e.g., pharmaceutical packs). The kits provided may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the kits provided may optionally further include a second container that includes a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound provided in the first container and the second container are combined to form a single unit dosage form.

[0136] Thus, in one aspect, a kit is provided that comprises a first container that comprises the compound or pharmaceutical composition described herein.In certain embodiments, the kit is useful for treating disease (e.g., proliferation disease, inflammatory disease, infectious disease, autoimmune disease, heteroimmune disease, neurological disorder, metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or disease or disorder that is mediated by or associated with T cell dysregulation) in a subject that needs treatment.In certain embodiments, the kit is useful for preventing disease (e.g., proliferation disease, inflammatory disease, infectious disease, autoimmune disease, heteroimmune disease, neurological disorder, metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or disease or disorder that is mediated by or associated with T cell dysregulation) in a subject that needs prevention. In certain embodiments, the kit is useful for reducing the risk of developing a disease in a subject who needs to reduce the risk (e.g., a proliferative disease, an inflammatory disease, an infectious disease, an autoimmune disease, a heteroimmune disease, a neurological disorder, a metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or a disease or disorder mediated or associated with T cell dysregulation).In certain embodiments, the kit is useful for inhibiting the activity (e.g., aberrant activity, such as elevated activity) of HDAC6 in a subject or cell.

[0137] In certain embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for treating a disease (e.g., a proliferative disease, an inflammatory disease, an infectious disease, an autoimmune disease, a heteroimmune disease, a neurological disorder, a metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or a disease or disorder mediated by or associated with T cell dysregulation) in a subject in need of treatment. In certain embodiments, the kit and instructions provide for preventing a disease (e.g., a proliferative disease, an inflammatory disease, an infectious disease, an autoimmune disease, a heteroimmune disease, a neurological disorder, a metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or a disease or disorder mediated by or associated with T cell dysregulation) in a subject in need of prevention. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., a proliferative disease, an inflammatory disease, an infectious disease, an autoimmune disease, a heteroimmune disease, a neurological disorder, a metabolic disease, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or a disease or disorder mediated by or associated with T cell dysregulation) in a subject in need of such reduction. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., abnormal activity, such as increased activity) of HDAC6 in a subject or cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0138] Treatment methods HDAC6 is unique in structure and function among all HDAC paralogs. In particular, it has two catalytic (deacetylase) domains and a zinc finger ubiquitin-binding domain. HDAC6 does not deacetylate histones, but interacts with multiple substrates that affect disease-related pathways, including microtubule stability, axonal and mitochondrial trafficking, protein aggregation, and autophagy. For example, direct substrates of HDAC6 (e.g., tau, tubulin, and Hsp90) are involved in key mechanisms of Alzheimer's disease. As a result of its unique structure and function, selective targeting and inhibition of HDAC6 activity may avoid side effects typical of existing FDA-approved HDAC inhibitors that result in clinical toxicity due to broad inhibition of multiple HDAC paralogs and / or inhibition of HDAC1 and / or 2 (which have been shown to cause thrombocytopenia, the dose-limiting toxicity of most FDA-approved pan-HDAC inhibitors). Thus, treatment of HDAC6-associated diseases with HDAC6-selective inhibitors may be particularly effective.

[0139] The present disclosure provides methods for treating HDAC6-related diseases and disorders. In certain embodiments, the present application provides methods for treating proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heteroimmune diseases, neurological disorders, peripheral diseases or disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or diseases or disorders mediated by or associated with T cell dysregulation. In certain embodiments, the present application provides methods for treating proliferative diseases. In certain embodiments, the present application provides methods for treating cancer. In certain embodiments, the present application provides methods for treating hematological cancers. In certain embodiments, the present application provides methods for treating leukemia, T cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, or multiple myeloma. In certain embodiments, the present application provides methods for treating cancer, including solid tumors. In certain aspects, the present application provides methods of treating glioma, glioblastoma, non-small cell lung cancer, brain tumor, neuroblastoma, bone tumor, soft tissue sarcoma, head and neck cancer, genitourinary cancer, lung cancer, breast cancer, pancreatic cancer, melanoma, gastric cancer, brain cancer, liver cancer, thyroid cancer, clear cell carcinoma, uterine cancer, or ovarian cancer.

[0140] In certain embodiments, the present application provides a method for treating an inflammatory disease. In certain embodiments, the present application provides a method for treating osteoarthritis, rheumatoid arthritis, lupus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, anemia, leukocytosis, asthma, chronic obstructive pulmonary disease, appendicitis, bronchitis, bursitis, conjunctivitis, dermatitis, encephalitis, myelitis, myocarditis, sinusitis, dermatitis, psoriasis, eczema, or acne. In certain embodiments, the composition is used to treat a disease or disorder mediated by or associated with T cell dysregulation. In certain embodiments, the composition is used to treat arthritis, colitis, allograft rejection, lupus, asthma, psoriasis, inflammation, allergy, allergic encephalomyelitis, autoimmune lymphoproliferative disease, autoimmune polyglandular syndrome type II, type I diabetes, lymphoma, Wiskott-Aldrich syndrome, or myasthenia gravis.

[0141] In certain embodiments, the present application provides methods of treating an infectious disease.In certain embodiments, the present application provides methods of treating a bacterial, fungal, or protozoan infection.

[0142] In certain embodiments, the present application provides a method for treating an autoimmune disease. In certain embodiments, the present application provides a method for treating diabetes, thyroiditis, Graves' disease, Guillain-Barre syndrome, Addison's disease, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, chronic fatigue, or endometriosis.

[0143] In certain embodiments, the present application provides a method of treating a xenoimmune disease. In certain embodiments, the present application provides a method of treating graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergic conjunctivitis, or allergic rhinitis.

[0144] In certain embodiments, the present application provides methods of treating a neurological disease or disorder. In certain embodiments, the present application provides methods of treating a neurodegenerative, neurodevelopmental, neuropsychiatric, or neuropathic disease or disorder. In certain aspects, the application provides a method of treating fragile X syndrome, Charcot-Marie-Tooth disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, dementia with Lewy bodies, vascular dementia, amyotrophy, seizure-induced memory loss, schizophrenia, Rubinstein-Taybi syndrome, Rett syndrome, attention deficit hyperactivity disorder, dyslexia, bipolar disorder, social, cognitive and learning disorders associated with autism, attention deficit disorder, schizophrenia, major depressive disorder, peripheral neuropathy, diabetic retinopathy, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, chemotherapy-induced cognitive dysfunction, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), or a tauopathy. In certain embodiments, the present application provides a method of treating primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and parkinsonism, Richie-Bodig's disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, lipofuscinosis, Alzheimer's disease, or argyrophilic grain disease. In certain embodiments, the present application provides a method of treating Alzheimer's disease. In certain embodiments, the compositions are used to treat Alzheimer's disease, Fragile X syndrome, Charcot-Marie-Tooth disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Rett syndrome, major depressive disorder, chemotherapy-induced cognitive dysfunction, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), brain tumors, or tauopathies such as, for example, frontotemporal dementia, progressive supranuclear palsy, or corticobasal degeneration.

[0145] In certain aspects, the present application provides methods of treating a neurological or peripheral disease or disorder.

[0146] In certain aspects, the present application provides methods of treating a neurodegenerative, neurodevelopmental, neuropsychiatric, or neuropathic disease or disorder.

[0147] In certain embodiments, the present application provides a method for treating cystic fibrosis. In certain embodiments, the present application provides a method for treating polycystic kidney disease. In certain embodiments, the present application provides a method for treating pulmonary hypertension. In certain embodiments, the present application provides a method for treating cardiac dysfunction.

[0148] The present disclosure provides methods of inhibiting HDAC activity. In certain embodiments, the application provides methods of inhibiting HDAC6 activity. In certain embodiments, the application provides methods of inhibiting HDAC6 activity in vitro. In certain embodiments, the application provides methods of inhibiting HDAC6 activity in vivo. In certain embodiments, the application provides methods of inhibiting HDAC6 activity in cells. In certain embodiments, the application provides methods of inhibiting HDAC6 activity in human cells.

[0149] In certain embodiments, the method comprises administering to a subject in need of administration (e.g., a subject with a neurological disorder) a compound that interacts with HDAC6, such as an inhibitor of HDAC6, a modulator of HDAC6, a binder of HDAC6, or a compound that modifies HDAC6. In certain embodiments, the method comprises administering to a subject in need of administration a compound of the present disclosure (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or a composition thereof. In some embodiments, the method comprises administering to a subject in need of administration a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or a composition thereof.

[0150] In certain embodiments, the compound of formula (I) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for preventing cancer in a subject in need of prevention. In certain embodiments, the effective amount is an amount effective for treating hematological cancer in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for treating cancer, including solid tumors, in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for treating an inflammatory disease in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for preventing an inflammatory disease in a subject in need of prevention. In certain embodiments, the effective amount is an amount effective for treating an infectious disease in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective for preventing an infectious disease in a subject in need of prevention. In certain embodiments, the effective amount is an amount effective for treating a cardiovascular disease in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective to treat a neurological disorder in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective to prevent a neurological disorder in a subject in need of prevention. In certain embodiments, the effective amount is an amount effective to treat a neurodegenerative, neurodevelopmental, neuropsychiatric, or neurological disorder in a subject in need of treatment. In certain embodiments, the effective amount is an amount effective to prevent a neurodegenerative, neurodevelopmental, neuropsychiatric, or neurological disorder in a subject in need of prevention.

[0151] In certain embodiments, the effective amount is an amount effective to reduce the risk of developing a disease (e.g., a proliferative disease, an inflammatory disease, an infectious disease, a neurological disorder, a peripheral disease, or a cardiovascular disease) in a subject in need of such risk reduction.

[0152] In certain embodiments, an effective amount is an amount effective to inhibit activity (eg, abnormal activity, such as elevated activity) of HDAC6 in a subject, tissue, biological sample, or cell.

[0153] In certain embodiments, the subject to be treated or to which the compounds described herein are administered is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a livestock animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a pet animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is an experimental animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically modified animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mouse and transgenic pig). In certain embodiments, the subject is a fish or reptile.

[0154] In certain embodiments, an effective amount is an amount effective to inhibit the activity of HDAC6 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of HDAC6 by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0155] In certain embodiments, pharmaceutical compositions containing a compound of formula (I) are administered orally or parenterally at dosage levels of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg in one or more doses (depending on the mode of administration) over a period of one or more days. In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, based on the subject's body weight per day, one or more times per day to achieve the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be administered at a dosage level sufficient to deliver about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times per day, twice per day, once per day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). In certain embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes non-specific effects.

[0156] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0157] definition Chemical Definition The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. (inside cover), and specific functional groups are generally defined as described in the literature. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0158] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron, 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). The present invention further includes the compounds as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0159] In the formula: [ka] is a single bond with no specified stereochemistry at the directly attached moiety, [ka] is absent or a single bond, [ka] or [ka] is a single bond or a double bond.

[0160] 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, the replacement of hydrogen with deuterium or tritium. 19 F 18 Substitution with F, or 12 C 13 C or 14 Compounds having the subject structures, except for the substitutions at C, are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0161] When a range of values ​​is recited, this is intended to encompass each value and subrange within the range. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0162] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0163] The term "alkyl" refers to the radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6Alkyl, e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1~10 Alkyl (e.g., substituted C 1~6 Alkyl, for example, -CF3, Bn).

[0164] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0165] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1~4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1~2 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0166] The term "alkoxyalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1~2 "alkoxyalkyl").

[0167] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-18In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-16 In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group as defined herein is a partially unsaturated group, such as a carbonyl group, having one or more heteroatoms and at least one unsaturated carbon in the parent chain. For example, a heteroalkyl group can include an amide or ester functionality in its parent chain, such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 It is an alkyl.

[0168] The term "alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 In addition to alkenyl groups, examples include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In an alkenyl group, there is a C=C double bond with no specified stereochemistry (e.g., -CH=CHCH3 or [ka] ) may be an (E) double bond or a (Z) double bond.

[0169] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~10In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0170] The term "alkynyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 In addition to alkynyl groups, examples include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0171] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroalkynyl"). 2~10 In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0172] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms ("C 3~14 "Carbocyclyl" refers to a radical that has no heteroatoms in its non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 4 to 7 ring carbon atoms ("C 4~7 In some embodiments, the carbocyclyl group has 4 to 8 ring carbon atoms ("C 4~8 In some embodiments, the carbocyclyl group has 4 to 10 ring carbon atoms ("C 4~10 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the preceding examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0173] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Other cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In certain embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0174] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), saturated, or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, with the point of attachment either on the carbocyclyl ring or on the heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment on the heterocyclyl ring, in which case the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0175] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 6-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("6-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0176] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazomethane, 1H-benzo[e][1,4]dihydropyrrole ... zepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0177] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the radical or point of attachment being on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0178] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0179] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, as valence permits. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, with the point of attachment being on the heteroaryl ring, in such cases the number of ring members still indicates the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. The point of attachment of polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be on either ring, i.e., either the ring containing the heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0180] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl.

[0181] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0182] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group where the point of attachment is on the alkyl portion.

[0183] The term "polycyclic spiro ring system" refers to a ring system having two or more rings joined by one common atom. The common atom is known as the spiro atom. The ring system may be fully carbocyclic (all carbon) or heterocyclic (having one or more non-carbon atoms). If the spiro atom or any atom in any ring is not a carbon atom, the ring system is considered to be heterocyclic.

[0184] The term "bridged ring system" refers to a ring system having two or more rings that contains a bridge, i.e., a single atom or an unbranched chain of atoms (or simply a valence bond) connecting two "bridgehead" atoms. A bridgehead atom is defined as an atom that is not hydrogen and is part of the backbone structure of a molecule that is connected to three or more other backbone atoms. The ring system may be fully carbocyclic (all carbon) or heterocyclic (having one or more non-carbon atoms). If any atom is not a carbon atom, the ring system is considered to be heterocyclic.

[0185] The term "unsaturated bond" refers to a double bond or a triple bond.

[0186] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0187] The term "saturated" refers to a moiety that contains no double or triple bonds, i.e., only single bonds.

[0188] The attachment of the suffix "-ene" to the base indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of an alkyl, alkenylene is a divalent moiety of an alkenyl, alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, heteroalkenylene is a divalent moiety of a heteroalkenyl, heteroalkynylene is a divalent moiety of a heteroalkynyl, carbocyclylene is a divalent moiety of a carbocyclyl, heterocyclylene is a divalent moiety of a heterocyclyl, arylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl. As one further example, haloalkylene is a divalent moiety of a haloalkyl (i.e., an alkylene group substituted with one or more halogens).

[0189] A group is optionally substituted unless otherwise specified. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., a compound that does not naturally undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" includes substitution with any acceptable substituent of an organic compound and is intended to include any of the substituents described herein that result in the formation of a stable compound. The invention contemplates all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The invention is in no way intended to be limited by the exemplary substituents described herein.

[0190] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(Rbb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )3、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SRaa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc ) 4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc ) 4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X group; - is the counterion; Or, the two geminal hydrogens on a carbon atom can be substituted with the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc Replaced by; R aa Each case of C is independent. 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represent 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)Raa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represent 0, 1, 2, 3, 4, or 5 R dd substituted with X group; - is the counterion; R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represent 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(Rff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg groups) or two geminal R dd The substituents may be linked to form =O or =S; X - is the counterion; R ee Each case of C is independent. 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C3~10 Carbocyclyl, C 6~10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5-10 membered heteroaryl, or two R ff groups are linked to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represent 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - , -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 Alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3-C(=S)N(C1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; X - is the counter ion.

[0191] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0192] The term "hydroxyl" or "hydroxy" refers to an -OH group. By extension, the term "substituted hydroxyl" or "substituted hydroxyl" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, including, but not limited to, -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2)2, where X - , R aa , R bb , and R cc is as defined herein.

[0193] The term "amino" refers to the group -NH2. In turn, the term "substituted amino" refers to mono-, di-, or tri-substituted amino. In certain embodiments, "substituted amino" is a mono- or di-substituted amino group.

[0194] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, including -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb 2)2)2, where R aa , R bb and R cc is as defined herein, and -NH(R bb) group R bb is not hydrogen.

[0195] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, including -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb 2)2)2, where R aa , R bb , and R cc is as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not replaced with hydrogen.

[0196] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, including -N(R bb )3 and -N(R bb )3 + X - where R bb and X - is as defined herein.

[0197] The term "sulfonyl" means -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0198] The term "sulfinyl" means -S(=O)R aa refers to the group, where R aa is as defined herein.

[0199] The term "acyl" refers to a group having the general formula: -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , or -C(=NR X1 )N(R X1 )2, wherein R X1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, ... or two R are substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; X1The groups taken together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroaryl amino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc. (each of which may or may not be further substituted)).

[0200] The term "oxo" refers to the group ═O and the term "thioxo" refers to the group ═S.

[0201] Nitrogen atoms may be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR. aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc, -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl; or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined herein.

[0202] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(Rcc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0203] For example, a nitrogen protecting group such as an amide group (e.g., -C(C=O)NR aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0204] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy- l)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Troc), and 2-trimethylsilylethyl carbamate (Troc). carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc) ), 2-(2- and 4-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 1-methyl-1-cyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0205] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- These include, but are not limited to, dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4,8-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0206] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, Np-toluenesulfonylaminoacyl derivatives, N-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclopentadiene. Tandem adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, Quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine amine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0207] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). An oxygen protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb)N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, where X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0208] Exemplary oxygen protecting groups are methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-Trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methyl 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-( imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIP S), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethy Cyanacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p -Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- Examples of alkyl aryl groups include, but are not limited to, (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0209] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). A sulfur protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, where R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0210] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electroneutrality. Anionic counterions can be monovalent (i.e., containing one formal negative charge). Anionic counterions can also be multivalent (i.e., containing multiple formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 -, Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., ions of tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, and the like), and carboranes.

[0211] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims, and the invention is in no way intended to be limited by the above list of exemplary substituents.

[0212] Other definitions The following definitions are of more general terms used throughout this application.

[0213] As used herein, the term "salts" refers to any and all salts, including pharma- ceutically acceptable salts.

[0214] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and / or animal tissues without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include the following: Adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1~4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0215] The term "solvate" refers to a form of a compound or its salt associated with a solvent, usually by solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, and methanolates.

[0216] The term "hydrate" refers to a compound associated with water molecules. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form multiple types of hydrates, including, for example, monohydrates (x is 1), hypohydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0217] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that results in a tautomeric pair) may be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0218] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0219] Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". For example, if a compound has an asymmetric center and is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and are called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0220] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). Many compounds can be in a variety of different crystalline forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or may differ in some or all of the following properties: melting point, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate in a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0221] The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more other component(s), including but not limited to an atom, ion, molecule, or solvent molecule. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more acids or bases. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more components related to said compound, including but not limited to isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of said compound.

[0222] The term "prodrug" refers to a compound having a cleavable group that is removed by solvolysis or under physiological conditions to yield a compound described herein that is pharmacologic in vivo. Examples of such include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both acid form and acid derivative, but the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant on the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, Aryl, C 7~12 Substituted aryl, and C 7~12 Aryl alkyl esters may be preferred.

[0223] The terms "composition" and "formulation" are used interchangeably.

[0224] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, or an adolescent), or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially significant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially significant bird such as a chicken, a duck, a goose, or a turkey)). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease. The subject may be a plant. In certain embodiments, the plant is a terrestrial plant. In certain embodiments, the plant is a non-vascular terrestrial plant. In certain embodiments, the plant is a vascular terrestrial plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicotyledonous plant. In certain embodiments, the plant is a monocotyledonous plant. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, such as a soybean plant. In some embodiments, the plant is a tree or shrub.

[0225] The term "biological sample" refers to any sample, including tissue samples (e.g., tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (e.g., Pap or blood smears) or samples of cells obtained by microdissection); whole organism samples (e.g., yeast or bacterial samples); or cellular fractions, fragments or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from an initial biological sample.

[0226] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto the body of a subject.

[0227] The terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be performed after one or more signs or symptoms of a disease have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a subject susceptible to a disease before symptoms develop (e.g., based on a history of the disease). Treatment may be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0228] The terms "condition," "disease," and "disorder" are used interchangeably.

[0229] An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. For example, in the treatment of cancer, an effective amount of the composition of the present invention can prevent tumor regrowth, reduce tumor burden, or stop tumor growth or spread. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple doses.

[0230] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting HDAC6 (e.g., inhibiting at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the activity of HDAC6). In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder (e.g., neurological disorder, cancer). In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit HDAC6 and treat a disease or disorder (eg, a neurological disorder, cancer).

[0231] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition or one or more signs or symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient to inhibit HDAC6. In certain embodiments, a prophylactically effective amount is an amount sufficient to treat a disease or disorder (e.g., neurological disorders, cancer). In certain embodiments, a prophylactically effective amount is an amount sufficient to inhibit HDAC6 and treat a disease or disorder (e.g., neurological disorders, cancer).

[0232] As used herein, the term "inhibit" or "inhibition" in the context of enzyme, for example, in the context of HDAC6, refers to the reduction of the activity of enzyme.In some embodiments, this term refers to the level of enzyme activity, for example, HDAC6 activity, being reduced to a level that is statistically significantly lower than the starting level, which may be, for example, the baseline level of enzyme activity.In some embodiments, this term refers to the level of enzyme activity, for example, HDAC6 activity, being reduced to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the starting level, which may be, for example, the baseline level of enzyme activity.

[0233] "Proliferative disease" refers to a disease caused by abnormal growth or elongation due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases may be associated with: 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from normal locations (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis or diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0234] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue in which the growth of the mass exceeds and is out of step with the growth of normal tissue. A neoplasm or tumor may be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, characteristically slower growing than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of neoplastic cells of the tumor, and such tumors are referred to as "premalignant neoplasms." An example of a premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characteristically rapidly growing, with progressive infiltration, invasion, and destruction of surrounding tissue. Moreover, malignant neoplasms generally have the ability to metastasize to distant sites.

[0235] The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor, rather than the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is considered to be metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0236] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct adenocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast carcinoma, medullary carcinoma of the breast); brain tumors (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer ( For example, adenocarcinoma of the esophagus, Barrett's adenocarcinoma; Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); blood cancer (e.g., leukemia, for example, acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldemarcated lymphoma, and T-cell NHL, e.g., precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL), e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; leukemia / lymphoma; multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; bone marrow Proliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;Pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); peritoneal cancer; pinealoma; pituitary cancer; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasm; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., For example, the cancer may include, but is not limited to, appendix cancer; soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0237] The term "immunotherapy" refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to induce or amplify an immune response are classified as activating immunotherapies, whereas immunotherapies that reduce or suppress are classified as suppressing immunotherapies. Immunotherapies are typically, but not necessarily, biological therapeutic agents. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.

[0238] The terms "biologic," "biological drug," and "biological product" refer to a wide range of products, such as vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologics may contain sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living organisms such as cells and tissues. Biologics may be isolated from a variety of natural sources (e.g., human, animal, microbial) or may be produced by biotechnological and other techniques.

[0239] The term "small molecule" or "small molecule therapeutic agent" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially made (e.g., by chemical synthesis). Typically, small molecules are organic compounds (i.e., contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocycles, and the like). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges are also possible (e.g., at least about 200 g / mol and up to about 500 g / mol). In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate government or regulatory agency.For example, drugs approved for human use are listed by the FDA under 21 C.FR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference, and veterinary drugs are listed by the FDA under 21 C.FR §§ 500-589, which are incorporated herein by reference. All of the drugs listed are considered acceptable for use in accordance with the present invention.

[0240] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, usually beneficial, effect. For example, a therapeutic agent may treat, ameliorate, and / or prevent a disease. A therapeutic agent as disclosed herein may be a biologic or a small molecule therapeutic, or a combination thereof.

[0241] The term "chemotherapeutic agent" refers to a therapeutic agent known to be useful in chemotherapy against cancer.

[0242] "Blood cancer" includes cancers affecting hematopoietic cells or tissues. Hematopoietic cancers include cancers associated with abnormalities in the content and / or function of blood. Examples of blood cancers include leukemias such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL), non-Hodgkin's lymphoma, and the like. (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldensch Trehm's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, primary central nervous system (CNS) lymphomas, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, These include, but are not limited to, T-cell NHL, such as subcutaneous panniculus-like T-cell lymphoma, and lymphomas, such as anaplastic large cell lymphoma, one or more of the mixed leukemia / lymphomas listed above, multiple myeloma, heavy chain diseases (such as alpha chain disease, gamma chain disease, mu chain disease, etc.), acute nonlymphocytic leukemia (ANLL), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, Wilms' tumor, and Ewing's sarcoma.

[0243] The term "xenoimmune disease" refers to conditions in which an immune response to a foreign antigen (e.g., drug, pathogen) causes immunopathological changes. Because the immune response is triggered by a foreign antigen (xenoimmunity), unlike infectious diseases, the emphasis is on the immune response rather than on the foreign species (infectious pathogen) that causes the disease. EXAMPLES

[0244] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any way.

[0245] Synthesis method Compounds of formula (I) were prepared according to the synthetic schemes and procedures detailed below. The examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any manner. Compounds of the present disclosure that are not explicitly described in the procedures below may be prepared by similar methods. Those skilled in the art will understand from the disclosure provided herein how to prepare such compounds by means known in the art of organic synthesis. For example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Huts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions, are representative and useful. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products, are known in the art.

[0246] General Details All oxygen- and moisture-sensitive reactions were carried out under a nitrogen (N2) atmosphere in glassware that was flame-dried under vacuum (~0.5 mmHg) and purged with N2 before use. All reagents and solvents were purchased from commercial suppliers and used as received or were synthesized according to previously reported methods. NMR spectra were obtained using a Bruker 300 (300 MHz 1 H, 75MHz 13 C) or Varian UNITY INOVA 500 (500MHz 1 H, 125MHz 13C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) relative to the NMR solvent. Data are reported as follows: chemical shift, multiplicity (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet; coupling constant(s) in Hz). NMR data were collected at 25° C. unless otherwise noted. Flash chromatography was performed using a Teledyne Isco Combiflash R f Analytical analysis was performed on 40-60 μm silica gel (60 Å mesh) at 37°C. Tandem liquid chromatography / mass spectrometry (LC / MS) was performed on a Waters 2795 separations module and a 3100 mass detector. Analytical thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates.

[0247] LCMS_Conditions_01: Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm), Mobile phase: A-0.025% FA aqueous solution, Mobile phase: B-ACN, Flow rate: 1.2 mL / min (gradient).

[0248] LCMS condition_02: Column: X-Select CSH C-18 (150 × 4.6 mm, 3.5 μm), Mobile phase: A-0.025% formic acid in water, Mobile phase: B-ACN, Flow rate: 1.0 mL / min (gradient).

[0249] HPCL_Conditions_01: Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5μ), Mobile phase A: 0.05% TFA:acetonitrile (95:05), Mobile phase B: acetonitrile:0.05% TFA (95:05), Flow rate: 1.0 mL / min, Diluent: ACN:water.

[0250] HPLC_Conditions_02: Column: XSELECT CSHC18 (150×4.6 mm, 3.5μ), Mobile phase A: 5 mM ammonium acetate, Mobile phase ACN, Flow rate: 1.0 mL / min, Diluent: ACN:water.

[0251] Reversed phase PREP purification method: Preparative column X-SELECT (250*30mm), 5u; Mobile phase A 10mM ABC aqueous solution; Mobile phase B ACN; Flow rate 25mL; Instrument IDPrep-14 gradient (time / %B) 0 / 10, 3 / 10, 10 / 25, 20 / 40, 30 / 55, 40 / 60, 50 / 75, 60 / 95.

[0252] Compounds of formula (I) were prepared according to the synthetic schemes and procedures detailed below. General scheme - Formula (I) [ka] In general, compounds of formula (I) can be prepared by nucleophilic displacement of a leaving group (LG) in the presence of a base (e.g., K2CO3 or Ag2CO3) at temperatures above room temperature. Other synthetic strategies may be employed according to the synthesis described below. The synthesis of the disclosed compounds employs reaction methods known to those skilled in the art. 2-(Difluoromethyl)-5-(6-(((5-fluoropyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (19) [ka]

[0253] Step 1: Synthesis of 6-methylnicotinohydrazide: To a solution of methyl 6-methylnicotinate (3.0 g, 19.867 mmol, 1.0 equiv) in EtOH (15 mL) was added hydrazine hydride (4.0 g, 79.47 mmol, 4.0 equiv) at room temperature and stirred for 5 min. The reaction mixture was refluxed for 16 h and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The obtained crude product was triturated with diethyl ether (50 mL) to obtain the desired product (2.0 g, 93%) as a white solid. LC-MS: m / z 151.00 (M+1).

[0254] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole: To a solution of 6-methylnicotinohydrazide (2, 2.8 g, 18.543 mmol, 1.0 equiv.) in DCM (20 mL) was added imidazole (3.70 g, 55.62 mmol, 3.0 equiv.), and DFAA (9.64 g, 55.62 mmol, 3.0 equiv.) at room temperature and stirred for 5 min. The resulting reaction mixture was heated to 50° C. and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and the aqueous layer was extracted with DCM (30 mL×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (2.40 g) as a sticky solid. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (15%) as the eluent to give the desired product (1.80 g, 47%) as a white solid. LC-MS: m / z 212.00 (M+1).

[0255] Step 3: Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole: To a solution of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (1.80 g, 8.53 mmol, 1.0 equiv) in DCM (15 mL) was added NBS (2.30 g, 12.79 mmol, 1.5 equiv) at room temperature, followed by AIBN (420 mg, 2.55 mmol, 0.3 equiv). The reaction mixture was stirred at 50° C. for 16 h. The progress of the reaction was monitored by TLC, which showed a new spot of product along with unreacted starting material. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (10%) as the eluent to give the product (950 mg, 39%). LCMS: m / z 292.00 (M+1).

[0256] Step 4: Synthesis of 2-(difluoromethyl)-5-(6-(((5-fluoropyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (19): To a stirred solution of 5-fluoropyridin-3-ol (46.0 mg, 0.4136 mmol, 1.2 equiv.) in DMF (2 mL) was added K2CO3 (142 mg, 1.034 mmol, 3.0 equiv.) at room temperature and stirred for 15 min. To the resulting reaction mixture was added 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (100 mg, 0.3447 mmol, 1.0 equiv.) at room temperature. The reaction mixture was heated at 100° C. for an additional 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (5 mL) and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The organic layer was washed with water (10 ml) followed by brine (10 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash chromatography eluted with ethyl acetate:n-heptane (40%) to give the desired product (19, 30 mg, 27%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm5.43(s,2H)7.45-7.71(m,2H)7.83(d,J=8.4Hz,1H)8.14-8.24(m,1H),8.34(br.s,1H) ),8.52(dd,J=2.4Hz,J=10.4Hz,1H),9.20-9.30(m,1H).19F-NMR(400MHz,DMSO-d6):-120.70,126.28.LC-MS:m / z 322.85[M+H].

[0257] The following compounds were prepared using a method similar to that used to prepare compound (19). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0258] 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (A) [ka] Step 1: 6-Methylpyridine-3-carbohydrazide: To a solution of methyl 6-methylpyridine-3-carboxylate (30 g, 198.46 mmol, 1 equiv) in EtOH (300 mL) was added NH2NH2.H2O (39.74 g, 793.85 mmol, 38.58 mL, 4 equiv). The mixture was then stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc (200 mL) at 30 °C to give 6-methylpyridine-3-carbohydrazide (29 g, 189.92 mmol, 95.70% yield, 99% purity) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm9.86(brs,1H)8.84(d,J=2.00Hz,1H)8.04(dd,J=8.07,2.31Hz ,1H)7.32(dd,J=8.00,2.25Hz,1H)4.51(brs,2H)2.50(s,3H)LCMS:MS(ESI):152.2[M+H]+

[0259] Step 2: N'-(2,2-difluoroacetyl)-6-methyl-pyridine-3-carbohydrazide: A mixture of 6-methylpyridine-3-carbohydrazide (13 g, 86.00 mmol, 1 eq.) and TEA (13.05 g, 129.00 mmol, 17.95 mL, 1.5 eq.) in THF (130 mL) was degassed and purged twice with N2 at 25 °C. 2,2-difluoroacetic anhydride (22.45 g, 129.00 mmol, 1.5 eq.) was added dropwise at 25 °C. The mixture was stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was extracted with DCM (120 mL x 3). The combined organic layers were washed with H2O (80 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2) to give N'-(2,2-difluoroacetyl)-6-methyl-pyridine-3-carbohydrazide (14 g, 59.25 mmol, 68.90% yield, 97% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=11.12-10.94(m,1H),10.87-10.74(m,1H),8.92(d,J=1.8Hz,1H),8.12( dd,J=2.3,8.1Hz,1H),7.54-7.33(m,1H),6.63-6.37(m,1H),2.55(s,3H)LCMS(ESI):230.0[M+H]+

[0260] Step 3: 2-(Difluoromethyl)-5-(6-methyl-3-pyridyl)-1,3,4-oxadiazole: A mixture of N'-(2,2-difluoroacetyl)-6-methyl-pyridine-3-carbohydrazide (11 g, 46.56 mmol, 97% purity, 1 equiv.), methoxycarbonyl-(triethylammonio)sulfonyl-azanide (16.64 g, 69.83 mmol, 1.5 equiv.) in THF (120 mL) was degassed and purged with N2 three times, after which the mixture was stirred at 80° C. under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2) to give 2-(difluoromethyl)-5-(6-methyl-3-pyridyl)-1,3,4-oxadiazole (7.3 g, 34.54 mmol, 74.18% yield, 99.9% purity) as a yellow solid. MS (ESI): 212.0 [M+H]+

[0261] Step 4: 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (A): To a solution of 2-(difluoromethyl)-5-(6-methyl-3-pyridyl)-1,3,4-oxadiazole (7.2 g, 34.10 mmol, 1 equiv.) in CHCl3 (150 mL) was added NBS (8.50 g, 47.73 mmol, 1.4 equiv.) and AIBN (559.89 mg, 3.41 mmol, 0.1 equiv.) at 25° C. The mixture was then stirred at 70° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was extracted with DCM (120 mL×2). The combined organic layers were washed with H2O (80 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2) to give 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (5.1 g, 16.20 mmol, 49.52% yield, 97% purity) as a red solid. 1 H NMR(400MHz,DMSO-d6)δ=9.20(d,J=1.8Hz,1H),8.47(dd,J=2.3,8.1Hz,1H),7.82(d,J=8.1Hz,1H),7.72-7.45(m,1H),4.81(s,2H).MS(ESI):289.9[M+H]+ .

[0262] 2-(Difluoromethyl)-5-[6-[(3,4-difluorophenoxy)methyl]-3-pyridyl]-1,3,4-oxadiazole (9) [ka] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (500 mg, 1.72 mmol, 1 equiv.) and 3,4-difluorophenol (224.25 mg, 1.72 mmol, 1 equiv.) in MeCN (8 mL) was added K2CO3 (476.47 mg, 3.45 mmol, 2 equiv.) at 25° C. The mixture was stirred at 60° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral) to give 2-(difluoromethyl)-5-[6-[(3,4-difluorophenoxy)methyl]-3-pyridyl]-1,3,4-oxadiazole (165.39 mg, 486.50 umol, 28.22% yield, 99.8% purity) as an off-white solid. 1 H NMR (400MHz, methanol-d4) δ=9.28(d,J=1.8Hz,1H),8.55(dd,J=2.3,8.3Hz,1H),7.85(d,J=8.3Hz,1H),7.2 8-7.14(m,2H),7.04(ddd,J=3.1,6.6,12.2Hz,1H),6.89-6.84(m,1H),5.30(s,2H).MS(ESI):319.2[M+H] +

[0263] 2-(Difluoromethyl)-5-[6-(8-quinolyloxymethyl)-3-pyridyl]-1,3,4-oxadiazole (10) [ka] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 equiv.) and quinolin-8-ol (75.07 mg, 517.13 umol, 89.36 μL, 1 equiv.) in MeCN (4 mL) was added K2CO3 (142.94 mg, 1.03 mmol, 2 equiv.) at 25° C. The mixture was then stirred at 60° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral) to give 2-(difluoromethyl)-5-[6-(8-quinolyloxymethyl)-3-pyridyl]-1,3,4-oxadiazole (18.0 mg, 50.24 umol, 9.72% yield, 98.9% purity) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=9.31(d,J=1.6Hz,1H),8.90(dd,J=1.6,4.3Hz,1H),8.52(dd,J=2.1,8.3Hz,1H),8.38(dd,J=1.6,8.3Hz,1H),8.04 (d,J=8.3Hz,1H),7.62(dd,J=4.3,8.4Hz,1H),7.58-7.55(m,1H),7.54-7.50(m,1H),7.40-7.13(m,2H),5.62(s,2H).MS(ESI):355.0[M+H]+

[0264] 2-(Difluoromethyl)-5-[6-[(3-fluoro-2-pyridyl)oxymethyl]-3-pyridyl]-1,3,4-oxadiazole (77) [ka] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 equiv.) and 3-fluoropyridin-2-ol (58.48 mg, 517.13 umol, 1 equiv.) in toluene (3 mL) was added Ag2CO3 (285.19 mg, 1.03 mmol, 46.91 μL, 2 equiv.) at 25° C. The mixture was then stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (neutral) to give 2-(difluoromethyl)-5-[6-[(3-fluoro-2-pyridyl)oxymethyl]-3-pyridyl]-1,3,4-oxadiazole (80.12 mg, 248.38 umol, 48.03% yield, 99.9% purity) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ = 9.26 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 2.3, 8.3 Hz, 1H), 7.92 (d, J = 1.4, 5.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 1.5, 8.0, 10.5 Hz, 1H), 7.27 (t, J = 51.7 Hz, 1H), 7.02 (d, J = 3.3, 4.8, 7.9 Hz, 1H), 5.68 (s, 2H). MS (ESI): 323.2 [M+H]+. HSQC showed the chemical shift of C9 to be 66 ppm.

[0265] 2-[6-[(5-cyclopropyl-2-pyridyl)oxymethyl]-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (85) [ka] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 equiv.) in MeCN (3 mL) was added K2CO3 (142.94 mg, 1.03 mmol, 2 equiv.) and 5-cyclopropylpyridin-2-ol (69.90 mg. 517.13 umol, 1 equiv.) at 25° C. The mixture was stirred at 60° C. for 12 h. LCMS showed the reaction was complete and two peaks with the desired mass (59% and 14%) were detected. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (neutral) to give 5-cyclopropyl-1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]pyridin-2-one (80.56 mg, 232.80 umol, 45.02% yield, 99.5% purity) as a white solid. 1 H NMR (400MHz, methanol-d4) δppm9.21(d,J=2.13,0.63Hz,1H)8.46(d,J=8.19,2.19Hz,1H)7.64(d,J=2.63Hz,1H)7.53(d,J=8.25Hz,1H)7.42(d,J=9.32 ,2.56Hz,1H)7.25(t,J=51.59Hz,1H)6.55(d,J=9.26Hz,1H)5.37(s,2H)1. 77-1.86(m,1H)0.89-0.95(m,2H)0.61-0.68(m,2H).MS(ESI):345.1[M+H] + HSQC showed the chemical shift of C25 to be 54 ppm.

[0266] 2-[6-[(5-cyclopropyl-2-pyridyl)oxymethyl]-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (85) (15.41 mg, 44.62 umol, 8.63% yield, 99.7% purity) was obtained as a white solid. 1H NMR (400MHz, methanol-d4) δppm9.25(d,J=1.63Hz,1H)8.50(d,J=8.32,2.19Hz,1H)7.94(d,J=2.50Hz,1H)7.76(d,J=8.25Hz,1H)7.43(d,J=8.57 ,2.44Hz,1H)7.10-7.38(m,1H)6.89(d,J=8.63Hz,1H)5.55(s,2H)1.86-1.94(m,1H)0.95-1.00(m,2H)0.64-0.69(m,2H).MS(ESI):345.1[M+H] + .HSQC showed the chemical shift of C25 to be 66 ppm.

[0267] Synthesis of 2-(6-(((2-oxadamantan-1-yl)methoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (20) [ka] To a solution of (2-oxadamantan-1-yl)methanol (100 mg, 594.42 umol, 1 eq) in THF (3 mL) was added NaH (30.91 mg, 772.74 umol, 60% purity, 1.3 eq) at 0°C. The mixture was stirred at 60°C for 1 h. Then 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (224.14 mg, 772.74 umol, 1.3 eq) was added. The mixture was stirred at 25°C for 11 h. LCMS showed that 28% of the desired mass was detected. The reaction mixture was quenched with MeOH (5 mL) at 25°C and diluted with H2O (10 mL). The mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with H2O (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 150 x 25 mm x 10 μm, mobile phase: [water (ammonia hydroxide v / v)-ACN], B%: 33%-63%, 8 min) to give the desired compound (9.35 mg, 23.04 umol, yield 3.88%, purity 93%) as a white solid. 1H NMR (400MHz, methanol-d4) δppm9.21(d,J=1.88Hz,1H)8.53(dd,J=8.19,2.19Hz,1H)7.83(d,J=8.25Hz,1H)7.27(t,J=51 .65Hz,1H)4.77(s,2H)3.41(s,2H)2.20(brd,J=3.00Hz,2H)1.92-2.01(m,6H)1.68-1.76(m,5H).MS(ESI):378.2[M+H] +

[0268] 2-(Difluoromethyl)-5-(6-((pyridin-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (16) [ka] To a stirred solution of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 100 mg, 0.344 mmol, 1.0 equiv.) in toluene (1 mL) was added pyridin-2-ol (33 mg, 0.344 mmol, 0.344 equiv.) at room temperature, followed by Ag2CO3 (0.286 g, 1.034 mmol, 3.0 equiv.) and stirred for 10 min. The reaction mixture was heated at 100° C. and stirred for 3 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a pad of Celite® bed. The resulting filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (30%) as the eluent to give (16) (55.0 mg, 52.3%) as a yellow liquid. 1 H NMR(400MHz,DMSO-d6)δppm5.55(s,2H),6.99-7.10(m,2H),7.44-7.70(m,2H),7.7 5-7.85(m,1H),8.10-8.20(m,1H),8.45(dd,J=2.4Hz,J=10.4Hz,1H),9.19(s,1H). 19F NMR (400 MHz, DMSO-d6): δ ppm -120.69. LC-MS: m / z 304.95.6.9 [M+H] at 30 min + HPLC: 99.30%

[0269] 2-(Difluoromethyl)-5-(6-((pyridin-3-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (17) [ka] To a stirred solution of pyridin-3-ol (73.0 mg, 0.775 mmol, 1.5 equiv) in DMF (3 mL) was added K2CO3 (214 mg, 1.551 mmol) at room temperature and stirred for 15 min. To the resulting reaction mixture was added 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 150 mg, 0.5171 mmol, 1.0 equiv) at room temperature and the reaction mixture was heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with water (5 ml), brine (5 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to afford (17) (20 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm5.41(s,2H),7.30-7.40(m,2H),7.45-7.70(m,2H),7.7 8-7.88(m,1H),8.05-8.15(m,1H),8.51(dd,J=2.4Hz,J=10.4Hz,1H),9.23(s,1H). 19 F NMR(400MHz,DMSO-d6):δppm-120.70.LC-MS:m / z305.30[M+H] +

[0270] 2-(Difluoromethyl)-5-(6-((pyridin-4-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (18): [ka] To a stirred solution of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 200 mg, 0.689 mmol, 1.0 equiv.) in toluene (2 mL) was added pyridin-4-ol (65.6 mg, 0.0.689 mmol, 1.0 equiv.) at room temperature, followed by Ag2CO3 (0.570 g, 1.034 mmol, 3.0 equiv.) and stirred for 10 min. The reaction mixture was heated to 100° C. and stirred for 1 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a pad of Celite® bed. The resulting filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (60%) as the eluent to give (18) (55.0 mg, 26.3%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm5.42(s,2H),7.0-7.15(m,2H),7.45-7.79(m,2H),8.10-8.20(m,2H),8.45(dd,J=2.4Hz,J=10.4Hz,1H),9.19(s,1H). 19 F NMR(400MHz,DMSO-d6):δppm-115.904.LC-MS:m / z305.00[M+H] + HPLC at 5.072 min: 97.66%

[0271] 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (118) [ka] To a stirred solution of 4-hydroxybenzonitrile (61 mg, 0.5171 mmol) in THF (2 mL) was added NaH (34.4 mg, 0.8617 mmol, 60% dispersion in oil) at 0° C. and stirred for 30 min. To the resulting reaction mixture was added 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 100 mg, 0.3447 mmol, 1.0 equiv.) at room temperature. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with water (5 ml) and brine (5 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give (118) (15 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm5.42(s,2H),7.20-7.30(m,2H),7.71(t,J=102.4Hz, 1H),7.75-7.85(m,3H),8.51(dd,J=2.4Hz,J=10.4Hz,1H),9.20(t,J=1.6Hz,1H). 19 F NMR(400MHz,DMSO-d6):δppm-120.70. LC-MS:m / z329.2[M+H] + HPLC at 5.562 min: 99.52%

[0272] 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzamide (122): [ka] To a stirred solution of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 100 mg, 0.344 mmol, 1.0 equiv) in DMF (2 mL) was added K2CO3 (95.3 mg, 0.689 mmol) at room temperature and stirred for 15 min. To the resulting reaction mixture was added 4-hydroxybenzonitrile (53.4 mg, 0.448 mmol, 1.3 equiv) at room temperature and the reaction mixture was heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with water (5 ml), brine (5 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC followed by lyophilization to give (122) (20 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm5.38(s,2H),6.59(t,J=106.4Hz,1H),7.23(d,J=9.20Hz,2H),7.69(d,J= 8.0Hz,1H),7.81(d,J=9.6Hz,2H),8.29(dd,J=2.4Hz,J=10.4Hz,1H),9.02(s,1H),10.97(br.s,2H). 19 F NMR(400MHz,DMSO-d6):δppm-126.383,-126.525. LC-MS:m / z345.15[M+H] +

[0273] 2-(Difluoromethyl)-5-(6-(1-(4-fluorophenoxy)ethyl)pyridin-3-yl)-1,3,4-oxadiazole (AAA) [ka] Step 1: Synthesis of 1-(5-bromopyridin-2-yl)ethan-1-ol (C): To a stirred solution of compound B (0.5 g, 2.68 mmol) in anhydrous THF (10 mL) was added methylmagnesium bromide (1.79 mL, 5.37 mmol) at -10 °C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by using 100-200 mesh silica gel column chromatography to obtain product C (0.3 g, 55.24% yield) as a colorless thick oil. LC-MS: m / z 203.90 [M+H] + .

[0274] Step 2: Synthesis of 5-bromo-2-(1-(4-fluorophenoxy)ethyl)pyridine (E): Compound D (0.299 g, 2.67 mmol), PPh3 (0.544 g, 2.07 mmol) were added to a stirred solution of compound C (0.3 g, 1.48 mmol) in THF (5 mL) under cooling, the reaction mixture was stirred for 15 min, then DIAD (0.419 g, 2.07 mmol) was added at 0 °C, and then stirred at room temperature for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by using 100-200 mesh silica gel column chromatography to obtain product E (0.2 g, 45.66% yield) as a light brown liquid. LC-MS: m / z 296.00 [M+H] +

[0275] Step 3: Synthesis of 6-(1-(4-fluorophenoxy)ethyl)nicotinonitrile (F): Zn(CN)2 (0.198 g, 1.69 mmol) and Zn powder (0.030 g, 0.474 mmol) were added to a stirred solution of compound E (0.2 g, 0.677 mmol) in DMA (5 mL) at room temperature, the reaction mixture was purged with argon for 30 min, Pd2(dba)3 (0.070 g, 0.067 mmol) and dppf (0.112 g, 0.203 mmol) were added, and the reaction mixture was purged with argon again for 15 min. The reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through Celite® and washed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by 100-200 mesh silica gel column chromatography eluting with 0-20% ethyl acetate in hexane to give product F (0.110 g, 67.07% yield) as an off-white solid. LC-MS: m / z 243.05 [M+H] +

[0276] Step 4: Synthesis of 2-(1-(4-fluorophenoxy)ethyl)-5-(1H-tetrazol-5-yl)pyridine (G): To a stirred solution of compound F (0.11 g, 0.454 mmol) in DMF (10 mL), sodium azide (0.088 g, 1.36 mmol), NHCl (0.073 g, 1.36 mmol) and LiCl (0.019 g, 0.454 mmol) were added, and the reaction mixture was stirred at 100° C. for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure, acidified with 6N HCl, and the precipitated solid was filtered and dried to give product G (0.100 g, 77.51% yield) as a light brown solid. LC-MS: m / z 286.05 [M+H] +

[0277] Step 5: Synthesis of 2-(difluoromethyl)-5-(6-(1-(4-fluorophenoxy)ethyl)pyridin-3-yl)-1,3,4-oxadiazole (AAA): To a stirred solution of compound G (0.1 g, 0.35 mmol) in DCM (5 mL) at 0 °C, difluoroacetic anhydride (0.122 g, 0.701 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL), basified with saturated sodium bicarbonate solution (20 mL) and extracted with 5% methanol in DCM (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by using 230-400 mesh silica gel column chromatography eluting with 30% ethyl acetate in hexane to obtain the product (AAA) (0.060 g, 51.28% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=9.20(s,1H),8.43(dd,J=2.0,8.3Hz,1H),7.78-7.38(m,2H) ,7.13-7.01(m,2H),7.00-6.89(m,2H),5.56(q,J=6.4Hz,1H),1.62(d,J=6.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δppm=-120.70(s,1F),-120.83(s,1F),-123.28(td,J=4.2,8.2Hz,1F).LC-MS:m / z336.05[M+H] +

[0278] 2-(6-(difluoro(naphthalen-1-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (14): [ka] Step 1: 6-(difluoro(naphthalen-1-yloxy)methyl)nicotinonitrile (J): To a stirred solution of compound I (0.19 g, 1.30 mmol) in DMF (2 mL) was added NaH (60%, 0.08 g, 2.00 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 20 min. To the resulting reaction mixture, compound H (0.3 g, 1.30 mmol) dissolved in DMF (1 mL) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by using 100-200 mesh silica gel column chromatography eluting with 0-10% ethyl acetate in hexane to obtain compound J (0.32 g, 84.0%) as a brown liquid. LC-MS: m / z 296.9 [M+H] +

[0279] Step 2: 2-(difluoro(naphthalen-1-yloxy)methyl)-5-(1H-tetrazol-5-yl)pyridine (K): To a stirred solution of compound J (0.32 g, 1.00 mmol) in DMF (5 mL), sodium azide (0.35 g, 5.40 mmol) was added, followed by NH4Cl (0.27 g, 5.40 mmol) and LiCl (0.03 g), and the reaction mixture was stirred at 100° C. for 5 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure and acidified with 6N HCl. The product was extracted with ethyl acetate (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound K (0.30 g, 82.0%) as a light brown thick liquid, which was used directly in the next reaction. LC-MS: m / z 339.9 [M+H] +

[0280] Step 3: 2-(6-(difluoro(naphthalen-1-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (14): To a stirred solution of compound K (0.30 g, 0.88 mmol) in DCM (6 mL) was added difluoroacetic anhydride (0.5 mL, 4.40 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by 100-200 mesh silica gel column chromatography by eluting with 0-7% ethyl acetate in hexane to give (14) (0.10 g, 29.0% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.43(d,J=1.48Hz,1H),8.72(dd,J=8.37,1.97Hz,1H),8.30( s,1H),8.20(d,J=7.88Hz,1H),8.00-8.05(m,1H),7.90-7.95(m,1H),7.46-7.79(m,5H). 19 F NMR(400MHz,DMSO-d6)δppm-68(s,2F),-122(s,2F).LC-MS:m / z390.15[M+H] +

[0281] The following compounds were prepared by methods similar to those used to prepare compounds of formula (I) above. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

[0282] 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K) [ka] Step 1: Synthesis of methyl 5-fluoro-6-methylnicotinate: To a stirred solution of methyl 6-bromo-5-fluoronicotinate (1, 5.0 g, 21.36 mmol, 1.0 equiv.) in 1,4-dioxane (75 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (13.41 g, 106.8 mmol, 5.0 equiv.) at room temperature, followed by K2CO3 (4.429 g, 32.00 mmol, 1.5 equiv.) and the reaction mixture was degassed with argon for 15 min. To the resulting reaction mixture was added Pd(PPh3)4 (2.77 g, 0.235 mmol, 0.11 equiv.). The reaction mixture was heated at 100 °C and stirred for 16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (20%) to give methyl 5-fluoro-6-methylnicotinate (2.70 g, 75%) as an off-white solid.

[0283] Step 2: Synthesis of 5-fluoro-6-methylnicotinohydrazide: To a stirred solution of methyl 5-fluoro-6-methylnicotinate (0.740 g, 4.374 mmol, 1.0 equiv.) in EtOH (10 mL) at room temperature was added hydrazine hydrate (1.402 g, 43.74 mmol, 5.0 equiv.). The reaction mixture was heated to 70° C. and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude product (0.740 g, crude). The crude product was used directly in the next reaction without further purification.

[0284] Step 3: Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-1,3,4-oxadiazole: To a stirred solution of methyl 5-fluoro-6-methylnicotinohydrazide (0.740 g, 4.374 mmol, 1.0 equiv) in DCM (50 mL) was added imidazole (0.893 g, 13.12 mmol, 3.0 equiv) at room temperature for 15 min. To the resulting reaction mixture was added DFAA (2.28 g, 13.12 mmol) at 0° C. The reaction mixture was heated at 50° C. and stirred for 16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-1,3,4-oxadiazole (1.788 g, 89.4%, from two steps) as an off-white solid.

[0285] Step 4: Synthesis of 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K): To a stirred solution of methyl 5-fluoro-6-methylnicotinohydrazide 2-(difluoromethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-1,3,4-oxadiazole (0.900 g, 3.927 mmol, 1.0 equiv.) in DCE (18 mL) at room temperature for 15 min was added NBS (2.10 g, 23.56 mmol, 6.0 equiv.) followed by AIBN (0.322 g, 1.963 mmol, 0.5 equiv.). The reaction mixture was heated to 80° C. and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 0.600 g, 44%, 7, 550 mg, 35%) as an off-white solid. LC-MS: m / z=309.6. 1 H NMR(400MHz,CDCl3)δppm9.12(s,1H),8.13(br.d,J=8.80Hz,1H),6.76-7.10(m,1H),4.66(s,3H). Step 5: Synthesis of 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K): To a stirred solution of 2-(6-(dibromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.370 g, 0.953 mmol, 1.0 equiv.) in THF (10 mL) was added DIPEA (0.246 g, 1.907 mmol, 2.0 equiv.) at a temperature of 0° C., followed by diethyl phosphate (263.1 g, 1.907 mmol, 1.907 equiv.). The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 0.687 g, 72.3%) as an off-white solid. LC-MS: m / z=310.11; 1 H NMR(400MHz,CDCl3)δppm9.12(s,1H),8.13(d,J=8.80Hz,1H),6.76-7.10(m,1H),4.66(s,3H).

[0286] 2-(Difluoromethyl)-5-(5-fluoro-6-((naphthalen-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (182) [ka] 2-(Difluoromethyl)-5-(5-fluoro-6-((naphthalen-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (182): To a stirred solution of naphthalen-2-ol (47 mg, 0.324 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (113 mg, 0.817 mmol, 2.5 equiv), followed by 2-(difluoromethyl)-5-(5-fluoro-6-((naphthalen-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (Int-K, 100 mg, 0.324 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (30%) to give 2-(difluoromethyl)-5-[5-fluoro-6-(2-naphthyloxymethyl)-3-pyridyl]-1,3,4-oxadiazole (182, 70.0 mg, 40%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.12(d,J=1.13Hz,1H),8.45-8.51(m,1H),7.79-7.88(m,3H) ),7.44-7.73(m,3H),7.34-7.40(m,1H),7.25(dd,J=8.80,2.40Hz,1H),5.48(br.s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.75; -123.29. LC-MS: m / z = 371.9 [M+H]. 9. HPLC at 207 min: 99.56%

[0287] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (181) [ka] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (181): To a stirred solution of quinazolin-6-ol (47 mg, 0.321 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (112 mg, 0.400 mmol, 1.20 equiv), followed by 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 100 mg, 0.324 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (181, 57 mg, 30%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.49(s,1H),9.19(s,1H),9.12(s,1H),8.50(dd,J=10 .1,2.0Hz,1H),7.98(d,J=9.01Hz,1H),7.46-7.80(m,3H),5.56(d,J=1.50Hz,2H). 19 F NMR(400MHz,DMSO-d6):δ-120.75;-123.29.LC-MS:m / z371.9[M+H]9.207min HPLC:99.56%

[0288] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-7-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (180) [ka] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-7-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (180): To a stirred solution of quinazolin-7-ol (47 mg, 0.321 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (113 mg, 0.817 mmol, 2.5 equiv), followed by 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 100 mg, 0.324 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-7-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (180, 65 mg, 55%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.44(s,1H),9.18(s,1H),9.12(s,1H),8.51(dd,J=9.82,1.6 9Hz,1H),8.10(d,J=9.01Hz,1H),7.55-7.75(m,2H),7.40-7.50(m,1H),5.62(br.s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.75; -123.29. LC-MS: m / z 374.4 [M+H]. HPLC: 97.51% at 9.483 min.

[0289] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-5-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (179) [ka] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-5-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (179): To a stirred solution of quinazolin-5-ol (47 mg, 0.321 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (112 mg, 0.817 mmol, 2.5 equiv), followed by 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 100 mg, 0.324 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-((quinazolin-5-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (179, 37 mg, 30%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.67(s,1H),9.30(s,1H),9.11(s,1H),8.52(t,J=32.6,1H), 8.52(dd,J=9.82,1.69Hz,1H),7.47-7.72(m,2H),7.41(d,J=7.6Hz,1H),5.69(br.s,2H). 19F NMR (400 MHz, DMSO-d6): δ -120.76; -123.10. LC-MS: m / z 374.4 [M+H] 5.6 HPLC at 11 min: 98.83%

[0290] 2-(Difluoromethyl)-5-(5-fluoro-6-(((2-methyl-2H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (178) [ka] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-(((2-methyl-2H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (178): To a stirred solution of 2-methyl-2H-indazol-5-ol (47.12 mg, 0.317 mmol, 1.0 equiv) in acetonitrile (10 mL) at room temperature was added K2CO3 (113 mg, 0.817 mmol, 2.5 equiv), followed by 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 100 mg, 0.324 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-(((2-methyl-2H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (178, 25 mg, 28%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δppm9.10(s,1H),8.47(dd,J=1.6Hz,11.6Hz,1H),8.17(s,1H),7.47-7. 72(m,2H),7.15-7.25(m,1H),6.97(dd,J=1.0.1Hz,1.60Hz,1H),5.69(br.s,2H),4.11(s,3H). 19 F NMR (400 MHz, DMSO-d6): δ -120.75; -123.33. LC-MS: m / z 376.6 [M+H]. HPLC at 6.876 min: 96.40%

[0291] 6-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methoxy)-3-methylbenzo[d]isoxazole (137) [ka] Synthesis of 6-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methoxy)-3-methylbenzo[d]isoxazole (137): To a stirred solution of 3-methyl-1H-isoindol-6-ol (a, 36.4 mg, 0.244 mmol) in acetonitrile (5 mL) at room temperature was added K2CO3 (101 mg, 0.733 mmol) followed by 2-[6-(bromomethyl)-5-fluoro-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 75 mg, 0.244 mmol). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methoxy)-3-methylbenzo[d]isoxazole (137, 38 mg, 42%) as an off-white solid. 1 H NMR(400MHz,CDCl3)δppm9.18(s,1H),8.19(dd,J=9.82,1.69Hz,1H),7.50(d,J=8.40Hz,1H),7.15(s,1H) ,6.82-7.07(d,J=2.13Hz,2H),5.42(br.s,2H),2.53(s,3H).LC-MS:m / z:377.2[M+H]HPLC at 8.362 min:99.72%

[0292] 2-(Difluoromethyl)-5-(5-fluoro-6-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (139) [ka] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (139): To a stirred solution of 1-methyl-1H-indazol-5-ol (36.19 mg, 0.2442 mmol) in acetonitrile (5 mL) at room temperature was added K2CO3 (101.28 mg, 0.7328 mmol) followed by 2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 75 mg, 0.2442 mmol). The reaction mixture was heated at 60 °C and stirred for 2 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (2 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(difluoromethyl)-5-(5-fluoro-6-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (139, 61 mg, 50%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.10(s,1H),8.45(dd,J=9.82,1.69Hz,1H),7.92(d,J=0.75Hz,1H),7.55-7.60(m,2H),7.35(d,J=2 .13Hz,1H),7.13(dd,J=9.01,2.38Hz,1H),5.37(d,J=1.63Hz,2H),4.01(s,3H).LC-MS: m / z:376.44[M+H]+8.170 min HPLC:98.23%

[0293] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I) [ka] Step 1: Synthesis of 6-methylnicotinohydrazide: To a solution of methyl 6-methylnicotinate (50 g, 331.1 mmol, 1.0 equiv.) in ethanol (500 mL) was added hydrazine hydride (53.06 g, 1655.6 mmol, 5.0 equiv.) at room temperature. The resulting reaction mixture was refluxed for 16 h and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was triturated with diethyl ether (500 mL) to obtain 6-methylnicotinohydrazide (2, 50 g, crude) as a white solid. The crude product was used directly in the next reaction without further purification.

[0294] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole: To a solution of 6-methylnicotinohydrazide (50 g, 331.1 mmol, 1.0 equiv.) in DCM (1000 mL) was added imidazole (67.62 g, 993.37 mmol, 3.0 equiv.), and DFAA (172.84 g, 993.37 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 50° C. for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated aqueous NaHCO3 (500 mL) and the aqueous layer was extracted with DCM (500 mL×2). The combined organic layers were washed with brine solution (250 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound as a sticky solid. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (15%) to give 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (45 g, 71%, from two steps) as a white solid.

[0295] Step 3: Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I): To a solution of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (45 g, 213.2 mmol, 1.0 equiv) in DCE (450 mL) was added NBS (151.8 g, 426.54 mmol, 2.0 equiv) at room temperature, followed by AIBN (17.51 ​​mg, 106.4 mmol, 0.5 equiv). The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (500 mL), and extracted with DCM (3×500 mL). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by combiFlash column chromatography using ethyl acetate:n-heptane (10%) as eluent to give 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 21.0 g, 34%, dibromo by-product, 25 g, 32%) as an off-white solid.

[0296] Step 4: Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I): To a stirred solution of 2-(6-(dibromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (20 g, 54.206 mmol, 1.0 equiv.) in THF (200 mL) was added DIPEA (18 mL, 108.3 mmol, 2.0 equiv.) followed by diethyl phosphate (15 g, 108.6 mmol, 2.0 equiv.) at a temperature of 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 2 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate:n-heptane (30%) to give 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 10 g, 64%) as an off-white solid. LC-MS: m / z=291.0 (M + H)+; 1 H NMR(400MHz,CDCl3)δppm9.19(s,1H),8.47(dd,J=2.4Hz,8.0Hz,1H),7.82(d,J=8.80Hz,1H),7.71(t,J=47.2Hz,1H),4.80(s,2H).

[0297] 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-methylbenzamide (197) [ka] Synthesis of 3-hydroxy-N-methylbenzamide: To a stirred solution of 3-hydroxybenzoic acid (500 mg, 3.620 mmol, 1.0 equiv) in DMF (5 mL) was added DIPEA (3.14 mL, 18.10 mmol, 5.0 equiv) at room temperature, followed by HATU (2.06 g, 5.430 mmol, 1.5 equiv) and methylamine (488 mg, 7.24 mmol, 2.0 equiv) and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate:n-heptane (50%) to give 3-hydroxy-N-methylbenzamide (2, 546 mg, 98%) as a yellow solid.

[0298] Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-methylbenzamide (197): To a stirred solution of 3-hydroxy-N-methylbenzamide (99 mg, 0.655 mmol, 1.5 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (180 mg, 1.310 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 100 mg, 0.436 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate:n-heptane (20%) to give 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-methylbenzamide (197, 20 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.23(s,1H),8.40-8.52(m,2H),7.70-7.81(m,1H), 7.36-7.60(m,4H),7.21(d,J=8.31Hz,1H),5.37(s,2H),2.77(d,J=4.40Hz,3H). 19 F NMR(400MHz,DMSO-d6):δ-121.780;-121.917.LC-MS:m / z360.8[M+H].HPLC at 6.995 min:95.83%

[0299] 3-((5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-phenylbenzamide (196): [ka] Synthesis of 3-hydroxy-N-phenylbenzamide: To a stirred solution of 3-hydroxybenzoic acid (1.0 g, 7.240 mmol, 1.0 equiv) in DMF (20 mL) was added DIPEA (1.40 mL, 10.86 mmol, 1.5 equiv) at room temperature, followed by TBTU (3.48 g, 10.86 mmol, 1.5 equiv) and aniline (2, 674 g, 7.240 mmol, 1.0 equiv) and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-hydroxy-N-phenylbenzamide (600 mg, crude). The crude product was used directly in the next reaction without further purification.

[0300] Synthesis of 3-((5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-phenylbenzamide (196): To a stirred solution of 3-hydroxy-N-phenylbenzamide (147 mg, 0.690 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (143 mg, 1.034 mmol, 1.5 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 200 mg, 0.690 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase preparative HPLC to give 3-((5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-phenylbenzamide (196, 30 mg, 10%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δppm10.21(s,1H),9.24(s,1H),8.52(d,J=8.4Hz,1H),7.83(d,J=8.26,1H),7.77(d,J=8.0Hz,2H),7. 58-7.71(m,3H),7.50(t,J=17.6Hz,2H),7.37(t,J=16.0Hz,1H),7.30(d,J=8.0Hz,1H),7.12(t,J=14.4Hz,1H),5.42(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.653; -120.790. LC-MS: m / z 423.27 [M+H]. HPLC: 98.72% at 8.433 min.

[0301] 2-(6-(((2-chloropyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (189) [ka] Synthesis of 2-(6-(((2-chloropyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (189): To a stirred solution of 2-chloropyridin-4-ol (29 mg, 0.218 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (91 mg, 0.655 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 50 mg, 0.218 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase preparative HPLC to give 2-(6-(((2-chloropyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (189, 43 mg, 74%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.23(s,1H),8.52(d,J=8.4Hz,1H),8.26(d,J=8.8Hz,1H),7.8 0(d,J=8.0Hz,1H),7.70(t,J=52.2,1H),7.26(s,1H),7.10-7.20(m,1H),5.46(br.s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.658; -120.795. LC-MS: m / z 339.0 [M+H]. HPLC: 99.62% at 7.864 min.

[0302] 2-(6-(([1,1'-biphenyl]-3-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (188): [ka] Synthesis of 2-(6-(([1,1'-biphenyl]-3-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (188): To a stirred solution of [1,1'-biphenyl]-3-ol (118 mg, 0.692 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (287 mg, 2.076 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 200 mg, 0.692 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give 2-(6-(([1,1′-biphenyl]-3-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (188, 132 mg, 73%) as an off-white solid. 1 H NMR(400MHz,CDCl3)δppm9.33(d,J=1.50Hz,1H),8.43(dd,J=8.25,2.25Hz,1H),7.80(dd,J=8.25,0.63Hz,1H) ,7.56-7.60(m,2H),7.41-7.47(m,2H),7.33-7.40(m,2H),7.22-7.27(m,2H),6.80-7.08(m,2H),5.37(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ-119.14. LC-MS: m / z 380.35 [M+H]. 9. HPLC at 384 min: 98.50%

[0303] 2-(6-(([1,1'-biphenyl]-2-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (187) [ka] Synthesis of 2-(6-(([1,1'-biphenyl]-2-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (187): To a stirred solution of [1,1'-biphenyl]-2-ol (29 mg, 0.170 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (71 mg, 0.513 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 50 mg, 0.172 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (20%) to give 2-(6-(([1,1'-biphenyl]-2-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (187, 23 mg, 34%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.21(s,1H),8.45(dd,J=8.4Hz,2.4Hz,1H),7.41-7.70 (m,6H),7.30-7.40(m,3H),7.19(d,J=8.04Hz,1H),7.0-7.10(m,1H),5.33(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ-121.87. LC-MS: m / z 380.38 [M+H]. 9.486 min HPLC: 99.87%

[0304] 2-(Difluoromethyl)-5-(6-(((2-phenylpyridin-4-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (186) [ka] Synthesis of 2-(difluoromethyl)-5-(6-(((2-phenylpyridin-4-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (186): To a stirred solution of 2-phenylpyridin-4-ol (59 mg, 0.344 mmol, 1.9 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (71 mg, 0.513 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 50 mg, 0.172 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase preparative HPLC to give 2-(6-(([1,1'-biphenyl]-2-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (186, 22 mg, 34%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.27(s,1H),8.35-8.45(m,2H),8.09-8.15(m, 2H),7.80-7.90(m,1H),7.41-7.70(m,5H),7.05-7.15(m,1H),5.53(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ-121.85. LC-MS: m / z 381.39 [M+H]. HPLC: 99.19% at 5.578 min.

[0305] 2-(6-(([1,1'-biphenyl]-4-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (185) [ka] Synthesis of 2-(6-(([1,1'-biphenyl]-4-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (185): To a stirred solution of [1,1'-biphenyl]-4-ol (29 mg, 0.170 mmol, 1.0 equiv) in acetonitrile (5 mL) at room temperature was added K2CO3 (71 mg, 0.513 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 50 mg, 0.172 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (20%) to give 2-(6-2-(6-(([1,1'-biphenyl]-4-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (185, 23 mg, 34%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.24(br.s,1H),8.51(dd,J=9.6Hz,2.0Hz,1H),7.78-7.88(m,1H) ),7.58-7.70(m,5H),7.40-7.50(m,2H),7.28-7.38(m,1H),7.10-7.20(m,2H),5.37(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ-120.70. LC-MS: m / z 380.2 [M+H]. 9.667 min HPLC: 99.46%

[0306] 2-(6-(([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (184) [ka] Step-1: Synthesis of 4-(benzyloxy)-2-chloropyridine: To a stirred solution of phenylmethanol (4 g, 40 mmol) in DMF (100 mL, 1290 mmol) at 0° C. was added sodium hydride (1.3 g, 49 mmol, 1.2 equiv.) followed by 2-chloro-4-fluoro-pyridine (1, 5 g, 38.011 mmol, 0.95 equiv.) and stirred for 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-heptane (15%) to give 4-(benzyloxy)-2-chloropyridine (4.7 g, 57%) as an off-white solid.

[0307] Step 2: Synthesis of 4-(benzyloxy)-2-hydrazinylpyridine: To a stirred solution of 4-benzyloxy-2-chloropyridine (500 mg, 2.2761 mmol, 1 equiv.) in pyridine (5 mL) was added hydrazine solution (17.7 mg, 11.38 mmol, 5 equiv.) at room temperature. The reaction mixture was heated at 110° C. for 24 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give (4-benzyloxy-2-pyridyl)hydrazine (400 mg, crude). The crude product was used directly in the next reaction without further purification.

[0308] Step 3: Synthesis of 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine: To a stirred solution of (4-benzyloxy-2-pyridyl)hydrazine (4, 400 mg, 1.858 mmol, 1 equiv.) in trimethoxymethane (5, 5 mL) was added p-toluenesulfonic acid (360 mg, 2.102 mmol, 1.1 equiv.) at room temperature and stirred for 5 min. The reaction mixture was heated at 80° C. for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (6, 200 mg, crude) as an off-white solid. The crude product was used directly in the next reaction without further purification.

[0309] Step 4: Synthesis of [1,2,4]triazolo[4,3-a]pyridin-7-ol: To a stirred solution of 7-benzyloxy-[1,2,4]triazolo[4,3-a]pyridin (400 mg, 1.776 mmol, 1 equiv) in methanol (5 mL) was added 10% Pd / C (200 mg, 50% wt) at room temperature under nitrogen and stirred under 60 psi hydrogen pressure for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was filtered through a pad of Celite and the resulting filtrate was concentrated under reduced pressure to give [1,2,4]triazolo[4,3-a]pyridin-7-ol (200 mg, crude) as an off-white solid. The crude product was used directly in the next reaction without further purification.

[0310] Step 5: Synthesis of 2-(6-(([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (184): To a stirred solution of [1,2,4]triazolo[4,3-a]pyridin-7-ol (7, 280 mg, 2.0722 mmol, 2 equiv) in acetonitrile (5 mL) at room temperature was added KCO (429 mg, 3.10411 mmol, 3 equiv) and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 300 mg, 1.0343 mmol, 1 equiv). The reaction mixture was heated at 80° C. for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give 2-(6-(([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (184, 10 mg, 3.0%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.25(br.s,1H),9.06(br.s,1H),8.47-8.57(m,2H),7.85(d,J=8.4 Hz,1H),7.71(t,J=52.4Hz,1H),7.21(br.s,1H),6.86(dd,J=2.4Hz,10.0Hz,1H),5.44(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ-120.70. LC-MS: m / z 345.4 [M+H]. 5.2 HPLC at 19 min: 97.99%

[0311] 2-(Difluoromethyl)-5-(6-((pyrazolo[1,5-a]pyrimidin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (183) [ka] Step 1: Synthesis of pyrazolo[1,5-a]pyrimidin-6-ol: To a stirred solution of 6-bromopyrazolo[1,5-a]pyrimidine (150 mg, 0.7575 mmol, 1.0 equiv) in methanol (6 mL) was added KOH (259 mg, 4.620 mmol, 6.0 equiv) at a temperature of 0 °C. The reaction mixture was heated at 65 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with IPA:DCM (3:1, 3 x 20 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give pyrazolo[1,5-a]pyrimidin-6-ol (135 mg, crude). The crude product was used directly in the next reaction without further purification.

[0312] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-((pyrazolo[1,5-a]pyrimidin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (183): To a stirred solution of pyrazolo[1,5-a]pyrimidin-6-ol (2, 14 mg, 0.1034 mmol, 1.0 equiv) in acetonitrile (3 mL) at room temperature was added K2CO3 (42 mg, 0.3102 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 30 mg, 0.1034 mmol, 1.0 equiv). The reaction mixture was heated at 80 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give 2-(difluoromethyl)-5-(6-((pyrazolo[1,5-a]pyrimidin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (183, 20 mg, 56%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δppm9.30-9.40(m,1H),8.49-8.59(m,2H),8.30-8.40(m,1H),8.4(s,1H),7 .79(dd,J=0.4Hz,8.8Hz,1H),7.08(t,J=51.6Hz,1H),6.69(dd,J=0.8Hz,2.4Hz,1H),5.32(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.667, -120.804. LC-MS: m / z 345.3 [M+H]. HPLC: 96.29% at 6.997 min.

[0313] 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (118) and 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (214) [ka] Step 1: Synthesis of 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (118): To a stirred solution of 4-hydroxybenzonitrile (206 mg, 1.730 mmol, 1.0 equiv) in acetonitrile (5 mL) was added K2CO3 (710 mg, 5.190 mmol, 3.0 equiv) at room temperature and stirred for 5 min. To the resulting reaction mixture was added 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 500 mg, 1.730 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at 60 °C and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with ice-cold water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography using 20% ​​ethyl acetate in n-heptane to give 118 (190 mg, 34%) as an off-white solid.

[0314] Step 2: Synthesis of 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (214): To a solution of 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (118, 200 mg, 0.6092 mmol, 1 equiv.) in DMF (5 mL) was added NaN3 (118 mg, 1.815 mmol, 3 equiv.), NH4Cl (97.84 mg, 1.829 mmol, 3 equiv.) and lithium chloride (25 mg, 0.609 mmol, 1 equiv.) at room temperature. The reaction mixture was heated at 120° C. for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase preparative HPLC to give 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (214, 65 mg, 29%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.23(s,1H),8.49(d,J=8.31Hz,1H),7.89(d,J=8.31Hz, 2H),7.80(d,J=8.31Hz,1H),7.43-7.72(m,2H),7.06(d,J=8.31Hz,2H),5.34(s,2H). 19 F NMR (400 MHz, DMSO-d6): δ -120.674; -120.809. LC-MS: m / z 372.24 [M+H]. HPLC at 6.002 min: 98.17%

[0315] 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-6-methyl-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (191) [ka] Step 1: Synthesis of tert-butyl 3-oxo-3,4,5,7-tetrahydroisoxazolo[5,4-c]pyridine-6(2H)-carboxylate: Triethylamine (450 mg, 4.460 mmol, 2.5 eq.), DMAP (75.6 mg, 0.178 mmol, 0.1 eq.) were added to a solution of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one (250 mg, 1.785 mmol, 1 eq.) in DCM (10 mL) at 0° C. and stirred for 5 min. Boc anhydride (427 mg, 1.96 mmol, 1.1 eq.) was added to the resulting reaction mixture at the same temperature. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by combiFlash column chromatography using 20% ​​ethyl acetate in n-heptane to give tert-butyl 3-oxo-3,4,5,7-tetrahydroisoxazolo[5,4-c]pyridine-6(2H)-carboxylate (240 mg, 56%) as an off-white solid.

[0316] Step 2: Synthesis of tert-butyl 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate: 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,7-dihydroisoxazolo[5, To a solution of tert-butyl 4-c]pyridine-6(5H)-carboxylate (240 mg, 1.00 mmol, 1 equiv.) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 290 mg, 1.00 mmol, 1 equiv.) in acetonitrile (10 mL) was added K2CO3 (414 mg, 3.00 mmol, 3 equiv.) at room temperature and stirred for 5 min. The reaction mixture was heated at 80° C. for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give tert-butyl 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate (150 mg, 33%) as an off-white solid.

[0317] Step 3: Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine: To a solution of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-tert-butyl carboxylate (150 mg, 0.334 mmol, 1 eq.) in DCM (5 mL) was added TFA (0.5 mL) at 0° C. and stirred for 5 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (120 mg, crude). The crude product was used directly in the next reaction without further purification.

[0318] Step 4: Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-6-methyl-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (191): To a stirred solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methoxy]-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (4, 100 mg, 0.286 mmol, 1 equiv) in methanol (2.5 mL) was added triethylamine (57.87 mg, 0.57 mmol, 2 equiv) at a temperature of 0 °C and stirred for 5 min. To the resulting reaction mixture, formaldehyde (1 mL) and acetic acid (0.02 mL, 0.0286 mmol, 0.1 equiv.) were added and stirred at 0° C. for 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After 12 h, sodium cyanoborohydride (36 mg, 0.573 mmol, 2 equiv.) was added to the reaction mixture at 0° C. and stirred for 2 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (20 mL), methanol was concentrated, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-6-methyl-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (15 mg, 0.041 mmol, 15%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.21(s,1H),8.50(dd,J=2.0Hz,10.4Hz,1H),7.76(d,J=8.8Hz,1H),7.71 (t,J=51.2Hz,1H),5.45(br.s,2H),3.45(s,2H),2.60-2.70(m,2H),2.39-2.49(m,2H),2.35(s,3H). 19 F NMR (400 MHz, DMSO-d6): δ-120.70. LC-MS: m / z 364.1 [M+H]. 7.527 min HPLC: 98.53%

[0319] 2-(Difluoromethyl)-5-(6-((4-(1-methyl-1H-pyrazol-5-yl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (199) [ka] Step 1: Synthesis of 2-(6-((4-bromophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole: To a stirred solution of 4-bromophenol (149 mg, 0.8650 mmol, 1.0 equiv) in acetonitrile (2.5 mL) at room temperature was added K2CO3 (358 mg, 2.595 mmol, 3.0 equiv), followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 250 mg, 0.8650 mmol, 1.0 equiv). The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography using 0-30% ethyl acetate in n-heptane to give 2-(6-((4-bromophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (100 mg, 40%) as an off-white solid.

[0320] Step 2: Synthesis of 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-pyrazol-5-yl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (199): Stirred 2-(6-((4-bromophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (100 mg, 0.2616 To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3, 65 mg, 0.3139 mmol, 1.0 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3, 65 mg, 0.3139 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL) was added K2CO3 (108 mg, 0.7850 mmol, 3.0 equiv.) at room temperature and the reaction mixture was degassed with argon gas for 10 min. To the resulting reaction mixture was added Pd(PPh3)4 (30 mg, 0.0261 mmol) at room temperature. The reaction mixture was heated at 100 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a pad of celite bed. The resulting filtrate was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase preparative HPLC to give 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-pyrazol-5-yl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (199, 100 mg, 40%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm9.24(s,1H),8.48-8.53(m,1H),7.81(d,J=8.31Hz,1H),7.38-7.73(m,4H),7.1 8(d,J=8.80Hz,2H),6.33(s,1H),5.39(s,2H),3.82(s,3H).LC-MS:m / z383.93[M+H].HPLC in 7.959 minutes:95.03%

[0321] 2-(Difluoromethyl)-5-(6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (86) [ka] Step 1: Synthesis of methyl 6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)nicotinate: To a solution of methyl 6-(hydroxymethyl)pyridine-3-carboxylate (5.0 g, 29.91 mmol) in acetonitrile (100 mL) was added Cs2CO3 (17.0 g, 52.17 mmol) and 8-chloroimidazo[1,2-a]pyrazine (4.1 g, 27 mmol) at room temperature and stirred for 5 min. The reaction mixture was heated at 60 °C and stirred for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in water (100 mL) and extracted with ethyl acetate (2 x 250 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using methanol (0-10%) in DCM to give methyl 5-fluoro-6-methylnicotinate (2.70 g, 75%) as an off-white solid. LC-MS: m / z 285.4 [M+H].

[0322] Step 2: Synthesis of 6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)nicotinohydrazide: To a solution of methyl 6-(imidazo[1,2-a]pyrazin-8-yloxymethyl)pyridine-3-carboxylate (4.2 g, 15 mmol) in ethanol (100 mL) was added hydrazine hydride (3.5 g, 110 mmol) at room temperature and stirred for 5 min. The reaction mixture was heated at a temperature of 70° C. and stirred for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain 6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)nicotinohydrazide (3.6 g, crude). The crude product was used directly in the next reaction without further purification. LC-MS: m / z 286.0 [M+H].

[0323] Step 3: Synthesis of 2-(difluoromethyl)-5-(6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (86): To a solution of (6-(imidazo[1,2-a]pyrazin-8-yloxymethyl)pyridine-3-carbohydrazide (6.05 g, 21.3 mmol) in DCM (200 mL) was added imidazole (4.34 g, 62.5 mmol) and difluoroacetic anhydride (11.12 g, 54.31 mmol) at 0° C. and stirred for 5 min. The resulting reaction mixture was heated at 50° C. and stirred for 4 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in water (100 mL) and extracted with DCM (2×250 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using methanol (0–5%) in DCM to give methyl 5-fluoro-6-methylnicotinate (86, 6.0 g, 82%, from two steps) as an off-white solid. LC-MS: m / z 344.93 [M+H]. 1 H NMR(400MHz,DMSO-d6)δppm9.22(d,J=1.47Hz,1H),8.48(dd,J=8.25,2.14Hz,1H),8.27(d,J=4.65Hz,1H ),8.12(d,J=0.98Hz,1H),7.69-7.77(m,2H),7.37-7.59(m,2H),5.74(s,2H).HPLC=97.54%, RT=6.815 min.

[0324] The following compounds were prepared using a method similar to that used to prepare compound (86). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0325] 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J) [ka] Step 1: Synthesis of 2-methylpyrimidine-5-carbohydrazide: To a stirred solution of methyl 2-methylpyrimidine-5-carboxylate (1.1 g, 6.57 mmol) in EtOH (30 mL) was added hydrazine hydrate (1.05 g, 32.86 mmol) at room temperature under N2 atmosphere. The reaction mixture was heated at 80° C. and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 2-methylpyrimidine-5-carbohydrazide (1.2 g, crude). The crude product was used directly in the next reaction without further purification. LC-MS: m / z 153.1 [M+H].

[0326] Step 2: Synthesis of 2-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1,3,4-oxadiazole: To a stirred solution of 2-methylpyrimidine-5-carbohydrazide (1.9 g, 12 mmol) in DCM (25 mL) was added imidazole (2.55 g, 37.5 mmol) followed by 2,2-difluoroacetic acid (2,2-difluoroacetyl) (6.52 g, 37.49 mmol) at a temperature of 0° C. and stirred for 5 min. The reaction mixture was heated at 50° C. for 12 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate (0-5%) in n-heptane to give 2-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1,3,4-oxadiazole (2.0 g, 80%) as a white solid. LC-MS: m / z 213.0 [M+H].

[0327] Step 4: Synthesis of 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J): A solution of 2-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1,3,4-oxadiazole (100 mg, 0.471 mmol) in DCE (5.00 mL) was added with NBS (503 mg, 2.82 mmol) and AIBN (38 mg, 0.226 mmol) at room temperature. The reaction mixture was heated at 80° C. and stirred for 12 h. The progress of the reaction was monitored by TLC. After 12 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL) and extracted with DCM (2×25 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate in n-heptane to give 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J, 20 mg, 30 mg, Int-5, 35%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 9.41 (s, 1H), 7.71 (t, J = 47.2 Hz, 1H), 4.81 (s, 2H).

[0328] Step 5: Synthesis of 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J): To a stirred solution of 2-[2-(dibromomethyl)pyrimidin-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (700 mg, 1.89 mmol) in THF (30 mL) was added DIPEA (492 mg, 3.84 mmol), 1-ethoxyphosphonoyloxyethane (527 mg, 3.816 mmol) at 0° C. and the reaction mixture was stirred under nitrogen for 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate (0-10%) in n-heptane to give 2-(2-(dibromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J, 200 mg, 36%) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 9.41 (s, 1H), 7.71 (t, J = 47.2 Hz, 1H), 4.81 (s, 2H).

[0329] 2-(Difluoromethyl)-5-(2-((4-fluorophenoxy)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (166) [ka] Synthesis of 2-(difluoromethyl)-5-(2-((4-fluorophenoxy)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (166): To a stirred solution of 3-hydroxybenzonitrile (411 mg, 3.45 mmol) in acetonitrile (20 mL, 381 mmol) was added K2CO3 (1.427 g, 10.33 mmol) and 2-[2-(bromomethyl)pyrimidin-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J, 1.0 g, 3.43 mmol) at room temperature. The reaction mixture was heated at 60 °C and stirred for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water (20 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate:n-hexane (30%) to give 2-(difluoromethyl)-5-(2-((4-fluorophenoxy)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole (166, 830 mg, 75%) as a yellow solid. LC-MS: m / z 330.15 [M+H]. 1 H NMR(400MHz,DMSO-d6)δppm9.44(s,2H),7.47-7.74(m,3H),7.41-7.45(m,1H),7.37(dd,J=2.8,9.2Hz,1H),5.54(s,2H)HPLC=98.09%, RT=7.863min

[0330] Biological Assay Data and Procedures The enzymatic activity of the compounds of this disclosure was determined in one of two biochemical assays described below. Both follow the same protocol. The first method relies on caliper tip readings, while the second method relies on fluorescence readings.

[0331] Caliper endpoint assay of HDAC enzyme activity HDAC reactions were assembled in a total volume of 20 μL in 384-well plates (Greiner) as follows: HDAC proteins (and their regulatory subunits, if applicable) were pre-diluted in assay buffer containing 100 mM HEPES, pH 7.5, 0.1% BSA, 0.01% TritonX-100, 25 mM KCl and dispensed into 384-well plates (10 μL per well). Examples of enzyme concentrations used in each assay are shown in the table below. [Table 4]

[0332] Test compounds were pre-diluted serially in 100% DMSO using 3-fold dilution steps and added to protein samples by a microautomatic dispenser (LabcyteEcho). The concentration of DMSO was equal to 1% in all samples. Final compound concentrations in the assay typically ranged from 100 μM to 0.00056 μM in a 12-point concentration-response format.

[0333] Control samples (no inhibitor, 0% inhibition with DMSO only) and 100% inhibition (no enzyme) were constructed in quadruplicate (at each caliper) and used to calculate the % inhibition in the presence of compound. In this step, compounds were pre-incubated with enzyme for 30 min at room temperature (20-23 °C). The reaction was initiated by adding 10 μL of FAM-labeled substrate peptide (see table above) pre-diluted in the same assay buffer. The final concentration of substrate peptide was 1 μM. The reaction was allowed to proceed at room temperature (20-23 °C). The typical incubation time for each HDAC varied based on the previously determined enzyme reaction progress curve and is listed in the table above.

[0334] After incubation, the reaction was stopped by adding 50 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01% TritonX-100, 0.05% SDS). Finished plates were analyzed on a microfluidic electrophoresis device (Caliper LabChip® 3000, Caliper Life Sciences / Perkin Elmer) capable of electrophoretically separating deacetylated products from acetylated substrates. The change in relative intensity of peptide substrate and product is the parameter measured. The activity of each test sample was determined as product to total ratio (PSR):P / (S+P), where P is the product peak height and S is the substrate peak height. Percent inhibition (P inh ) is determined using the following equation: P inh =(PSR 0%inh -PSR 化合物 ) / (PSR 0%inh -PSR 100%inh )*100, where PSR 化合物 is the product / total ratio in the presence of compound, PSR 0%inh is the product / total ratio in the absence of compound, PSR 100%inh is the product / total ratio in the absence of enzyme. IC of compound 50 The %-inh data were analyzed using XLfit software (IDBS) to determine the 50% inhibition (P inh vs compound concentration) were fitted to a four-parameter sigmoidal dose-response model.

[0335] Nanosyn Biochemical HDAC6 Assay (Fluorescent Format) The composition of HDAC proteins and their respective substrate peptides are summarized in the table below. [Table 5]

[0336] The biochemical HDAC6 assay was performed using fluorescence detection (Fluor-De-Lys assay). In this assay, deacetylation of lysine residues in the LGK(Ac)-AMC peptide substrate generates a cleavable bond between the amino-methylcoumarin (AMC) fluorescent moiety and the lysine. AMC is released by auxiliary treatment with trypsin, which is added to the termination buffer. Cleaved AMC produces a strong fluorescent signal that is detected (360 nm excitation and 460 nm emission).

[0337] HDAC reactions are set up in a total volume of 20 mL in black low binding 384-well plates (Corning) as follows. Pre-dilute HDAC6 protein in assay buffer containing 100 mM HEPES, pH 7.5, 0.01% BSA, 0.01% TritonX-100, 25 mM KCl and dispense into a 384-well plate (10 uL per well). Test compounds are serially pre-diluted in DMSO and added to the protein samples by a microautomatic dispenser (Labcyte Echo), the concentration of DMSO being equal in all samples at 1%. Control samples (no inhibitor, DMSO only, 0% inhibition) and 100% inhibition (no enzyme) are set up on the same plate and used to calculate % inhibition in the presence of compound. In this step, the compounds are pre-incubated with the enzyme for 30 minutes. The reaction is initiated by the addition of 10 uL of LGK(Ac)-AMC substrate peptide pre-diluted in the same assay buffer. The final concentration of hHDAC6 enzyme is 0.5 nM. The final concentration of mHDAC6 enzyme is 1 nM. The final concentration of substrate peptide is 1.25 uM. The reaction is allowed to proceed at room temperature for 1 hour. After incubation, the reaction is stopped by adding 20 mL of termination buffer containing Trichostatin A (included as a terminator) and Trypsin (BPS Cat. No. 50030). Terminated plates are read on a Synergy Neo2 luminometer. The parameter measured is the change in relative luminescence intensity (RLU). Percent inhibition (Pinh ) is determined using the following equation: P inh =(RLU 0%inh -RLU 化合物 ) / (RLU 0%inh -RLU 100%inh )*100, where RLU 化合物 is the luminescence of the sample in the presence of the compound, RLU 0%inh is the luminescence of the sample in the absence of compound, RLU 100%inh is the luminescence of the sample in the absence of enzyme. To determine the IC50 (50% inhibition) of the compounds, %-inh data (P inh vs compound concentration) were fitted to a four-parameter sigmoidal dose-response model.

[0338] Exemplary compounds were evaluated for inhibitory activity against a panel of HDAC paralogs. The results in Table 1 show that the compounds disclosed herein have potent activity against HDAC6, with many of the compounds selectively inhibiting HDAC6 over HDAC8, a class I HDAC paralog.

[0339] IC50 range: A: 0.001-0.1 μM, B: >0.1-1 μM, C: >1-10 μM, D: >10-100 μM, E: >100 μM.

[0340] Selectivity range (ratio of HDAC8 IC50 / HDAC6 IC50): I: 0.1-1, II: >1-10, III: >10-100, IV: >100-1000, V: >1000 [Table 6-1] [Table 6-2] [Table 6-3]

[0341] Equivalence and Scope In the claims, articles such as "a," "an," and "the" may mean one or more, unless indicated to the contrary or otherwise clear from the context. A claim or description including "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all group members are present in, employed in, or otherwise relevant to a given product or process.

[0342] Moreover, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other c...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, X is N or CR １ And Y is CR １ or N, where at least one of X and Y is N; R １ is hydrogen or halogen; R ａ and R ｂ Each is independently either hydrogen or halogen; L is a bond, or C is optionally substituted with one or more halogens. １～４ It is alkylene; A is a heteroaryl, aryl, carbocykryl, or heterocyclyl, and A has one or more substituents R ２ It is arbitrarily replaced with; R ２ Each of these entities is independently a halogen, amide, cyano, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs ２ are linked to its intervening atom to form a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, the compound or a pharmaceutically acceptable salt thereof.

2. X is N; R １ is hydrogen or fluoro; R ａ and R ｂ Each of them is independently hydrogen; L is a bond; A is a 5-11 member heteroaryl, C ６～１４ Ariel, C ３～１０ The compound is a cycloalkyl or a 4- to 11-membered heterocycline, where A is one to three independent substituents R ２ It can be optionally replaced by; R ２ Each of these entities is independent of halogen, cyano, and C. １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl, or C ２～６ It is an alkynyl, and each C １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl, or C ２～６ The compound according to claim 1, wherein the alkynyl is optionally substituted with one or more halogens or cyano compounds.

3. A is a 5,6-bicyclic heteroaryl ring system containing one or more nitrogen or oxygen heteroatoms, and A is composed of 1 to 3 independent substituents R ２ It can be optionally replaced by; Each R ２ These independently produce chloro, fluoro, -CN, and -CH ２ CN, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ The compound according to claim 2, which is a haloalkyl, acyl, amide, or a 5-6 membered heterocycline containing one or more nitrogen, oxygen, or sulfur heteroatoms.

4. A is unsubstituted, or a single R ２ It is replaced by and the R ２ The compound according to claim 3, wherein is methyl.

5. A 【Chemistry 2】 The compound according to claim 4.

6. A 【Transformation 3】 The compound according to claim 5.

7. Y is CR １ And R １ Is it hydrogen, or R １ The compound according to any one of claims 1 to 6, wherein is fluoro.

8. A compound according to any one of claims 1 to 6, wherein Y is N.

9. The aforementioned compound, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 The compound according to claim 1.

10. The aforementioned compound, 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. The aforementioned compound, 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound, 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound, 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound described in any one of claims 1 to 6.

15. Use of the compound according to any one of claims 1 to 6 for the manufacture of a drug for the treatment of neurological disorders.

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