Oxadiazole HDAC6 inhibitors and uses thereof

Abstract

Provided herein are compounds that selectively inhibit HDAC6, which is a protein whose activity is associated with a variety of diseases (e.g., cancer, neurological disorders). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating HDAC6-related 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

[0001] Related patent applications

[0002] This patent application claims priority under Section 119(e) of Title 35 of the United States Code to U.S. Provisional Patent Application USSN 63 / 329,143, filed on April 8, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Histone deacetylases (HDACs) are divided 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 one ubiquitin-binding domain, allowing HDAC6 to play a role in different cell signaling systems involving protein acetylation and ubiquitination, respectively. Importantly, it does not deacetylate histones. HDAC6 deacetylates tubulin, tau, Hsp90, cortical actin (cortactin), and other emerging 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, movement and migration, as well as cell growth and survival. In addition to the deacetylase function, HDAC6 also forms a complex with partner proteins connected to ubiquitin-dependent functions and affects protein aggregation, transport, and degradation through the aggresome pathway. HDAC6 expression is elevated in postmortem brain samples from Alzheimer's disease patients. Small molecule compounds that inhibit HDAC6 are being developed as potential therapies for Alzheimer's disease patients. Summary of the invention

[0004] The cytoplasmic location, different substrates and structure of HDAC6 are unique among HDAC paralogs, and HDAC6 selective treatment regimens are expected to avoid many side effects of the first generation of pan-HDAC inhibitors. However, paralog selectivity is difficult to obtain. The present disclosure stems from the following recognition: Among HDAC paralogs, the unique structure and function of HDAC6 provide opportunities for designing selective HDAC6 inhibitors. The present disclosure also recognizes that targeting HDAC6-mediated pathways can provide improved treatment for neurological disorders. Regarding neurodegeneration, HDAC6 (1) impairs microtubule function by deacetylation of tubulin, resulting in defects in axonal and mitochondrial transport; (2) promotes tau aggregation by deacetylation of tau, resulting in pathological tau phosphorylation and neurofibrillary tangle formation; and (3) prevents degradation of HSP90 client proteins (including misfolded tau) by deacetylation of HSP90, thereby stabilizing the molecular chaperone complex associated with protein refolding / recycling. Therefore, the present disclosure provides brain-permeable, selective HDAC6 inhibitors. These compounds provide novel compositions and methods for treating diseases associated with HDAC6 activity (e.g., neurological disorders such as Alzheimer's disease and other tauopathies, amyotrophic lateral sclerosis, and cancer).

[0005] In one aspect, there is provided a compound of formula (I):

[0006]

[0007] and pharmaceutically acceptable salts thereof, wherein:

[0008] X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N;

[0009] R a and R b are each independently hydrogen or halogen;

[0010] L is a bond or C optionally substituted by one or more halogens 1-4 Alkylene;

[0011] A is aryl, heteroaryl, carbocyclic or heterocyclic, wherein A is optionally substituted by one or more substituents R 2 replace;

[0012] R 1 is hydrogen or a halogen; and

[0013] Each occurrence of R 2R 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 two occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0014] In certain embodiments of the compound of formula (I): R a and R b are each independently hydrogen or fluorine; L is a bond or -CH2-; R 1 is hydrogen or fluorine; A is a C6 monocyclic aromatic group, a C6 aromatic group or a 6-membered heteroaromatic group fused to a C6 carbocyclic group or a 6-membered heterocyclic group containing nitrogen, oxygen or sulfur heteroatoms, a C6 aromatic group or a 6-membered heteroaromatic group; 10 bicyclic aryl, a 5-6 membered monocyclic heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, a 9-10 membered bicyclic heteroaryl containing one or more nitrogen or oxygen heteroatoms (e.g., a 5,6-bicyclic heteroaryl or a 6,6-bicyclic heteroaryl), C 4-10 Carbocyclic groups (e.g., C 4-7 Monocyclic carbocyclic group or C 4-7 A is optionally substituted with one or more substituents R 2 Replace; and each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, acyl, amide or a 5-6 membered heterocyclic group containing one or more nitrogen, oxygen or sulfur atoms.

[0015] In certain embodiments of the compound of formula (I): R a and R b Each is hydrogen; L is a bond; R 1 is hydrogen or fluorine; A is substituted by one or more R 2 Substituted C 5-6 monocyclic aromatic group; and each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4Haloalkyl, acyl, amide or a 5-6 membered heterocyclic group containing one or more nitrogen, oxygen or sulfur atoms.

[0016] In certain embodiments of the compound of formula (I): R a and R b are each independently hydrogen or fluorine; L is a bond; R 1 is hydrogen or fluorine; A is optionally substituted by one or more substituents R 2 substituted 6,6-bicyclic aryl ring system, 5,6-bicyclic heteroaryl ring system or 6,6-bicyclic heteroaryl ring system; and each R 2 are independently chlorine, fluorine, C 1-4 Alkyl or C 1-4 The 6,6-bicyclic aryl ring system (or group), the 5,6-bicyclic heteroaryl ring system (or group) and the 6,6-bicyclic heteroaryl ring system (or group) refer to fused ring systems (eg, 5,6 means a 5-membered ring is fused to a 6-membered ring).

[0017] In certain embodiments of the compound of formula (I): R a and R b Each is hydrogen; L is a bond; R 1 is hydrogen; A is a bicyclic ring containing a C6 aryl or 6-membered heteroaryl fused to a C6 carbocyclic or 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur heteroatom, wherein A is optionally substituted by one or more substituents R 2 Replace; and each R 2 are independently chlorine, fluorine, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0018] In certain embodiments of the compound of formula (I): R a and R b Each is hydrogen; L is a bond or -CH2-; R 1 is hydrogen or fluorine; A is C 4-7 Monocyclic carbocyclic group, C 4-7 A bridged polycyclic ring system, a 6-7 membered monocyclic heterocyclyl ring having one or more nitrogen, oxygen or sulfur heteroatoms, or a fused or bridged 7-10 membered polycyclic ring system, wherein A is optionally substituted by one or more substituents R 2 Replace; and each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, acyl, amide or a 5-6 membered heterocyclic group containing one or more nitrogen, oxygen or sulfur atoms.

[0019] In certain embodiments of the compounds of formula (I): X is N; R 1 is hydrogen or fluorine; Ra and R b are each independently hydrogen; L is a bond; A is a 5-11 membered heteroaryl, C 6-14 Aryl, C 3-10 Cycloalkyl or 4-11 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 Replace; and each occurrence of R 2 are independently halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, in which 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 compounds of formula (I): A is optionally substituted with 1-3 independent substituents R 2 substituted 5,6-bicyclic heteroaryl; and each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 haloalkyl, acyl, amide or a 5-6 membered heterocyclyl containing one or more nitrogen, oxygen or sulfur heteroatoms. 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 replaced by a single R 2 In certain embodiments of the compound of formula (I): R 2 It is C 1-4 In certain embodiments of the compound of formula (I): R 2 In certain embodiments of the compound of formula (I): A is

[0020] In certain embodiments of compounds of Formula (I): A is unsubstituted.

[0021] In certain embodiments of the compounds of formula (I): Y is CR 1 And R 1 is hydrogen or fluorine, or Y is N.

[0022] In another aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0023] On the other hand, there is provided a method for treating the nervous system or peripheral diseases or illnesses of a subject in need, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) to the subject. In certain embodiments, the nervous system disease or illness treated using a compound as described herein or a composition is a neurodegenerative, neurodevelopmental, neuropsychiatric or neuropathy disease. In certain embodiments, a nervous system disease or illness 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 depression, cognitive dysfunction caused by chemotherapy, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), brain cancer or tau disease such as 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.

[0024] On the other hand, there is provided a method for inhibiting the activity of HDAC6, the method comprising contacting HDAC6 with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, inhibiting the activity of HDAC6 comprises selectively inhibiting the activity of HDAC6 relative to the activity of HDAC8. In certain embodiments, HDAC6 is in a cell (e.g., a human cell). In certain embodiments, the inhibition of HDAC6 activity occurs in vitro. In certain embodiments, the inhibition of HDAC6 activity occurs in vivo.

[0025] In another aspect, a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, is provided. In certain embodiments, the kit further comprises instructions for administration (eg, human administration).

[0026] The details of certain embodiments of the invention are set forth in the detailed description set forth below. Other features, objects and advantages of the invention will be apparent from the definitions, examples and claims. DETAILED DESCRIPTION

[0027] Provided herein are compounds as HDAC inhibitors (e.g., HDAC6 inhibitors). The compounds described herein have favorable properties, such as the selective inhibition of HDAC6 and / or the ability to pass through the blood-brain barrier, which make the compounds useful as therapeutic agents. In one aspect, the HDAC6 inhibitors provided are compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-labeled derivatives, prodrugs, and pharmaceutical compositions thereof. Therefore, the compounds can be used to treat and / or prevent diseases and disorders (e.g., nervous system disorders or diseases, or peripheral diseases or disorders) associated with HDAC6 activity in subjects in need.

[0028] The compounds described herein interact with HDAC6. As described herein, the therapeutic effect can be the result of the inhibition, regulation, combination and / or modification of HDAC6 by the compounds described herein. The compounds can be provided as pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs thereof for use in any composition, kit or method described herein.

[0029] Compound of formula (I)

[0030] In one aspect, disclosed are compounds of formula (I):

[0031]

[0032] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein:

[0033] X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N;

[0034] R a and R b are each independently hydrogen or halogen;

[0035] L is a bond or C optionally substituted by one or more halogens 1-4 Alkylene;

[0036] A is aryl, heteroaryl, carbocyclic or heterocyclic, wherein A is optionally substituted by one or more substituents R 2 replace;

[0037] R 1 is hydrogen or a halogen;

[0038] Each occurrence of R 2R 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 two occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0039] In one aspect, disclosed are compounds of formula (I):

[0040]

[0041] or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein:

[0042] X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N;

[0043] R a and R b are each independently hydrogen or halogen;

[0044] L is a bond or C optionally substituted by one or more halogens 1-4 Alkylene;

[0045] A is aryl, heteroaryl, carbocyclic or heterocyclic, wherein A is optionally substituted by one or more substituents R 2 replace;

[0046] R 1 is hydrogen or a halogen;

[0047] Each occurrence of R 2 R is independently 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 occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0048] In certain embodiments, the compound of formula (I) is wherein X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N; and L is a bond or -(CH2)-.

[0049] In certain embodiments, the compound of formula (I) is wherein X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N; L is a bond or -(CH2)-; and R a and R b are each independently hydrogen or fluorine.

[0050] In certain embodiments, the compound of formula (I) is wherein X is CR 1 or N and Y is CR 1 or N, provided that at least one of X and Y is N; L is a bond or -(CH2)-; R a and R b are each independently hydrogen or fluorine; and A is a C6 monocyclic aryl, a bicyclic ring containing a C6 aryl or 6-membered heteroaryl fused to a C6 carbocyclic ring or a 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur heteroatom, a C6 10 bicyclic aryl, a 5-6 membered monocyclic heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, a 9-10 membered bicyclic heteroaryl containing one or more nitrogen or oxygen heteroatoms (e.g., a 5,6-bicyclic heteroaryl or a 6,6-bicyclic heteroaryl), C 4-10 Carbocyclic groups (e.g., C 4-7 Monocyclic carbocyclic group or C 4-7 A is optionally substituted with one or more substituents R 2 Replace; and each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, acyl, amide or a 5-6 membered heterocyclic group containing one or more nitrogen, oxygen or sulfur atoms.

[0051] In certain embodiments, the compound of formula (I) is a compound wherein: R a and R b are each independently hydrogen; L is a bond; R 1 is hydrogen or fluorine; A is substituted by one or more R 2 substituted C6 monocyclic aromatic group; and each R 2are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, acyl, amide or a 5-6 membered heterocyclic group containing one or more nitrogen, oxygen or sulfur atoms.

[0052] X and Y

[0053] As used herein, X is CR 1 or N, and Y is CR 1 or N, provided that at least one of X and Y is N; and R 1 is hydrogen or a halogen.

[0054] In certain embodiments, X is N. In certain embodiments, X is CR 1 In certain embodiments, X is CR 1 ; and R 1 is hydrogen or halogen. In certain embodiments, X is CR 1 ; and R 1 In certain embodiments, X is CH or CF. In certain embodiments, X is CH. In certain embodiments, X is CF.

[0055] In certain embodiments, Y is N. In certain embodiments, Y is CR 1 In certain embodiments, Y is CR 1 ; and R 1 is hydrogen or halogen. In certain embodiments, Y is CR 1 ; and R 1 In certain embodiments, Y is CH or CF. In certain embodiments, Y is CH. In certain embodiments, Y is CF.

[0056] In certain embodiments, at least one of X and Y is N. In certain embodiments, 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.

[0057] In certain embodiments, Y is N and X is CR 1 In certain embodiments, Y is N and X is CH. In certain embodiments, Y is N and X is CF. In certain embodiments, Y is N and X is N.

[0058] R 1

[0059] As described in this article, R 1 is hydrogen or halogen. In certain embodiments, R 1 is hydrogen or fluorine. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 It's fluorine.

[0060] R a and R b

[0061] As described in this article, R a and R b Each is independently hydrogen or halogen. In certain embodiments, R a and R b Each is independently halogen. In certain embodiments, R a and R b Each is independently hydrogen or fluorine. In certain embodiments, R a and R b In certain embodiments, R a and R b Each is fluorine.

[0062] In certain embodiments, R a is hydrogen or a halogen, and R b In certain embodiments, R a is hydrogen or a halogen, and R b is hydrogen. In certain embodiments, R a is hydrogen, and R b 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 It's hydrogen.

[0063] In certain embodiments, R a is hydrogen or fluorine, and R b In certain embodiments, R a is hydrogen or fluorine, and R b is hydrogen. In certain embodiments, R a is hydrogen, and R b is hydrogen or fluorine. In certain embodiments, R a is fluorine, and R b It is hydrogen or fluorine.

[0064] In certain embodiments, R a is hydrogen, and Rb In certain embodiments, R a is fluorine, and R b is hydrogen. In certain embodiments, R a is fluorine, and R b It's hydrogen.

[0065] L

[0066] As used herein, L is a bond or a C optionally substituted with one or more halogens. 1-4 In certain embodiments, L is a bond or 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 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 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 fluorines. 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 1-2 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 an unsubstituted methylene.

[0067] A

[0068] As described herein, A is aryl, heteroaryl, carbocyclyl or heterocyclyl, wherein A is optionally substituted by one or more substituents R 2 replace;

[0069] In certain embodiments, A is C 6-14 Aryl, 5-11 membered heteroaryl, C 3-10 Cycloalkyl or 4-11 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0070] In certain embodiments, A is phenyl, C 9-14 A fused bicyclic aryl, a 5-6 membered heteroaryl or a 9-14 membered fused bicyclic heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R2 replace.

[0071] In certain embodiments, A is a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or a C 4-6 A is a phenyl group fused to a carbocyclic ring, or A is a phenyl group, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclic fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 4-6 membered heterocyclyl or a C 4-6 A is a phenyl group fused to a carbon ring, or A is a 4-6 membered heterocyclic group or a C 4-6 A carbocyclic fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0072] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 Substituted C 6-14 In certain embodiments, A is phenyl or C 9-14 A fused bicyclic aryl group, wherein A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is phenyl or naphthyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is unsubstituted phenyl. In certain embodiments, A is substituted by 1-3 independent substituents R 2 Substituted phenyl.

[0073] In certain embodiments, A is substituted by 1-3 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 are independently fluorine, chlorine, cyano, cyclopropyl, C 2-4 Alkynyl or C optionally substituted by one or more fluorine, cyano or alkynyl 1-4 In certain embodiments, A is substituted by 1-3 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 R is independently fluorine, chlorine, cyano, methyl optionally substituted with one or more fluorine, or methyl optionally substituted with cyano. In certain embodiments, A is substituted with 1-3 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 is independently fluoro, chloro, cyano, methyl optionally substituted by one or more fluoro groups, or methyl optionally substituted by cyano.

[0074] In certain embodiments, A is substituted by 1-2 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 are independently fluorine, chlorine, cyano, cyclopropyl, C 2-4 Alkynyl or C optionally substituted by one or more fluorine, cyano or alkynyl 1-4 In certain embodiments, A is substituted by 1-2 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 R is independently fluorine, chlorine, cyano, methyl optionally substituted with one or more fluorine, or methyl optionally substituted with cyano. In certain embodiments, A is substituted with 1-2 independent substituents R 2 Substituted phenyl, where each occurrence of R 2 is independently fluoro, chloro, cyano, methyl optionally substituted by one or more fluoro groups, or methyl optionally substituted by cyano.

[0075] In certain embodiments, A is wherein p is 0, 1, 2 or 3. In certain embodiments, A is wherein p is 1, 2 or 3. In certain embodiments, A is wherein p is 1 or 2. In certain embodiments, A is wherein p is 1. In certain embodiments, A is wherein p is 2. In certain embodiments, A is Where p is 3.

[0076] In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is

[0077] In certain embodiments, A is In certain embodiments, A is

[0078] In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is

[0079] In certain embodiments, A is C 9-14 A fused bicyclic aryl group, wherein A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is

[0080] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic or bicyclic heteroaryl group, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In some embodiments, A is optionally substituted by 1-3 independent substituents R 2 substituted 5-membered monocyclic heteroaryl, which is optionally substituted by 1-3 independent substituents R 2 In some embodiments, A is optionally substituted by 1-3 independent substituents R 2 substituted 5-membered monocyclic heteroaryl, which is optionally substituted by 1-3 independent substituents R 2 In some embodiments, A is optionally substituted by 1-3 independent substituents R 2 substituted 6-membered monocyclic heteroaryl, which is optionally substituted by 1-3 independent substituents R 2 In some embodiments, A is optionally substituted by 1-3 independent substituents R2 substituted 6-membered monocyclic heteroaryl, which is optionally substituted by 1-3 independent substituents R 2 The substituted another 6-membered monocyclic heteroaryl is fused.

[0081] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, phenylthio, oxazolyl, thiazolyl, isoxazolyl, pyrazinyl, pyridazinyl or oxadiazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is pyridyl or pyrimidinyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is substituted by 1-3 independent substituents R 2 Substituted 2-pyridyl or 3-pyridyl.

[0082] In certain embodiments, A is wherein p is 0, 1, 2 or 3. In certain embodiments, A is wherein p is 0, 1, 2 or 3. In certain embodiments, A is wherein p is 0, 1, 2 or 3. In certain embodiments, A is wherein p is 0 or 1. In certain embodiments, A is wherein p is 0 or 1. In certain embodiments, A is where p is either 0 or 1.

[0083] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-2 independent substituents R2 In certain embodiments, A is optionally substituted with 1 substituent R 2 Substituted pyrimidinyl.

[0084] In certain embodiments, A is

[0085] In certain embodiments, A is

[0086] In certain embodiments, A is

[0087] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is

[0088] In certain embodiments, A is

[0089] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 Substituted 9-14 membered fused bicyclic heteroaryl.

[0090] In certain embodiments, A is a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or a C 4-6 A is a phenyl group fused to a carbocyclic ring, or A is a phenyl group, a 5-6 membered heteroaryl group, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclyl ring-fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is substituted with 5-6 membered heteroaryl, 4-6 membered heterocyclyl or C 4-6 A is a phenyl group fused to a carbocyclic ring, or A is a phenyl group, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclyl ring-fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 4-6 membered heterocyclyl or a C 4-6 A is a phenyl group fused to a carbocyclic ring, or A is a 4-6 membered heterocyclic group or a C 4-6 A carbocyclic fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is phenyl fused to a 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R2 In certain embodiments, A is a phenyl group fused to a 4-6 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is 4-6 A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is a 5-6 membered heteroaryl fused to a phenyl group, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a 5-6 membered heteroaryl fused to a 4-6 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is 4-6 A carbocyclic fused 5-6 membered heteroaryl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0091] 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, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is benzoxazolyl, indazolyl, isoquinolyl, tetrahydroisoquinolyl, quinazolinyl, triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, quinolyl, benzisoxazolyl, benzimidazolyl or quinoxalinyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl or benzopyrazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is phenyl, quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl or benzopyrazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl or benzopyrazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is quinazolinyl, wherein A is optionally substituted by 1-3 independent substituents R 2In certain embodiments, A is imidazo[1,2-a]pyrazinyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is benzisoxazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is benzopyrazolyl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0092] In certain embodiments, A is Where R x and R y Connected to form a 5-6 membered heteroaryl, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, R 2 Can be connected to the benzene ring of A or to the R x and R y The 5-6 membered heteroaryl, 4-6 membered heterocyclic group or C 4-6 Carbocyclic ring.

[0093] In certain embodiments, A is Where R x and R y Connected to form a 5-6 membered heteroaryl, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y to form a 5-6 membered heteroaryl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y to form a 4-6 membered heterocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y Connect to form C 4-6 A carbocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0094] In certain embodiments, A is wherein A is optionally substituted by 1 to 3 independent substituents R2 replace.

[0095] In certain embodiments, A is wherein A is optionally substituted by 1 to 3 independent substituents R 2 In certain embodiments, A is

[0096] In certain embodiments, A is Where R x and R y Connected to form a 5-6 membered heteroaryl, a 4-6 membered heterocyclic group or a C 4-6 A carbocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y to form a 5-6 membered heteroaryl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y to form a 4-6 membered heterocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is Where R x and R y Connect to form C 4-6 A carbocyclyl ring, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is

[0097] In certain embodiments, A is In certain embodiments, A is

[0098] In certain embodiments, A is In certain embodiments, A is

[0099] In certain embodiments, A is

[0100] In certain embodiments, A is a carbocyclyl or heterocyclyl group, wherein A is optionally substituted by one or more substituents R 2 In certain embodiments, A is C 3-10 Cycloalkyl or 4-11 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0101] In certain embodiments, A is optionally substituted with one or more substituents R 2 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 3-10 In certain embodiments, A is C 5-10 Bridged cycloalkyl, C 5-10 Spirocyclic cycloalkyl or C 3-8 Monocyclic cycloalkyl, wherein A is optionally substituted by one or more substituents R 2 In certain embodiments, A is C 5-10 Bridged cycloalkyl or C 3-8 Monocyclic cycloalkyl, wherein A is optionally substituted by one or more substituents R 2 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 5-10 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 5-10 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 8-10 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 3-8 In certain embodiments, A is optionally substituted with one or more substituents R 2 Substituted C 3-6 Monocyclic cycloalkyl.

[0102] In certain embodiments, A is bicyclo[1.1.1]pentan-1-yl, tetrahydronaphthyl, or adamantyl, wherein A is optionally substituted by 1-3 independent substituents R2 In certain embodiments, A is adamantyl or bicyclo[1.1.1]pentan-1-yl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0103] In certain embodiments, A is

[0104] In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is 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, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is a monocyclic 4-7 membered heterocyclyl or a 5-10 membered bridged heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is optionally substituted by 1-3 independent substituents R 2 Substituted 9-membered heterocyclic spiro ring system.

[0105] In certain embodiments, A is azabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, quinuclidinyl, morpholinyl, or oxadamantyl, wherein A is optionally substituted by 1-3 independent substituents R 2 In certain embodiments, A is (1r,3r,5r,7r)-2-oxadamantyl.

[0106] In certain embodiments, A is

[0107] In certain embodiments, A is phenyl, pyridyl, quinolyl, or naphthyl, wherein A is optionally substituted by 1-3 independent substituents R 2 replace.

[0108] In certain embodiments, A is In certain embodiments, A is

[0109] In certain embodiments, A is In certain embodiments, A is

[0110] In some embodiments, A is In some embodiments, A is

[0111] In some embodiments, A is

[0112] R 2

[0113] As used herein, each occurrence of R 2R 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 two occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 R is independently 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 occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 R is independently 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. In certain embodiments, each occurrence of R 2 and R is independently 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, or substituted or unsubstituted heterocyclyl.

[0114] In certain embodiments, R 2 is a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted amidoalkyl, optionally substituted by C 1-4 Alkyl-substituted amino, or optionally C 1-4 In certain embodiments, R 2 is optionally C 1-4 Alkyl-substituted amino or amide.

[0115] In certain embodiments, each occurrence of R 2are independently 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, 4-6 membered substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 2-6 Alkenyl, or substituted or unsubstituted C 2-6 In certain embodiments, each occurrence of R 2 are independently halogen, cyano, -NH2, -NHCH3, -(C=O)OH, -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHPh, C 1-6 Alkyl, aminoalkyl, 4-6 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 C 2-6 Alkynyl, in which 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. 2 are independently halogen, cyano, -(C=O)NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 2-6 Alkenyl or C 2-6 Alkynyl, in which each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups are optionally substituted with one or more halogen or cyano groups.

[0116] In certain embodiments, each occurrence of R 2 is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, -(C=O)NH2, cyano, cyanomethyl, ethynyl, or morpholinyl. In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 is independently -(C=O)NH2. In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 is independently cyanomethyl. In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 are independently morpholinyl.

[0117] In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 It's fluorine.

[0118] In certain embodiments, each occurrence of R 2 are independently halogen, cyano, or substituted or unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently halogen, cyano or unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently fluoro, cyano or methyl.

[0119] In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently halogen, cyano, -(C=O)NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 2-6 Alkenyl or C 2-6 Alkynyl, in which each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups are optionally substituted with one or more halogen or cyano groups.

[0120] In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, -(C=O)NH2, cyano, cyanomethyl, ethynyl or morpholinyl.

[0121] In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, chlorine, cyano, cyclopropyl, C 2-4 Alkynyl or C optionally substituted by one or more fluorine, cyano or alkynyl 1-4 alkyl.

[0122] In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 In certain embodiments, A is replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 It's fluorine.

[0123] In certain embodiments, A is C 6-14 Aryl, 5-11 membered heteroaryl, C 3-10 Cycloalkyl or 4-11 membered heterocyclyl, wherein A is optionally substituted by 1-3 independent substituents R 2 Replace each occurrence of R 1 is independently hydrogen, halogen or C optionally substituted by one or more halogen or alkoxy 1-6 alkyl; and each occurrence of R 2 are independently halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, in which each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups are optionally substituted with one or more halogen or cyano groups.

[0124] In certain embodiments, each occurrence of R 1 is independently hydrogen, halogen, or methyl optionally substituted with one or more halogen or alkoxy; and each occurrence of R 2 are independently halogen, cyano, methyl, cyclopropyl, C 2-3 Alkenyl or C 2-3 Alkynyl, in which each methyl, cyclopropyl, C 2-3 Alkenyl or C 2-3Alkynyl groups are optionally substituted with one or more halogen or cyano groups.

[0125] In certain embodiments, R 1 , R 2 , R a and R b In certain embodiments, each halogen in is fluorine or chlorine. 1 , R 2 , R a and R b Each halogen in is fluorine.

[0126] In certain embodiments, the compound of Formula (I) has Formula (Ia):

[0127]

[0128] or a pharmaceutically acceptable salt thereof; wherein A and Y are as defined herein.

[0129] 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.

[0130] In certain embodiments of Formula (Ia), A is a bicyclic fused heteroaryl group comprising at least two heteroatoms (eg, S, N, O), and A is optionally substituted by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, cyano, or substituted or unsubstituted C 1-6 In certain embodiments of formula (Ie), A is a 5,6 bicyclic fused heteroaryl group containing at least two heteroatoms (eg, S, N, O), and A is optionally substituted by 1 or 2 R 2 Group substitution, where each occurrence of R 2 In certain embodiments of formula (Ia), A is a 5,6 bicyclic fused heteroaryl group containing at least two heteroatoms (e.g., S, N, O), and A is optionally substituted by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, cyano, or substituted or unsubstituted C 1-6 In certain embodiments of formula (Ia), A is quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl or benzopyrazolyl, and A is optionally substituted by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, cyano, or substituted or unsubstituted C1-6 In certain embodiments of formula (Ia), A is imidazo[1,2-a]pyrazinyl, and A is optionally substituted by 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, cyano, or substituted or unsubstituted C 1-6 In certain embodiments of Formula (Ia), A is unsubstituted 5,6-bicyclic heteroaryl. In certain embodiments of Formula (Ia), A is unsubstituted imidazo[1,2-a]pyrazinyl.

[0131] In certain embodiments of Formula (Ia), A is phenyl, pyridinyl or pyrimidinyl, and A is optionally replaced by 1 or 2 R 2 Group substitution, where each occurrence of R 2 R is independently fluorine, chlorine, cyano, methyl optionally substituted with one or more fluorine, or methyl optionally substituted with cyano. In certain embodiments of formula (Ia), A is phenyl, quinazolinyl, imidazo[1,2-a]pyrazinyl, benzisoxazolyl or benzopyrazolyl, and A is optionally substituted with 1 or 2 R 2 Group substitution, where each occurrence of R 2 are independently fluorine, cyano, or substituted or unsubstituted C 1-6 alkyl.

[0132] 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; and A is phenyl or pyridinyl substituted with halogen, alkyl, amide, haloalkyl, aryl, aralkyl or heteroaryl, wherein amide is optionally substituted with alkyl, aryl or heteroaryl, and 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 phenyl or pyridinyl substituted with halogen, C 1-4 Alkyl, benzyl, C 1-4 In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with one or more fluorine or chlorine. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with one or two fluorine or chlorine. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with fluorine. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with one or two fluorine or chlorine. 1-4 Alkyl or C 1-4Phenyl or pyridyl substituted with haloalkyl. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with methyl or -CF3. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is pyridyl substituted with methyl. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with -CF3. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with alkylamide. In certain embodiments of formula (Ia), Y is CH, CF or N; and A is phenyl or pyridyl substituted with -NHC(=O)R aa Substituted phenyl or pyridyl, wherein R aa It is C 1-4 In certain embodiments of Formula (Ia), Y is CH, CF, or N; and A is -NR aa R bb C(=O)R cc or -C(=O)NR aa R bb Substituted phenyl or pyridyl, wherein R aa , R bb and R cc are independently hydrogen or C 1-4 alkyl.

[0133] In certain embodiments, the compound of formula (I) is one of the following compounds or a pharmaceutically acceptable salt thereof:

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] In certain embodiments, the compound of formula (I) is one of the following compounds or a pharmaceutically acceptable salt thereof:

[0146]

[0147]

[0148]

[0149]

[0150] 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); 2-(6-((2-chloro-4-fluorophenoxy)methyl)pyridin-5-yl)-1,3,4-oxadiazole (4); 2-(6-((2-chloro-5-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-5-fluorophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (7); 2-(6-((4 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-3-yl)-1,3,4-oxadiazole (10); 2-(Difluoromethyl)-5-(6-((naphthalen-1-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (11); 2-(Difluoromethyl)-5-(6-((naphthalen-1-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (12); )-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).

[0151] In certain embodiments, provided compounds (eg, compounds of Formula (I)) inhibit HDAC6, wherein IC 50 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.

[0152] In certain embodiments, provided compounds (e.g., compounds of formula (I)) selectively inhibit HDAC6 relative to any one of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, the compounds selectively inhibit HDAC6 relative to each of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certain embodiments, the compounds are 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 selective inhibitors of HDAC6 relative to any one 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 selective inhibitor of HDAC6 relative to 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 selective inhibitor of HDAC6 relative to HDAC8.

[0153] Pharmaceutical compositions and kits

[0154] The present disclosure provides a pharmaceutical composition comprising a disclosed compound (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, and an optional pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0155] The present disclosure provides a pharmaceutical composition for treating an HDAC6-related disease or condition in a subject in need, the pharmaceutical composition comprising a compound that interacts with HDAC6 (e.g., inhibits HDAC6). The present disclosure provides a pharmaceutical composition for treating a disease or condition related to the abnormal activity of HDAC6 in a subject in need, the pharmaceutical composition comprising a compound that interacts with HDAC6 (e.g., inhibits HDAC6). The present disclosure provides a pharmaceutical composition for treating a disease or condition related to an increase in the activity of HDAC6 in a subject in need, the pharmaceutical composition comprising a compound that interacts with HDAC6 (e.g., inhibits HDAC6).

[0156] In certain embodiments, the composition is used to treat a nervous system or peripheral disorder. In certain embodiments, the composition is used to treat a neurodegenerative, neurodevelopmental, neuropsychiatric or neuropathic disease or disorder.

[0157] Compounds or compositions as described herein can be used in combination with one or more other medicaments (for example, treatment and / or prevention active agents). The compound or composition can be used in combination with other medicaments, and the other medicaments improve their activity (for example, in treating the disease of a subject in need, preventing the disease of a subject in need and / or reducing the risk of the development disease of a subject in need (for example, efficacy and / or efficacy)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or change metabolism, inhibit excretion and / or change the distribution in a subject or cell. It should also be understood that the therapy used can achieve the desired effect for the same disease, and / or it can achieve different effects. In certain embodiments, the pharmaceutical composition described herein comprising a compound as described herein and another medicament shows a synergistic effect, which is not present in a pharmaceutical composition comprising one of the compound and the other medicament but not both.

[0158] 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 prepare a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to prepare 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.

[0159] After being formulated with appropriate pharmaceutically acceptable excipients at desired doses, the pharmaceutical compositions of the present disclosure can be administered to humans and other animals orally, parenterally, intracisternal, intraperitoneal, topically, buccally, etc., depending on the disease or condition to be treated.

[0160] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparation methods include the steps of associating a composition comprising a compound of formula (I) with a carrier and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, molding and / or packaging the product into a desired single or multiple dose unit.

[0161] The pharmaceutical composition can be prepared, packaged and / or sold as a single unit dose and / or as a plurality of single unit doses in batches. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and / or a suitable fraction of such a dose, such as one-half or one-third of such a dose.

[0162] The relative amounts of active ingredients, pharmaceutically acceptable excipients and / or any additional ingredients in the pharmaceutical compositions of the present invention will vary according to the identity, size and / or condition of the subject being treated, and also according to the route of administration of the composition. For example, the composition may contain 0.1% to 100% (w / w) of active ingredient.

[0163] Pharmaceutically acceptable excipients for making the provided pharmaceutical compositions include, but are not limited to, inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and fragrances may also be present in the compositions.

[0164] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dibasic calcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0165] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0166] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, 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, esters, 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., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (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 (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor TM), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij 30)), 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-188, cetyltrimethylammonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and / or mixtures thereof.

[0167] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabinogalactan), alginates, polyoxyethylene, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and / or mixtures thereof.

[0168] 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.

[0169] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0170] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium EDTA, disodium EDTA, trisodium EDTA, disodium EDTA calcium, dipotassium EDTA, 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, ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0171] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0172] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenethyl alcohol.

[0173] 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.

[0174] 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.

[0175] Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glucuronate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, tricalcium 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, disodium hydrogen phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0176] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, 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.

[0177] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, black currant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, palm wax oil, castor oil, cinnamon oil, cocoa butter oil, 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, macadamia oil, lavender oil, lavender Oil, lemon oil, litsea cubeba oil, macadamia 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, camellia oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, tsubaki 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.

[0178] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, the liquid dosage form may contain inert diluents commonly used in the art (such as water or other solvents); solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (particularly 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, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics. In certain embodiments for parenteral administration, the agent of the present invention is mixed with a solubilizer such as CREMOPHOR (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and combinations thereof.

[0179] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectable preparations.

[0180] The injectable formulations can be sterilized by, for example, filtration through a bacteria-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.

[0181] 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, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or the following substances: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0182] Solid compositions of similar types may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules with coatings and shells such as enteric coatings and other coatings known in the field of pharmaceutical formulations may be prepared. They may optionally contain opacifiers and may also have a composition that allows them to release the active ingredient only or preferentially in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar types may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols.

[0183] The activating agent can also be in the form of microencapsulation 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, controlled release coatings and other coatings known in the field of pharmaceutical preparations. In such solid dosage forms, the activating agent can be mixed with at least one inert diluent such as sucrose, lactose or starch. It is common practice that such dosage forms can also include other substances except the inert diluent, 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 form can also include a buffer. They can optionally contain an emulsifier, and can also have a composition that allows it to optionally only or preferentially release the active ingredient in a delayed manner in a certain part of the intestinal tract. Examples of usable embedded compositions include polymeric substances and waxes.

[0184] Preparations suitable for topical application include liquid or semi-liquid preparations, such as liniments, lotions, gels, compresses, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or solutions or suspensions such as drops. Preparations for topical application to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Useful carriers can form a film or layer on the skin to position application and inhibit removal. For topical application to the internal tissue surface, the agent can be dispersed in a liquid tissue adhesive or other substances known to enhance adsorption to the tissue surface. For example, hydroxypropylcellulose or fibrinogen / thrombin solutions can be advantageously used. Alternatively, tissue coating solutions such as preparations containing pectin can be used. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present disclosure encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of the agent to the body. Such dosage forms can be prepared by dissolving or distributing the agent in an appropriate medium. Absorption enhancers can also be used to increase the flux of the agent across the skin.The rate can be controlled by providing a rate controlling membrane or by dispersing the agent in a polymer matrix or gel.

[0185] In addition, carriers for topical preparations may be in the form of hydroalcoholic systems (e.g., liquids and gels), anhydrous systems or emulsion systems based on oils or silicones, including but not limited to oil-in-water, water-in-oil, water-in-oil-in-water, and water-in-oil-in-silicone emulsions. Emulsions can cover a wide range of consistencies, including dilute lotions (which may also be suitable for spray or aerosol delivery), milky lotions, dilute creams, thick creams, etc. Emulsions may also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and water-based mousse systems.

[0186] The present disclosure also encompasses medicine boxes (e.g., drug packs). The medicine boxes 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 medicine boxes provided may optionally further include a second container, which contains a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a unit dosage form.

[0187] Therefore, on the one hand, a medicine box including a first container is provided, wherein the first container comprises a compound or a pharmaceutical composition as described herein. In certain embodiments, the medicine box can be used to treat a disease of a subject in need (e.g., proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heterologous immune diseases, nervous system disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or mediated by T cell dysregulation or a disease or condition associated with T cell dysregulation). In certain embodiments, the medicine box can be used to prevent a disease of a subject in need (e.g., proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heterologous immune diseases, nervous system disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or mediated by T cell dysregulation or a disease or condition associated with T cell dysregulation). In certain embodiments, the kit can be used to reduce 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 or associated with T cell dysregulation) in a subject in need thereof. In certain embodiments, the kit can be used to inhibit the activity (e.g., abnormal activity, such as increased activity) of HDAC6 in a subject or cell.

[0188] In certain embodiments, medicine box as described herein also includes instructions for using the medicine box.Medicine box as described herein may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA).In certain embodiments, the information included in the medicine box is prescription information.In certain embodiments, the medicine box and instructions are provided for treating the disease of a subject in need (e.g., proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heteroimmune diseases, nervous system disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or mediated by T cell disorder or diseases or conditions associated with T cell disorder).In certain embodiments, the medicine box and instructions are provided for preventing the disease of a subject in need (e.g., proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heteroimmune diseases, nervous system disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or mediated by T cell disorder or diseases or conditions associated with T cell disorder). In certain embodiments, the medicine box and instructions provide for reducing the risk of developing diseases (e.g., proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heteroimmune diseases, nervous system disorders, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or diseases or disorders mediated by or associated with T cell disorders) in subjects in need. In certain embodiments, the medicine box and instructions provide for inhibiting the activity (e.g., abnormal activity, such as increased activity) of HDAC6 in subjects or cells. The medicine box described herein may include one or more additional agents described herein as a separate composition.

[0189] Treatment

[0190] 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 a variety of substrates that affect disease-related pathways (including microtubule stability, axonal and mitochondrial transport, protein aggregation and autophagy). For example, direct substrates of HDAC6 (e.g., tau, tubulin and HSP90) are involved in the key mechanisms of Alzheimer's disease. Due to its unique structure and function, selectively targeting HDAC6 and inhibiting HDAC6 activity can avoid the typical side effects of existing FDA-approved HDAC inhibitors, which cause clinical toxicity (which has been shown to cause thrombocytopenia, which is the dose-limiting toxicity of most FDA-approved pan-HDAC inhibitors) due to extensive inhibition of multiple HDAC paralogs and / or inhibition of HDAC1 and / or 2. Therefore, it may be particularly effective to use HDAC6 selective inhibitors to treat HDAC6-related diseases.

[0191] The present disclosure provides methods for treating HDAC6 related diseases and conditions. In certain embodiments, the present application provides methods for treating proliferative diseases, inflammatory diseases, infectious diseases, autoimmune diseases, heterologous immune diseases, nervous system disorders, peripheral diseases or conditions, metabolic diseases, cystic fibrosis, polycystic kidney disease, pulmonary hypertension, cardiac dysfunction, or diseases or conditions mediated by T cell dysregulation or related to 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 blood 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 cancers including solid tumors. In certain embodiments, the present application provides methods for 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.

[0192] In certain embodiments, the application provides a method for treating an inflammatory disease. In certain embodiments, the 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 condition mediated by T cell disorder or associated with T cell disorder. In certain embodiments, the composition is used to treat arthritis, colitis, allogeneic transplant rejection, lupus, asthma, psoriasis, inflammation, allergy, allergic encephalomyelitis, autoimmune lymphoproliferative disease, autoimmune polyglandular syndrome type II, type I diabetes, lymphoma, Wiskott-Aldrich syndrome (Wiskott-Aldrich syndrome) or myasthenia gravis.

[0193] In certain embodiments, the present application provides methods for treating infectious diseases. In certain embodiments, the present application provides methods for treating bacterial, fungal or protozoan infections.

[0194] In certain embodiments, the present application provides methods for treating autoimmune diseases. In certain embodiments, the present application provides methods for treating diabetes, thyroiditis, Graves' disease, Guillain-Barre syndrome, Addison's disease, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, chronic fatigue, or endometriosis.

[0195] In certain embodiments, the present application provides methods for treating heteroimmune diseases. In certain embodiments, the present application provides methods for treating graft-versus-host disease, transplantation, transfusion, allergic reaction, allergic conjunctivitis or allergic rhinitis.

[0196] In certain embodiments, the present application provides methods for treating a neurological disease or disorder. In certain embodiments, the present application provides methods for treating a neurodegenerative, neurodevelopmental, neuropsychiatric or neuropathic disease or disorder. In certain embodiments, the present application provides methods 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, muscular dystrophy, memory loss due to epilepsy, 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 tauopathy. In certain embodiments, the present application provides a method for treating primary age-related tauopathy (PART) / neurofibrillary tangle-dominant Alzheimer's disease, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, frontotemporal dementia and Parkinson's syndrome associated with chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, lead poisoning encephalopathy, tuberous sclerosis, lipofuscinosis, Alzheimer's disease or argyrophilic granule disease. In certain embodiments, the present application provides a method for treating Alzheimer's disease. In certain embodiments, the composition is used to treat Alzheimer's disease, fragile X syndrome, Chuck-Marie-Douglas 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 cancer, or tauopathies such as frontotemporal dementia, progressive supranuclear palsy, or corticobasal degeneration.

[0197] In certain embodiments, the present application provides methods of treating a nervous system or peripheral disease or disorder.

[0198] In certain embodiments, the present application provides methods of treating a neurodegenerative, neurodevelopmental, neuropsychiatric or neuropathic disease or disorder.

[0199] 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.

[0200] The present disclosure provides methods for inhibiting the activity of HDAC. In certain embodiments, the present application provides methods for inhibiting the activity of HDAC6. In certain embodiments, the present application provides methods for inhibiting the activity of HDAC6 in vitro. In certain embodiments, the present application provides methods for inhibiting the activity of HDAC6 in vivo. In certain embodiments, the present application provides methods for inhibiting the activity of HDAC6 in cells. In certain embodiments, the present application provides methods for inhibiting the activity of HDAC6 in human cells.

[0201] In certain embodiments, the method includes administering a compound that interacts with HDAC6 to a subject in need (e.g., a subject with a neurological disorder), such as a compound that is an inhibitor of HDAC6, a modulator of HDAC6, a binder of HDAC6, or a compound that modifies HDAC6. In certain embodiments, the method includes administering a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug or composition thereof to a subject in need. In some embodiments, the method includes administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug or composition thereof.

[0202] In certain embodiments, the compound of formula (I) is provided in a pharmaceutical composition in an effective amount. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a preventive effective amount. In certain embodiments, the effective amount is an amount that effectively treats a proliferative disease in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats a cancer in a subject in need. In certain embodiments, the effective amount is an amount that effectively prevents cancer in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats a blood cancer in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats cancers including solid tumors in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats an inflammatory disease in a subject in need. In certain embodiments, the effective amount is an amount that effectively prevents an inflammatory disease in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats an infectious disease in a subject in need. In certain embodiments, the effective amount is an amount that effectively prevents an infectious disease in a subject in need. In certain embodiments, the effective amount is an amount that effectively treats cardiovascular disease in a subject in need. In certain embodiments, an effective amount is an amount effective to treat a neurological disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to prevent a neurological disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to treat a neurodegenerative, neurodevelopmental, neuropsychiatric, or neuropathic disease in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to prevent a neurodegenerative, neurodevelopmental, neuropsychiatric, or neuropathic disease in a subject in need thereof.

[0203] In certain embodiments, an effective amount is an amount effective to reduce the risk of developing a disease (eg, a proliferative disease, an inflammatory disease, an infectious disease, a nervous system disorder, a peripheral disease, or a cardiovascular disease) in a subject in need thereof.

[0204] In certain embodiments, an effective amount is an amount effective to inhibit the activity (eg, abnormal activity, such as increased activity) of HDAC6 in a subject, tissue, biological sample, or cell.

[0205] In certain embodiments, the subject treated or administered with the compounds described herein is an animal. The animal can be of either sex and can be 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 domesticated animal, such as a dog, cat, cattle, pig, horse, sheep or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cattle, pig, horse, sheep or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig or non-human primate. In certain embodiments, the animal is a genetically engineered 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 a reptile.

[0206] In certain embodiments, the effective amount is an amount that effectively inhibits 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, the effective amount is an amount that effectively inhibits the activity of HDAC6, and its range is between one percentage described in this paragraph and another percentage described in this paragraph (including the end value).

[0207] In certain embodiments, the pharmaceutical composition comprising formula (I) compound is enough to deliver about 0.001mg / kg to about 200mg / kg in one or more dosage administrations with each pharmaceutical composition for one or more dosage levels (depending on the mode of administration) for oral or parenteral administration. In certain embodiments, the effective amount of each dosage is from about 0.001mg / kg to about 200mg / kg per day, about 0.001mg / kg to about 100mg / kg, about 0.01mg / kg to about 100mg / kg, about 0.01mg / kg to about 50mg / kg, preferably about 0.1mg / kg to about 40mg / kg, preferably about 0.5mg / kg to about 30mg / kg, about 0.01mg / kg to about 10mg / kg, about 0.1mg / kg to about 10mg / kg subject weight changes, once a day or multiple times, to obtain desired treatment and / or preventive effect. In certain embodiments, the compounds described herein can be 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, and more preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight, once or more per day to obtain the desired therapeutic and / or preventive effect. The desired dose can be delivered three times a day, twice a day, once a day, every other day, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more administrations) may be used to deliver the desired dose. In certain embodiments, the compositions described herein are administered at a dose lower than that at which the agent causes nonspecific effects.

[0208] In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dosage of about 0.1 mg to about 10 mg per unit dose.

[0209] definition

[0210] Chemical Definition

[0211] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivity 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.

[0212] The compounds described herein may contain one or more asymmetric centers and thus may exist in various stereoisomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture enriched in one or more stereoisomers. Isomers may be separated from the mixture 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 may 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, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses compounds that are individual isomers that are substantially free of other isomers, and alternatively, compounds that are mixtures of different isomers.

[0213] In the formula, is a single bond, wherein the stereochemistry of the moiety to which it is directly attached is unspecified,---is absent or is a single bond, and Is a single bond or a double bond.

[0214] Unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium, 19 F 18 F substitution or 12 C is 13 C or 14 In addition to C substitution, compounds having the present structures are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0215] When a range of values ​​is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , C1-5 , 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.

[0216] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0217] The term "alkyl" refers to a straight 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 (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 C 1-6Examples 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, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) 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 example of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (such as unsubstituted C 1-6 Alkyl, such as -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, such as unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, such as 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, alkyl is substituted C 1-10 Alkyl (such as substituted C 1-6 Alkyl, e.g., -CF3, Bn).

[0218] The term "haloalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluorine, bromine, chlorine, or iodine. 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 "haloalkyl"). Examples of haloalkyl include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl and the like.

[0219] 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 1-6In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (“C 1-4 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 "alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0220] The term "alkoxyalkyl" is a substituted alkyl group in which one or more 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").

[0221] The term "heteroalkyl" refers to an alkyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, which is within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl"). 1-20 In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-18 In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-16 In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-14 In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-10In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroalkyl”). 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroalkyl”). 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroalkyl”). 1-2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (a "heteroC1 alkyl"). In some embodiments, a heteroalkyl group as defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and having at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may contain an amide or ester functional group 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 (an "unsubstituted heteroalkyl group") or substituted (a "substituted heteroalkyl group") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC1 alkyl group. 1-20 In certain embodiments, heteroalkyl is an unsubstituted heteroC 1-10 In certain embodiments, heteroalkyl is substituted heteroC 1-20 In certain embodiments, heteroalkyl is an unsubstituted heteroC 1-10 alkyl.

[0222] The term "alkenyl" refers to 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, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an 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, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadiene (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C 2-4 In some embodiments, alkenyl is an unsubstituted C 1-1, 1-dienyl (C 1-1), 1-hexenyl (C 1-1), 1-hexenyl (C 1-1), and 1-hexenyl (C 1-1). Other examples of alkenyl include heptenyl (C 1-7), octenyl (C 1-8), octatrienyl (C 1-8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl group”) or substituted (a “substituted alkenyl group”) with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C 1-1, 1-dienyl (C 1-1), 1-hexenyl (C 1-1), and 1-hexenyl (C 1-1). 2-10 In certain embodiments, alkenyl is a substituted C 2-10 In alkenyl, the stereochemistry of an unspecified C=C double bond (e.g., -CH=CHCH3 or ) can be an (E)- or (Z)-double bond.

[0223] The term "heteroalkenyl" refers to an alkenyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, which is within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroalkenyl"). 2-10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2-9 In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2-8 In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2-7 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2-6 In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-4In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl group”) or substituted (a “substituted heteroalkenyl group”) with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, heteroalkenyl is a substituted heteroC 2-10 Alkenyl.

[0224] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 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 aforementioned C 2-4 In some embodiments, alkynyl is an unsubstituted C alkynyl, 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 (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0225] 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, which is within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroalkynyl"). 2-10 In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms (“hetero C 2-9 In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms (“hetero C 2-8 In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms (“hetero C 2-7 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms (“hetero C 2-6 In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“hetero C 2-5 In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“hetero C 2-4 In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“hetero C 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroalkynyl group. 2-10 In certain embodiments, heteroalkynyl is substituted heteroC 2-10 Alkynyl.

[0226] The term "carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the 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 3-8In 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, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 In some embodiments, a carbocyclyl group has 4 to 7 ring carbon atoms (“C 4-7 In some embodiments, a carbocyclyl group has 4 to 8 ring carbon atoms (“C 4-8 In some embodiments, a carbocyclyl group has 4 to 10 ring carbon atoms (“C 4-10 In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5–6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 (Carbocyclyl)) Exemplary C 3-6 Carbocyclic 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. 3-8 Carbocyclic groups include but are not limited to the aforementioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. As illustrated by the foregoing examples, in certain embodiments, the carbocyclyl is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in this case, the number of carbons continues to represent the number of carbons in the carbocyclyl system. Unless otherwise specified, each instance of a carbocyclyl is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, a carbocyclyl is an unsubstituted C 3-14 In certain embodiments, a carbocyclyl group is a substituted C 3-14 Carbocyclic group.

[0227] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl ("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 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl is unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 Cycloalkyl.

[0228] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("3-14 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl") or a tricyclic ring system ("tricyclic heterocyclyl")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused to one or more carbocyclyls, where the point of attachment is on the carbocyclyl or heterocyclyl ring; or includes ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-14 membered heterocyclyl.

[0229] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 6-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“6-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur.

[0230] Exemplary 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiranyl. Exemplary 4-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiranyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazine. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepane alkyl, and thiacycloheptane alkyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepane alkyl, and thiacycloheptane alkyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepine 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.

[0231] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in the ring array) provided with 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls, wherein the radical or point of attachment is 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 (an "unsubstituted aryl") or substituted (a "substituted aryl" group) with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, aryl is substituted C 6-14 Aryl.

[0232] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, wherein the point of attachment is on the alkyl portion.

[0233] 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., having 6, 10 or 14 shared π electrons in the ring array) in which ring carbon atoms and 1-4 ring heteroatoms are provided, wherein 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 a carbon or nitrogen atom, where valence permits. Heteroaryl polycyclic ring systems may include 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 carbocyclic or heterocyclic groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent 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, wherein the point of attachment is on 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. In polycyclic heteroaryls in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0234] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system, provided with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system, provided with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system, provided with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, each instance of heteroaryl is independently unsubstituted (“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”) with one or more substituents. In certain embodiments, heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-14 membered heteroaryl.

[0235] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, aza Oxalic acid thia Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzophenylthio, isobenzophenylthio, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryls include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0236] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, wherein the point of attachment is on the alkyl portion.

[0237] The term "polycyclic spiro ring system" refers to a ring system having two or more rings connected by one common atom. The common atom is called a spiro atom. The ring system can be completely carbocyclic (all carbon) or heterocyclic (having one or more non-carbon atoms). If the spiro atom or any atom in either ring is not a carbon atom, the ring system is considered to be heterocyclic.

[0238] The term "bridged ring system" refers to a ring system having two or more rings that contain a bridge - a single atom or unbranched chain of atoms (or even a valence bond) connecting two "bridgehead" atoms. A bridgehead atom is defined as an atom that is not hydrogen and is part of the molecular backbone that is bonded to three or more other backbone atoms. Ring systems can 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 heterocyclic.

[0239] The term "unsaturated bond" refers to a double bond or a triple bond.

[0240] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.

[0241] The term "saturated" refers to a moiety that contains no double or triple bonds, ie, the moiety contains only single bonds.

[0242] The suffix "-ene" is attached to a group to indicate that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl. As another example, haloalkylene is a divalent moiety of haloalkyl (i.e., alkylene substituted with one or more halogens).

[0243] Unless otherwise clearly provided, a group is optionally substituted.The term "optionally substituted" refers to substituted or unsubstituted.In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic radical, heterocyclic radical, aryl and heteroaryl are optionally substituted. "Optionally substituted" refers to a group that can be substituted or unsubstituted (for example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclic radical, "substituted" or "unsubstituted" heterocyclic radical, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted" means that at least one hydrogen present on a group is replaced by a permissible substituent, for example, a substituent that produces a stable compound (e.g., a compound that does not spontaneously transform, such as by rearrangement, cyclization, elimination, or other reactions) after substitution. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. It is contemplated that the term "substituted" includes substitutions with all permissible substituents of an organic compound, and includes any substituent described herein that causes the formation of a stable compound. The present invention contemplates any and all such combinations in order to obtain a stable compound. For purposes of the present invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent that satisfies the valence of a heteroatom and results in the formation of a stable portion as described herein. The present invention is not intended to be limited in any way to the exemplary substituents described herein.

[0244] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )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 、-OCO2Raa 、-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)SR aa 、-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, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counter ion;

[0245] or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)ORaa , =NNR bb S(=O)2R aa , =NR bb or = NOR cc Replacement;

[0246] R aa Each instance of is independently selected from 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0247] R bb Each instance of is independently selected from 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 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 1-10Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counter ion;

[0248] R cc Each instance of is independently selected from 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 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0249] R dd Each instance of is independently selected from 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)Ree 、-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(R ff )2.-NR ff S02R 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 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg group substituted, or two geminal R dd Substituents may be linked to form =O or =S; where X -is the counter ion;

[0250] R ee Each instance of is independently selected from 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 Carbocyclic group, 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 substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0251] R ff Each instance of is independently selected from 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 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg group substitution; and

[0252] R gg Each instance of is independently 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(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6Alkyl), -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 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0253] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0254] The term "hydroxy" or "hydroxyl" refers to the group -OH. The term "substituted hydroxy" or "substituted hydroxy", by extension, refers to a hydroxy group in which the oxygen atom directly attached to the parent molecule is replaced by a group other than hydrogen, and includes groups selected from: -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 As defined herein.

[0255] The term "amino" refers to the group -NH2. By extension, the term "substituted amino" refers to monosubstituted amino, disubstituted amino, or trisubstituted amino. In certain embodiments, "substituted amino" is monosubstituted amino or disubstituted amino.

[0256] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from: -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, where R aa , R bb and R cc As defined herein, and wherein the group -NH(R bb ) bb Not hydrogen.

[0257] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from: -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 S02R aa 、-NR bb P(=O)(ORcc )2 and -NR bb P(=O)(N(R bb )2)2, where R aa , R bb and R cc As defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not replaced by hydrogen.

[0258] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted by three groups, and includes amino groups selected from -N(R bb )3 and -N(R bb )3 + X - A group in which R bb and X - - as defined herein.

[0259] The term "sulfonyl" refers to a group selected from -SO2N(R bb 2. -SO2R aa and-SO2OR aa A group in which R aa and R bb As defined herein.

[0260] The term "sulfinyl" refers to the group -S(=O)R aa , where R aa As defined herein.

[0261] 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, where R X1is hydrogen; halogen; substituted or unsubstituted hydroxy; 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, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic thiooxy, heteroaliphatic thiooxy, alkylthiooxy, heteroalkylthiooxy, arylthiooxy, heteroarylthiooxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 The groups 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 substituents described herein that result in the formation of a stable portion (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocycle, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkylsulfoxy, heteroalkylsulfoxy, arylsulfoxy, heteroarylsulfoxy, acyloxy, etc., each of which may or may not be further substituted).

[0262] The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.

[0263] Where valence permits, the nitrogen atoms may be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups attached to the N atom cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd As defined herein.

[0264] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -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(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SORaa 、-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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0265] For example, a nitrogen protecting group such as an amide group (e.g., -C(=O)NR aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylpropylamino derivatives, benzamide, p-phenylbenzamide, o-nitrobenzylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0266] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include but are not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl l-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl 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-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), Allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrosinnamyl carbamate (Noc), 8-quinolinyl 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-methyl) phenylsulfonyl) ethyl ester, [2-(1,3-dithianyl)] methyl carbamate (Dmoc), 4-methylthienyl carbamate (Mtpc), 2,4-dimethylthienyl carbamate (Bmpc), 2-phosphorylethyl carbamate (Peoc), 2-triphenylphosphinopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazole methyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl ester, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, Isobutyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl 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-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.

[0267] A nitrogen protecting group such as a sulfonamide group (e.g., -S(=O)2R aa ) include, but are not limited to, 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-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), benzenemethylsulfonamide, trifluoromethylsulfonamide, and benzoylsulfonamide.

[0268] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N′-toluenesulfonylaminoacyl derivatives, N′-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-dimethylsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane- 2-ketone, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, 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-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF ), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-methylpyridine amino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)-mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxygen

[0063] The invention also includes the following: N-[(1-(2-nitro-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, N-amine oxides, diphenylphosphoramide (Dpp), dimethylthiophosphoramide (Mpt), diphenylthiophosphoramide (Ppt), dialkylphosphoramides, dibenzylphosphoramides, diphenylphosphoramides, benzenesulfonamides, o-nitrobenzenesulfonamide (Nps), 2,4-dinitrobenzenesulfonamide, pentachlorobenzenesulfonamide, 2-nitro-4-methoxybenzenesulfonamide, triphenylmethylsulfonamide, and 3-nitropyridinesulfonamide (Npys).In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), p-bromobenzenesulfonyl (Bs), nitrobenzenesulfonyl (Ns), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), or dansyl (Ds).

[0269] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxy protecting group"). Oxygen protecting groups include, but are not limited to: -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, where X - , R aa , R bb and R cc As defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition John Wiley & Sons, 1999, incorporated herein by reference.

[0270] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanebenzofuran-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-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyseleno)ethyl, tert-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-methylpyridine, 4-methylpyridine, 3-methyl-2-methylpyridine N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyl di phenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4"-tri(4,5-dichlorophthalimidephenyl)methyl, 4,4',4"-tri(chrysanthemum sugar oxyphenyl)methyl, 4,4',4"-tri(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-phenyldithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylethylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid acetal), pivalate, adamantanoate, 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 carbonate) 2-(Triphenylphosphine)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphine)ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2 -(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, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphoric acid diamide, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinothioyl, 2,In some embodiments, the oxygen protecting group is tert-butyldiphenylsilyl (TBDPS), tert-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-methoxy-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), tert-butyl, benzyl (Bn), allyl or pivaloyl (Piv). ,

[0271] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to: -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, where R aa , R bb and R cc As defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 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-pyridinesulfinyl, 2-pyridine-sulfinyl or trityl.

[0272] "Counterions" or "anionic counterions" are negatively charged groups that associate with positively charged groups in order to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., include one formal negative charge). Anionic counterions can also be multivalent (i.e., include more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halides (e.g., F - , Cl - Br - ,I - )、NO3 - 、ClO4 - OH - 、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., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, 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 that may be multivalent include CO32- 、HPO4 2- PO4 3- 、B4O7 2- 、SO4 2- 、S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carborane.

[0273] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims.It is not intended that the present invention be limited in any way to the above list of exemplary substituents.

[0274] Other definitions

[0275] The following definitions are more general terms used throughout this application.

[0276] As used herein, the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0277] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with human and / or animal tissues without undue toxicity, irritation, allergic reactions, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. 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 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 amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with 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 methods) to form salts. Other pharmaceutically acceptable salts include 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, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Alkyl)4 - Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0278] The term "solvate" refers to a form of a compound or a salt thereof that is associated with a solvent, typically by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein may be prepared, for example, in a crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0279] The term "hydrate" refers to a compound associated with water molecules. Generally, the number of water molecules contained in the hydrate of a compound has a definite ratio to the number of compound molecules in the hydrate. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is a compound and x is a number greater than 0. A given compound can form more than one hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, such as a hemihydrate (R·0.5H2O)) and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0280] The term "tautomer" or "tautomeric" 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., 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., a reaction that provides a tautomeric pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different enamine) tautomerizations.

[0281] It is also 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."

[0282] Stereoisomers that are not mirror images of one another are termed "diastereomers," while stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, then a pair of enantiomers is possible. Enantiomers are 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 that the molecules rotate the plane of polarized light and are designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0283] The term "polymorph" refers to the crystalline form of a compound (or its salt, hydrate or solvate). 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 properties such as melting point, density, hardness, crystal shape, optical and electrical properties, stability, solubility and bioavailability. Recrystallization solvents, crystallization rates, storage temperatures and other factors may make a crystalline form dominant in a given formulation. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0284] The term "co-crystal" refers to a crystal structure consisting of at least two components. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more other components, including but not limited to atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more acids or bases. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more components related to the compound, including but not limited to isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of the compound.

[0285] The term "prodrug" refers to a compound with a cleavable group that is removed by solvent decomposition or under physiological conditions to provide a compound described herein that has pharmaceutical activity in vivo. Such examples include, but are not limited to, choline ester derivatives, N-alkyl morpholine esters, etc. Other derivatives of the compounds described herein are active in their acid and acid derivative forms, but generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms in acid-sensitive forms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners 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 anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups attached to the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare a double ester type prodrug, such as an (acyloxy)alkyl ester or a ((alkoxycarbonyl)oxy)alkyl ester. 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.

[0286] The terms "composition" and "formulation" are used interchangeably.

[0287] A "subject" to which administration is intended refers to a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or 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 monkey or a rhesus monkey), a commercially relevant 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 relevant 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 can be male or female at any stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease. The subject can also be a plant cell. In certain embodiments, the plant is a terrestrial plant. In certain embodiments, the plant is a nonvascular 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 dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a leguminous plant, such as a legume plant, such as a soybean plant. In some embodiments, the plant is a tree or a shrub.

[0288] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and biopsies of tissue); cell samples (e.g., cytological smears (such as Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from the first biological sample.

[0289] 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 a subject.

[0290] The terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or have 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 susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms). Treatment may also continue after symptoms have resolved, e.g., to delay or prevent recurrence.

[0291] The terms "disease," "disease," and "condition" are used interchangeably.

[0292] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. The effective amount of a compound described herein may vary according to factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being 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 preventive 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 terminate 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 combined amount of the compounds described herein in multiple doses.

[0293] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of an illness or to delay or minimize one or more symptoms associated with the illness. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of an illness. The term "therapeutically effective amount" may include an amount that improves overall therapy; reduces or avoids symptoms, signs, or causes of an illness; and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit HDAC6 (e.g., 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% inhibits HDAC6 activity). In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder (e.g., a nervous system disorder, cancer). In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit HDAC6 and treat a disease or disorder (e.g., a nervous system disorder, cancer).

[0294] The "preventive effective amount" of the compound described herein is sufficient to prevent the disease, or one or more signs or symptoms associated with the disease, or to prevent its recurrence. The preventive effective amount of a compound refers to the amount of a therapeutic agent alone or in combination with other agents, which provides a preventive benefit in the prevention of the disease. The term "preventive effective amount" can encompass an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In certain embodiments, the preventive effective amount is an amount sufficient to inhibit HDAC6. In certain embodiments, the preventive effective amount is an amount sufficient to treat a disease or disorder (e.g., a nervous system disorder, a cancer). In certain embodiments, the preventive effective amount is an amount sufficient to inhibit HDAC6 and treat a disease or disorder (e.g., a nervous system disorder, a cancer).

[0295] As used herein, in the context of enzymes, for example, in the context of HDAC6, the term "inhibit (inhibit)" or "inhibition (inhibition)" refers to the reduction of enzyme activity. In some embodiments, the term refers to the level of enzyme activity (for example, HDAC6 activity) is reduced to a level statistically significantly lower than the initial level, and the initial level can be, for example, the baseline level of enzyme activity. In some embodiments, the term refers to the level of enzyme activity (for example, HDAC6 activity) is reduced to less than 75% of the initial level, 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% level, and the initial level can be, for example, the baseline level of enzyme activity.

[0296] "Proliferative disease" refers to a disease caused by abnormal growth or spread due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, England, 1990). Proliferative diseases can be associated with: 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) pathological angiogenesis, as in 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.

[0297] The terms "vegetation" and "tumor" are used interchangeably herein and refer to abnormal tissue masses, wherein the growth of the mass exceeds normal tissue and is not coordinated with the growth of normal tissue. Vegetation or tumor can be "benign" or "malignant", depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign neoplasms" are usually well differentiated, characterized by slower growth than malignant neoplasms, and are still confined to the origin site. In addition, benign neoplasms do not have the ability to infiltrate, invade or metastasize to distant sites. Exemplary benign neoplasms include but are not limited to lipomas, chondromas, adenomas, soft droops, senile hemangiomas, seborrheic keratosis, nevi and sebaceous hyperplasia. In some cases, some "benign" tumors may cause malignant neoplasms later, which may be due to other genetic changes in tumor neoplastic cell subpopulations, and these tumors are referred to as "pre-malignant neoplasms". The example of pre-malignant neoplasms is teratoma. In contrast, "malignant neoplasms" are usually poorly differentiated (dysplastic) and have a characteristic rapid growth with progressive infiltration, invasion, and destruction of surrounding tissue. In addition, malignant neoplasms often have the ability to metastasize to distant sites.

[0298] The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue, and can often be identified by the presence of a "secondary tumor" or "secondary cell mass" in the same tissue type as the primary or original tumor, rather than in the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to the bone is called metastatic prostate cancer, and includes cancerous prostate cancer cells growing in the bone tissue.

[0299] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphovascular endothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast carcinoma); brain cancer (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 cancer); intestinal cancer (eg, colorectal cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (eg, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (eg, uterine cancer, uterine sarcoma); esophageal cancer (eg, esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (eg, intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; stomach cancer (eg, gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (eg, head and neck squamous cell carcinoma), oral cancer (eg, oral squamous cell carcinoma), pharyngeal cancer (eg, laryngeal cancer, pharyngeal cancer, nasal cancer); pharyngeal cancer, oropharyngeal cancer)); hematological cancers (e.g., 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), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large B-cell lymphoma 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, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycotic mycosis, Sezary 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); a mixture of one or more of the leukemias / lymphomas described above; and multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocytic amyloidosis; renal cancer (e.g., Wilms tumor, 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; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown cause (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CML), =Ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial neoplasm; prostate cancer (e.g., prostate 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., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small intestine cancer; sweat gland cancer; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva). ;

[0300] The term "immunotherapy" refers to a therapeutic agent that promotes the treatment of a disease by inducing, enhancing or suppressing an immune response. Immunotherapies designed to elicit or amplify an immune response are classified as activated immunotherapies, while immunotherapies that reduce or suppress them are classified as suppressive immunotherapies. Immunotherapies are usually, but not always, biological therapeutic agents. Many 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.

[0301] The terms "biologics," "biopharmaceuticals," and "biological products" refer to a wide variety of products, such as vaccines, blood and blood components, allergen preparations, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologics may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologics may be isolated from a variety of natural sources (e.g., humans, animals, microorganisms) and may be produced by biotechnological methods and other techniques.

[0302] The term "small molecule" or "small molecule therapeutic agent" refers to a molecule with a relatively low molecular weight, whether naturally occurring or artificially produced (e.g., via chemical synthesis). Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocycles, etc.). In certain embodiments, the molecular weight of a small molecule is no more than about 1,000 g / mol, no more than about 900 g / mol, no more than about 800 g / mol, no more than about 700 g / mol, no more than about 600 g / mol, no more than about 500 g / mol, no more than about 400 g / mol, no more than about 300 g / mol, no more than about 200 g / mol, or no more than about 100 g / mol. In certain embodiments, the molecular weight of small molecules is at least about 100g / mol, at least about 200g / mol, at least about 300g / mol, at least about 400g / mol, at least about 500g / mol, at least about 600g / mol, at least about 700g / mol, at least about 800g / mol, or at least about 900g / mol, or at least about 1,000g / mol. Combinations of the above ranges (e.g., at least about 200g / mol and no more than about 500g / mol) are also possible. In certain embodiments, small molecules are therapeutically active agents, such as drugs (e.g., molecules approved by the U.S. Food and Drug Administration (USFood and Drug Administration) as provided in the Federal Regulations (CFR) of the United States). Small molecules can also be complexed with one or more metal atoms and / or metal ions. In this case, small molecules are also referred to as "small organometallic molecules". Preferred small molecules have biological activity because they produce biological effects in animals, preferably mammals, more preferably humans. Small molecules include but are not limited to radionuclides and imaging agents. In certain embodiments, small molecules are drugs. Preferably, but not necessarily, the drug is one that has been deemed safe and effective for use in humans or animals by an appropriate governmental agency or regulatory agency. For example, the FDA lists drugs approved for human use under 21 C.FR §§330.5, 331 to 361, and 440 to 460 (incorporated herein by reference); the FDA lists veterinary drugs under 21 C.FR §§500 to 589 (incorporated herein by reference). All listed drugs are considered acceptable for use according to the present invention.

[0303] The term "therapeutic agent" refers to any substance with therapeutic properties that produces a desired, usually beneficial effect. For example, a therapeutic agent can treat, improve and / or prevent a disease. As disclosed herein, a therapeutic agent can be a biologic or a small molecule therapeutic agent or a combination thereof.

[0304] The term "chemotherapeutic agent" refers to a therapeutic agent known to be useful in cancer chemotherapy.

[0305] "Hematological cancer" includes cancers that affect hematopoietic cells or tissues. Hematological cancer includes cancers associated with abnormal blood content and / or function. Examples of hematological cancers include, but are not limited to, 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)), lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL), non-Hodgkin 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 lymphoma, lymphoma Plasma cell lymphoma (ie, Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, primary central nervous system (CNS) lymphoma, T-cell NHL such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (eg, cutaneous T-cell lymphoma (CTCL) (eg, mycosis fungoides, Sezary 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), a mixture of one or more of the leukemias / lymphomas described above, multiple myeloma, heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), acute non-lymphocytic leukemia (ANLL), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, Wilms' tumor, and Ewing's sarcoma.

[0306] The term "heteroimmune disease" refers to a state in which the immune response to foreign antigens (e.g., drugs, pathogens) results in immunopathological changes. The immune response is triggered by antigens from a different species (heteroimmunity), so it differs from infectious disease in that the focus is on the immune response rather than the foreign species (infectious pathogen) causing the disease.

[0307] Example

[0308] In order that the invention described herein may be more completely understood, the following examples are listed.The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting the scope thereof.

[0309] Synthesis method

[0310] The compound of formula (I) is prepared according to the synthesis scheme and procedure described in detail below. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and should not be interpreted in any way as limiting the scope thereof. The compounds of the present disclosure not explicitly described in the following procedures can be prepared by similar methods. One of ordinary skill in the art will understand how to prepare such compounds according to the disclosure provided herein and by means known in the field of organic synthesis. For example, as in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 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 versions thereof are representative and illustrative. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are known in the art.

[0311] General Details. All oxygen and / or moisture sensitive reactions were performed under a nitrogen (N2) atmosphere in glassware that had been flame dried under vacuum (approximately 0.5 mm Hg) and purged with N2 prior to use. All reagents and solvents were purchased from commercial suppliers and used as received or synthesized according to reported methods. NMR spectra were recorded on 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) referenced 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 constants in Hz). Unless otherwise indicated, NMR data were collected at 25°C. The data were acquired on a Teledyne Isco Combiflash R f Use 40-60μm silica gel ( Flash chromatography was performed on a Waters 2795 separation module and a 3100 mass detector. Analytical thin layer chromatography (TLC) was performed on EM reagent 0.25 mm silica gel 60-F plates.

[0312] LCMS_Conditions_01: Column: X-Bridge BEH C-18 (3.0X50 mm, 2.5 μm), Mobile phase: A-0.025% FA in water, Mobile phase: B-ACN, Flow rate: 1.2 mL / min (gradient).

[0313] LCMS Conditions_02: Column: X-Select CSH C-18 (150X 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).

[0314] HPCL_conditions_01: Column: XSELECT CSH C18 (150X 4.6mm, 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.

[0315] HPLC_conditions_02: Column: XSELECT CSH C18 (150X 4.6 mm, 3.5μ), Mobile phase-A: 5 mM ammonium acetate, Mobile phase-ACN, Flow rate: 1.0 mL / min, Diluent: ACN:water.

[0316] Reverse phase PREP purification method: preparative column X-SELECT (250*30 mm), 5u, mobile phase A 10 mm ABC in water, mobile phase B ACN, flow rate 25 mL, instrument ID Prep-14 gradient (time / %B) 0 / 10, 3 / 10, 10 / 25, 20 / 40, 30 / 55, 40 / 60, 50 / 75, 60 / 95.

[0317] The compounds of formula (I) are prepared according to the synthetic schemes and procedures described in detail below.

[0318] General Scheme - Formula (I)

[0319]

[0320] 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 a temperature 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 of ordinary skill in the art.

[0321] 2-(Difluoromethyl)-5-(6-(((5-fluoropyridin-3-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(19)

[0322]

[0323] Step-1: Synthesis of 6-methylnicotinylhydrazide: To a stirred solution of methyl 6-methylnicotinate (3.0 g, 19.867 mmol, 1.0 eq.) in EtOH (15 mL) was added hydrohydrazine (4.0 g, 79.47 mmol, 4.0 eq.) at room temperature and stirred for 5 minutes. The reaction mixture was refluxed for 16 hours 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 a crude product. The obtained crude product was triturated with ether (50 mL) to give the desired product (2.0 g, 93%) as a white solid. LC-MS: m / z 151.00 (M+1).

[0324] Step-2: Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole: To a solution of 6-methylnicotinamide (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 minutes. The resulting reaction mixture was heated and stirred at 50 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (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 obtain a crude product (2.40 g) as a sticky solid. The crude product was purified by CombiFlash column chromatography using eluent ethyl acetate: n-heptane (15%) to afford the desired product (1.80 g, 47%) as a white solid. LC-MS: m / z 212.00 (M+1).

[0325] 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 eq.) in DCM (15 mL) was added NBS (2.30 g, 12.79 mmol, 1.5 eq.) followed by AIBN (420 mg, 2.55 mmol, 0.3 eq.) at room temperature. The reaction mixture was stirred at 50 °C for 16 hours. The progress of the reaction was monitored by TLC, and TLC showed new product spots along with unreacted starting material. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column chromatography using eluent ethyl acetate: n-heptane (10%) to provide the product (950 mg, 39%). LCMS: m / z 292.00 (M+1).

[0326] 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 eq.) in DMF (2 mL) was added K2CO3 (142 mg, 1.034 mmol, 3.0 eq.) 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 eq.) at room temperature. The reaction mixture was heated at 100°C for another 6 hours. 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), then with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by CombiFlash chromatography eluting with ethyl acetate: n-heptane (40%) to give the desired product (19, 30 mg, 27%) as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 5.43(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): δ-120.70, 126.28. LC-MS: m / z 322.85 [M+H].

[0327] The following compounds were prepared in a similar manner to that used to prepare compound (19).

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] 2-[6-(Bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (A)

[0339]

[0340] Step 1: 6-methylpyridine-3-carbohydrazide: NH2NH2.H2O (39.74 g, 793.85 mmol, 38.58 mL, 4 eq.) was added to a solution of methyl 6-methylpyridine-3-carboxylate (30 g, 198.46 mmol, 1 eq.) in EtOH (300 mL). The mixture was then stirred at 80 ° C. under N2 atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc (200 mL) at 30 ° C. to obtain 6-methylpyridine-3-carbohydrazide (29 g, 189.92 mmol, 95.70% yield, 99% purity) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 9.86(br s,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]+

[0341] 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 with N2 three times 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was extracted with DCM (120 mLx3). The combined organic layer was washed with H2O (80 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 ) to afford 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]+

[0342] Step 3: 2-(Difluoromethyl)-5-(6-methyl-3-pyridinyl)-1,3,4-oxadiazole: A mixture of N'-(2,2-difluoroacetyl)-6-methyl-pyridine-3-carbohydrazide (11 g, 46.56 mmol, 97% purity, 1 eq), methoxycarbonyl-(triethylammonium)sulfonyl-azide (16.64 g, 69.83 mmol, 1.5 eq) in THF (120 mL) was degassed and purged with N2 three times, then the mixture was stirred at 80 °C under N2 atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2) to obtain 2-(difluoromethyl)-5-(6-methyl-3-pyridinyl)-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]+

[0343] Step 4: 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (A): To a solution of 2-(difluoromethyl)-5-(6-methyl-3-pyridinyl)-1,3,4-oxadiazole (7.2 g, 34.10 mmol, 1 eq.) in CHCl3 (150 mL) was added NBS (8.50 g, 47.73 mmol, 1.4 eq.) and AIBN (559.89 mg, 3.41 mmol, 0.1 eq.) at 25 °C. The mixture was then stirred at 70 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was extracted with DCM (120 mLx2). The combined organic layers were washed with H2O (80 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 ) to afford 2-[6-(bromomethyl)-3-pyridinyl]-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] + .

[0344] 2-(Difluoromethyl)-5-[6-[(3,4-difluorophenoxy)methyl]-3-pyridyl]-1,3,4-oxadiazole(9)

[0345]

[0346] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (500 mg, 1.72 mmol, 1 eq) and 3,4-difluorophenol (224.25 mg, 1.72 mmol, 1 eq) in MeCN (8 mL) was added K2CO3 (476.47 mg, 3.45 mmol, 2 eq) 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 obtain 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 (400 MHz, methanol-d4) δ = 9.28 (d, J = 1.8 Hz, 1H), 8.55 (dd, J = 2.3, 8.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.28-7.14 (m, 2H), 7.04 (ddd, J = 3.1, 6.6, 12.2 Hz, 1H), 6.89-6.84 (m, 1H), 5.30 (s, 2H). MS (ESI): 319.2 [M+H] + .

[0347] 2-(Difluoromethyl)-5-[6-(8-quinolyloxymethyl)-3-pyridyl]-1,3,4-oxadiazole (10)

[0348]

[0349] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 eq) and quinoline-8-ol (75.07 mg, 517.13 umol, 89.36 μL, 1 eq) in MeCN (4 mL) was added K2CO3 (142.94 mg, 1.03 mmol, 2 eq) at 25 °C. The mixture was then stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral) to obtain 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. 1H NMR (400MHz, methanol-d4) δ = 9.31 (d, J = 1.6 Hz, 1H), 8.90 ( dd, J = 1.6, 4.3 Hz, 1H), 8.52 ( dd, J = 2.1, 8.3 Hz, 1H), 8.38 ( dd, J = 1.6, 8.3 Hz, 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]+

[0350] 2-(Difluoromethyl)-5-[6-[(3-fluoro-2-pyridinyl)oxymethyl]-3-pyridinyl]-1,3,4-oxadiazole (77)

[0351]

[0352] AgCO (285.19 mg, 1.03 mmol, 46.91 μL, 2 equivalents) was added to a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 equivalent) and 3-fluoropyridine-2-ol (58.48 mg, 517.13 umol, 1 equivalent) in toluene (3 mL) at 25 ° C. The mixture was then stirred at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (neutral) to obtain 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 that the chemical shift of C9 was 66 ppm.

[0353] 2-[6-[(5-cyclopropyl-2-pyridyl)oxymethyl]-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (85)

[0354]

[0355] To a solution of 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (150 mg, 517.13 umol, 1 eq) in MeCN (3 mL) was added KCO (142.94 mg, 1.03 mmol, 2 eq) and 5-cyclopropylpyridine-2-ol (69.90 mg, 517.13 umol, 1 eq) at 25 °C. The mixture was stirred at 60 °C for 12 hours. LCMS showed that 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 obtain 5-cyclopropyl-1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]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) δppm 9.21(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 that the chemical shift of C25 was 54 ppm.

[0356] 2-[6-[(5-cyclopropyl-2-pyridinyl)oxymethyl]-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (85) was obtained as a white solid (15.41 mg, 44.62 umol, 8.63% yield, 99.7% purity). 1H NMR (400Mhz, methanol-d4) δppm 9.25(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 that the chemical shift of C25 was 66 ppm.

[0357] Synthesis of 2-(6-(((2-oxadamantan-1-yl)methoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (20)

[0358]

[0359] 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 hour. 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 hours. LCMS showed that 28% of the desired mass was detected. The reaction mixture was quenched by adding MeOH (5 mL) at 25 ° C, and then diluted with H2O (10 mL). The mixture was extracted with EtOAc (20 mL*2). The combined organic layer was washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 150×25 mm×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, 3.88% yield, 93% purity) as a white solid. 1H NMR (400Mhz, methanol-d4) δppm 9.21(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(br d,J=3.00Hz,2H)1.92-2.01(m,6H)1.68-1.76(m,5H). MS(ESI):378.2[M+H] +

[0360] 2-(Difluoromethyl)-5-(6-((pyridin-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(16)

[0361]

[0362] 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 eq) in toluene (1 mL) was added pyridine-2-ol (33 mg, 0.344 mmol, 0.344 eq) at room temperature, followed by addition of Ag2CO3 (0.286 g, 1.034 mmol, 3.0 eq) and stirring for 10 minutes. The reaction mixture was heated and stirred at 100 ° C for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The obtained filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column chromatography using an eluent of ethyl acetate:n-heptane (30%) to obtain (16) (55.0 mg, 52.3%) as a yellow liquid. 1 H NMR(400MHz,DMSO-d6)δppm 5.55(s,2H),6.99-7.10(m,2H),7.44-7.70(m,2H),7.75-7.85(m,1H),8.10-8.20(m,1H),8.45(dd,J=2.4Hz,J=10.4Hz,1H),9.19(s,1H). 19 F NMR (400MHz, DMSO-d6): δppm-120.69. LC-MS: m / z 304.95. [M+H] + HPLC: 99.30% at 6.930 min.

[0363] 2-(Difluoromethyl)-5-(6-((pyridin-3-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(17)

[0364]

[0365] To a stirred solution of pyridine-3-ol (73.0 mg, 0.775 mmol, 1.5 equivalents) in DMF (3 mL) was added K2CO3 (214 mg, 1.551 mmol) and stirred for 15 minutes at room temperature. 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (A, 150 mg, 0.5171 mmol, 1.0 equivalents) was added to the resulting reaction mixture at room temperature, and the reaction mixture was heated at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x10 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (17) (20 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 5.41(s,2H),7.30-7.40(m,2H),7.45-7.70(m,2H),7.78-7.88(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] +

[0366] 2-(Difluoromethyl)-5-(6-((pyridin-4-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (18):

[0367]

[0368] 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 eq) in toluene (2 mL) was added pyridine-4-ol (65.6 mg, 0.0.689 mmol, 1.0 eq) at room temperature, followed by addition of Ag2CO3 (0.570 g, 1.034 mmol, 3.0 eq) and stirring for 10 minutes. The reaction mixture was heated and stirred at 100 ° C for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The obtained filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column chromatography using an eluent of ethyl acetate:n-heptane (60%) to obtain (18) (55.0 mg, 26.3%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δppm 5.42 (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 / z 305.00[M+H] + HPLC: 97.66% at 5.072 min.

[0369] 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzonitrile (118)

[0370]

[0371] NaH (34.4 mg, 0.8617 mmol, 60% oil dispersion) was added to a stirred solution of 4-hydroxybenzonitrile (61 mg, 0.5171 mmol) in THF (2 mL) at 0 ° C and stirred for 30 minutes. 2- (6- (bromomethyl) pyridin-3-yl) -5- (difluoromethyl) -1,3,4- oxadiazole (A, 100 mg, 0.3447 mmol, 1.0 equivalent) was added to the resulting reaction mixture at room temperature. The reaction mixture was brought to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (3x10 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (118) (15 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 5.42(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). 19F NMR (400MHz, DMSO-d6): δppm-120.70. LC-MS:m / z 329.2[M+H] + HPLC: 99.52% at 5.562 min.

[0372] 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)benzamide (122):

[0373]

[0374] 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) and stirred for 15 minutes at room temperature. 4-Hydroxybenzonitrile (53.4 mg, 0.448 mmol, 1.3 equiv) was added to the resulting reaction mixture at room temperature, and the reaction mixture was heated at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water (5 mL) and extracted with ethyl acetate (3x5 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC and then freeze-dried to give (122) (20 mg, 13%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 5.38(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 FNMR (400MHz, DMSO-d6): δppm-126.383,-126.525. LC-MS:m / z345.15[M+H] + .

[0375] 2-(Difluoromethyl)-5-(6-(1-(4-fluorophenoxy)ethyl)pyridin-3-yl)-1,3,4-oxadiazole (AAA)

[0376]

[0377] Step-1: Synthesis of 1-(5-bromopyridin-2-yl)ethan-1-ol (C): Methylmagnesium bromide (1.79 mL, 5.37 mmol) was added to a stirred solution of compound B (0.5 g, 2.68 mmol) in anhydrous THF (10 mL) at -10 ° C, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by using 100-200 mesh silica gel column chromatography to give product C (0.3 g, 55.24% yield) as a colorless viscous oil. LC-MS: m / z 203.90 [M+H] + .

[0378] 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 minutes, then DIAD (0.419 g, 2.07 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by using 100-200 mesh silica gel column chromatography to give product C (0.2 g, 45.66% yield) as a light brown liquid. LC-MS: m / z 296.00 [M+H] + .

[0379] Step-3: Synthesis of 6-(1-(4-fluorophenoxy)ethyl)nicotinonitrile (F): To a stirred solution of compound E (0.2 g, 0.677 mmol) in DMA (5 mL) was added Zn(CN)2 (0.198 g, 1.69 mmol) and Zn powder (0.030 g, 0.474 mmol) at room temperature, the reaction mixture was purged with argon for 30 minutes, and Pd2(dba)3 (0.070 g, 0.067 mmol) and dppf (0.112 g, 0.203 mmol) were added and again purged with argon for 15 minutes. The reaction mixture was stirred at 100°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was purified by The mixture was filtered and washed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by eluting with 0%-20% ethyl acetate in hexane using a 100-200 mesh silica gel column to give product F (0.110 g, 67.07% yield) as an off-white solid. LC-MS: m / z 243.05 [M+H] + .

[0380] Step-4: Synthesis of 2-(1-(4-fluorophenoxy)ethyl)-5-(1H-tetrazolyl-5-yl)pyridine (G): To a stirred solution of compound F (0.11 g, 0.454 mmol) in DMF (10 mL) were added sodium azide (0.088 g, 1.36 mmol), NH4Cl (0.073 g, 1.36 mmol) and LiCl (0.019 g, 0.454 mmol), and the reaction mixture was stirred at 100°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and acidified with 6N HCl, and the precipitated solid was filtered and dried to give the product G (0.100 g, 77.51% yield) as a light brown solid. LC-MS: m / z 286.05 [M+H] + .

[0381] 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) was added difluoroacetic anhydride (0.122 g, 0.701 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL) and basified with saturated sodium bicarbonate solution (20 mL), extracted with 5% methanol in DCM (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by eluting with 30% ethyl acetate in hexane using 230-400 mesh silica gel column chromatography to give 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). 19F 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 / z 336.05[M+H] + .

[0382] 2-(6-(difluoro(naphthalen-1-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (14):

[0383]

[0384] Step-1: 6-(Difluoro(naphthalene-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 minutes. Compound H (0.3 g, 1.30 mmol) dissolved in DMF (1 mL) was slowly added to the resulting reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (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 give a crude product. The crude product was purified by 100-200 mesh silica gel column chromatography by eluting with 0%-10% ethyl acetate in hexane to give compound J (0.32 g, 84.0%) as a brown liquid. LC-MS: m / z 296.9[M+H] + .

[0385] 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) was added sodium azide (0.35 g, 5.40 mmol), 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 hours. After completion of the reaction (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 viscous liquid, which was used as it is in the next reaction. LC-MS: m / z 339.9 [M+H] + .

[0386] 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 hours. After completion of the reaction (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 / z 390.15[M+H] + .

[0387] The following compounds were prepared in a manner analogous to that used to prepare the compounds of formula (I) above.

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409] 2-(6-(Bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K)

[0410]

[0411]

[0412] Step-1: Synthesis of 5-fluoro-6-methylnicotinate: To a stirred solution of 6-bromo-5-fluoronicotinate (1, 5.0 g, 21.36 mmol, 1.0 eq.) 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 eq.) at room temperature followed by K2CO3 (4.429 g, 32.00 mmol, 1.5 eq.) and the reaction mixture was degassed with argon for 15 min. Pd(PPh3)4 (2.77 g, 0.235 mmol, 0.11 eq.) was added to the resulting reaction mixture. The reaction mixture was heated at 100°C and stirred for 16 h. After the starting material is completely consumed (monitored by TLC), the reaction mixture is diluted with water (100mL) and extracted with DCM (2x100mL). The combined organic layer is washed with saline solution (100mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product is purified by CombiFlash column chromatography using ethyl acetate: n-hexane (20%) to obtain 5-fluoro-6-methylnicotinate (2.70g, 75%) as an off-white solid.

[0413] Step-2: Synthesis of 5-fluoro-6-methylnicotinic acid hydrazide: To a stirred solution of 5-fluoro-6-methylnicotinic acid methyl ester (0.740 g, 4.374 mmol, 1.0 eq.) in EtOH (10 mL) was added hydrazine hydrate (1.402 g, 43.74 mmol, 5.0 eq.) at room temperature. The reaction mixture was heated and stirred at 70 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain a crude product (0.740 g, crude). The crude product was used directly in the next reaction without further purification.

[0414] 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-methylnicotinamide (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 minutes. DFAA (2.28 g, 13.12 mmol) was added to the resulting reaction mixture at 0 °C. The reaction mixture was heated and stirred at 50 °C for 16 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with DCM (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate: n-heptane (30%) to afford 2-(difluoromethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-1,3,4-oxadiazole (1.788 g, 89.4% from 2 steps) as an off-white solid.

[0415] 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-methylnicotinylhydrazide 2-(difluoromethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-1,3,4-oxadiazole (0.900 g, 3.927 mmol, 1.0 eq.) in DCE (18 mL) was added NBS (2.10 g, 23.56 mmol, 6.0 eq.) followed by AIBN (0.322 g, 1.963 mmol, 0.5 eq.) for 15 min at room temperature. 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 diluted with water (30 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a 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.

[0416] LC-MS: m / z=309.6. 1H NMR (400MHz, CDCl3) δppm 9.12 (s, 1H), 8.13 (br.d, J = 8.80Hz, 1H), 6.76-7.10 (m, 1H), 4.66 (s, 3H).

[0417] 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 eq.) in THF (10 mL) was added DIPEA (0.246 g, 1.907 mmol, 2.0 eq.) followed by diethyl phosphate (263.1 g, 1.907 mmol, 1.907 eq.) at 0°C. The resulting reaction mixture was allowed to reach room temperature and stirred for 1 hour. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3x15 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a 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).

[0418] 2-(Difluoromethyl)-5-(5-fluoro-6-((naphthalen-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(182)

[0419]

[0420] 2-(Difluoromethyl)-5-(5-fluoro-6-((naphthalene-2-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (182): To a stirred solution of naphthalene-2-ol (47 mg, 0.324 mmol, 1.0 equiv) in acetonitrile (5 mL) was added KCO (113 mg, 0.817 mmol, 2.5 equiv) at room temperature followed by 2-(difluoromethyl)-5-(5-fluoro-6-((naphthalene-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 and stirred at 60 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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-pyridinyl]-1,3,4-oxadiazole (182, 70.0 mg, 40%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(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]. HPLC: 99.56% at 9.207 minutes.

[0421] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(181)

[0422]

[0423] 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) was added KCO (112 mg, 0.400 mmol, 1.20 equiv) at room temperature 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 and stirred at 60 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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)δppm 9.49(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 (400 MHz, DMSO-d6): δ -120.75; -123.29. LC-MS: m / z 371.9 [M+H]. HPLC: 99.56% at 9.207 min.

[0424] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-7-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(180)

[0425]

[0426] 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) was added KCO (113 mg, 0.817 mmol, 2.5 equiv) at room temperature 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 and stirred at 60 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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-((quinazolin-7-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (180, 65 mg, 55%) as an off-white solid. 1 HNMR(400MHz,DMSO-d6)δppm 9.44(s,1H),9.18(s,1H),9.12(s,1H),8.51(dd,J=9.82,1.69Hz,1H),8.1 0(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.

[0427] 2-(Difluoromethyl)-5-(5-fluoro-6-((quinazolin-5-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(179)

[0428]

[0429] 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) was added KCO (112 mg, 0.817 mmol, 2.5 equiv) at room temperature 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 and stirred at 60 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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-((quinazolin-5-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (179, 37 mg, 30%) as an off-white solid. 1 HNMR(400MHz,DMSO-d6)δppm 9.67(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). 19 F NMR (400 MHz, DMSO-d6): δ -120.76; -123.10. LC-MS: m / z 374.4 [M+H]. HPLC: 98.83% at 5.611 min.

[0430] 2-(Difluoromethyl)-5-(5-fluoro-6-(((2-methyl-2H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (178)

[0431]

[0432] 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) 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) at room temperature. The reaction mixture was heated and stirred at 60 °C for 12 h. After the complete consumption of starting material (monitored by TLC), the reaction mixture was cooled to room temperature and quenched with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with saline solution (10 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate: n-heptane (30%) to obtain 2- (difluoromethyl) -5- (5- fluoro- 6- (((2- methyl -2H- indazole -5- bases) oxygen base) methyl) pyridine -3- bases) -1,3,4- oxadiazole (178, 25 mg, 28%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.10(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: 96.40% at 6.876 min.

[0433] 6-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methoxy)-3-methylbenzo[d]isoxazole (137)

[0434]

[0435] 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) was added KCO (101 mg, 0.733 mmol) followed by 2-[6-(bromomethyl)-5-fluoro-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Int-K, 75 mg, 0.244 mmol) at room temperature. The reaction mixture was heated and stirred at 60 °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 (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. The crude product 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) δppm 9.18 (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: 99.72% at 8.362 min.

[0436] 2-(Difluoromethyl)-5-(5-fluoro-6-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (139)

[0437]

[0438] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred at 60 °C for 2 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and 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 a 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-(((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 (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1H), 8.45 (dd, J = 9.82, 1.69 Hz, 1H), 7.92 (d, J = 0.75 Hz, 1H), 7.55-7.60 (m, 2H), 7.35 (d, J = 2.13 Hz, 1H), 7.13 (dd, J = 9.01, 2.38 Hz, 1H), 5.37 (d, J = 1.63 Hz, 2H), 4.01 (s, 3H). LC-MS: m / z: 376.44 [M+H]+. HPLC: 98.23% at 8.170 min.

[0439] 2-(6-(Bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I)

[0440]

[0441] Step-1: Synthesis of 6-methylnicotinamide: To a solution of 6-methylnicotinic acid methyl ester (50 g, 331.1 mmol, 1.0 equivalent) in ethanol (500 mL) was added hydrohydrazine (53.06 g, 1655.6 mmol, 5.0 equivalent) at room temperature. The resulting reaction mixture was refluxed for 16 hours and the reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was ground with ether (500 mL) to give 6-methylnicotinamide (2, 50 g, crude) as a white solid. The crude product was used directly in the next reaction without further purification.

[0442] Step-2: Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole: To a solution of 6-methylnicotinylhydrazide (50 g, 331.1 mmol, 1.0 eq.) in DCM (1000 mL) was added imidazole (67.62 g, 993.37 mmol, 3.0 eq.) and DFAA (172.84 g, 993.37 mmol, 3.0 eq.) at room temperature. The reaction mixture was stirred at 50 °C for 16 hours and the progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (500 mL) and the aqueous layer was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine solution (250 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound as a sticky solid. The crude product was purified by combiFlash column chromatography using eluent ethyl acetate:heptane (15%) to give 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (45 g, 71% from 2 steps) as a white solid.

[0443] 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 eq.) in DCE (450 mL) was added NBS (151.8 g, 426.54 mmol, 2.0 eq.) followed by AIBN (17.51 ​​mg, 106.4 mmol, 0.5 eq.) at room temperature. The reaction mixture was stirred at 80 °C for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with water (500 mL), and extracted with DCM (3X500 mL). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by combiFlash column chromatography using eluent ethyl acetate: n-heptane (10%) to give 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 21.0 g, 34%, dibromo byproduct, 25 g, 32%) as an off-white solid.

[0444] 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 eq.) in THF (200 mL) was added DIPEA (18 mL, 108.3 mmol, 2.0 eq.) followed by diethyl phosphate (15 g, 108.6 mmol, 2.0 eq.) at 0 °C. The resulting reaction mixture was allowed to reach room temperature and stirred for 2 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a 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) + ; 1H NMR (400MHz, CDCl3) δppm 9.19 (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).

[0445] 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-methylbenzamide (197)

[0446]

[0447] Synthesis of 3-hydroxy-N-methylbenzamide: DIPEA (3.14mL, 18.10mmol, 5.0 equivalents) was added to a stirred solution of 3-hydroxybenzoic acid (500mg, 3.620mmol, 1.0 equivalents) in DMF (5mL) at room temperature, followed by addition of HATU (2.06g, 5.430mmol, 1.5 equivalents) and methylamine (488mg, 7.24mmol, 2.0 equivalents) and stirring for 12 hours. After the starting material was completely consumed (monitored by TLC), the reaction mixture was quenched with water (5mL) and extracted with ethyl acetate (10mLx3). The combined organic layer was washed with saline solution (10mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Combi Flash column chromatography using ethyl acetate: n-heptane (50%) to obtain 3-hydroxy-N-methylbenzamide (2,546mg, 98%) as a yellow solid.

[0448]

[0136] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred 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 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 a 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)δppm 9.23(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 FNMR (400 MHz, DMSO-d6): δ -121.780; -121.917. LC-MS: m / z 360.8 [M+H]. HPLC: 95.83% at 6.995 minutes.

[0449] 3-((5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-phenylbenzamide (196):

[0450]

[0451] Synthesis of 3-hydroxy-N-phenylbenzamide: DIPEA (1.40mL, 10.86mmol, 1.5 equivalents) was added to a stirred solution of 3-hydroxybenzoic acid (1.0g, 7.240mmol, 1.0 equivalents) in DMF (20mL) at room temperature, followed by addition of TBTU (3.48g, 10.86mmol, 1.5 equivalents) and aniline (2,674g, 7.240mmol, 1.0 equivalents) and stirring for 12 hours. After the starting material was completely consumed (monitored by TLC), the reaction mixture was quenched with water (10mL) and extracted with ethyl acetate (3X10 mL). The combined organic layer was washed with saline solution (10mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-hydroxy-N-phenylbenzamide (600mg, thick). The crude product was directly used in the next reaction without further purification.

[0452]

[0136] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred 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 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 3-((5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)methoxy)-N-phenylbenzamide (196, 30 mg, 10%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 10.21(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,3 H), 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). 19FNMR (400 MHz, DMSO-d6): δ -120.653; -120.790. LC-MS: m / z 423.27 [M+H]. HPLC: 98.72% at 8.433 minutes.

[0453] 2-(6-(((2-chloropyridin-4-yl)oxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (189)

[0454]

[0455] 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) was added KCO (91 mg, 0.655 mmol, 3.0 equiv) at room temperature 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 and stirred 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 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 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)δppm 9.23(s,1H),8.52(d,J=8.4Hz,1H),8.26(d,J=8.8Hz,1H),7.80(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.

[0456] 2-(6-(([1,1'-biphenyl]-3-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (188):

[0457]

[0458] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred 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 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 HNMR(400MHz,CDCl3)δppm 9.33(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]. HPLC: 98.50% at 9.384 min.

[0459] 2-(6-(([1,1'-biphenyl]-2-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (187)

[0460]

[0461] 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) was added KCO (71 mg, 0.513 mmol, 3.0 equiv) at room temperature 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 and stirred 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 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 a 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)δppm 9.21(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 FNMR (400 MHz, DMSO-d6): δ -121.87. LC-MS: m / z 380.38 [M+H]. HPLC: 99.87% at 9.486 minutes.

[0462] 2-(Difluoromethyl)-5-(6-(((2-phenylpyridin-4-yl)oxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (186)

[0463]

[0464] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred 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 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 obtain the crude product. The crude product 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 HNMR(400MHz,DMSO-d6)δppm 9.27(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 FNMR (400 MHz, DMSO-d6): δ -121.85. LC-MS: m / z 381.39 [M+H]. HPLC: 99.19% at 5.578 minutes.

[0465] 2-(6-(([1,1'-biphenyl]-4-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (185)

[0466]

[0467] 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) was added KCO (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) at room temperature. The reaction mixture was heated and stirred 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 quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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)δppm 9.24(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]. HPLC: 99.46% at 9.667 min.

[0468] 2-(6-(([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (184)

[0469]

[0470] Step-1: Synthesis of 4-(benzyloxy)-2-chloropyridine: Sodium hydride (1.3 g, 49 mmol, 1.2 eq) was added to a stirred solution of phenylmethanol (4 g, 40 mmol) in DMF (100 mL, 1290 mmol) at 0 ° C, followed by addition of 2-chloro-4-fluoro-pyridine (1,5 g, 38.011 mmol, 0.95 equivalents) and stirring for 5 minutes. The reaction mixture was allowed to reach room temperature and stirred for 30 minutes. After the starting material was completely consumed (monitored by TLC), the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with saline solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column chromatography using ethyl acetate: n-heptane (15%) to obtain 4-(benzyloxy)-2-chloropyridine (4.7 g, 57%) as an off-white solid.

[0471] Step-2: Synthesis of 4-(benzyloxy)-2-hydrazinepyridine: To a stirred solution of 4-benzyloxy-2-chloro-pyridine (500 mg, 2.2761 mmol, 1 eq.) in pyridine (5 mL) was added hydrazine solution (17.7 mg, 11.38 mmol, 5 eq.) at room temperature. The reaction mixture was heated at 110 °C for 24 hours. 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.

[0472] Step-3: Synthesis of 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine: p-Toluenesulfonic acid (360 mg, 2.102 mmol, 1.1 equivalents) was added to a stirred solution of (4-benzyloxy-2-pyridyl)hydrazine (4, 400 mg, 1.858 mmol, 1 equivalent) in trimethoxymethane (5, 5 mL) at room temperature and stirred for 5 minutes. The reaction mixture was heated at 80 ° C for 12 hours. After the starting material was completely consumed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layer was 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 directly used in the next reaction without further purification.

[0473] Step-4: Synthesis of [1,2,4] triazolo [4,3-a] pyridine-7-ol: 10% Pd / C (200 mg, 50% wt) was added to a stirred solution of 7-benzyloxy-[1,2,4] triazolo [4,3-a] pyridine (400 mg, 1.776 mmol, 1 equivalent) in methanol (5 mL) at room temperature under nitrogen, and stirred for 12 hours under 60 psi of hydrogen pressure. After complete consumption of the starting material (monitored by TLC), the reaction mixture was filtered through a celite pad, and the filtrate obtained was concentrated under reduced pressure to give [1,2,4] triazolo [4,3-a] pyridine-7-ol (200 mg, crude) as an off-white solid. The crude product was used directly in the next reaction without further purification.

[0474] 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 eq.) in acetonitrile (5 mL) was added KCO (429 mg, 3.10411 mmol, 3 eq.) and 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 300 mg, 1.0343 mmol, 1 eq.) at room temperature. 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 obtained residue was diluted with water (20 mL) and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with saline solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a 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)δppm 9.25(br.s,1H),9.06(br.s,1H),8.47–8.57(m,2H),7.85(d,J=8.4Hz,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). 19F NMR (400 MHz, DMSO-d6): δ -120.70. LC-MS: m / z 345.4 [M+H]. HPLC: 97.99% at 5.219 min.

[0475] 2-(Difluoromethyl)-5-(6-((pyrazolo[1,5-a]pyrimidin-6-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (183)

[0476]

[0477] 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 0 °C. The reaction mixture was heated at 65 °C and stirred for 12 hours. 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, 3x20 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.

[0478] 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 eq.) in acetonitrile (3 mL) was added K2CO3 (42 mg, 0.3102 mmol, 3.0 eq.) and then 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 30 mg, 0.1034 mmol, 1.0 eq.) at room temperature. The reaction mixture was heated and stirred at 80°C for 12 hours. After the starting material is completely consumed (monitored by TLC), the reaction mixture is cooled to room temperature and quenched with water (10mL), and extracted with ethyl acetate (3x10mL). The combined organic layer is washed with brine (10mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product is purified by reverse phase preparative HPLC to obtain 2- (difluoromethyl) -5- (6- ((pyrazolo [1,5-a] pyrimidine -6- bases oxygen) methyl) pyridine -3- bases) -1,3,4- oxadiazole (183, 20mg, 56%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δppm 9.30–9.40(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.

[0479] 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)

[0480]

[0481] 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 eq.) in acetonitrile (5 mL) was added K2CO3 (710 mg, 5.190 mmol, 3.0 eq.) at room temperature and stirred for 5 minutes. 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 eq.). The reaction mixture was heated at 60 °C and stirred for 12 hours. 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 (3x30 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combiflash column chromatography using 20% ​​ethyl acetate in n-heptane to afford 118 (190 mg, 34%) as an off-white solid.

[0482] 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 eq.) in DMF (5 mL) were added NaN3 (118 mg, 1.815 mmol, 3 eq.), NH4Cl (97.84 mg, 1.829 mmol, 3 eq.) and lithium chloride (25 mg, 0.609 mmol, 1 eq.) at room temperature. The reaction mixture was heated at 120°C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative HPLC to afford 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)δppm 9.23 (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 FNMR (400 MHz, DMSO-d6): δ -120.674; -120.809. LC-MS: m / z 372.24 [M+H]. HPLC: 98.17% at 6.002 minutes.

[0483] 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)

[0484]

[0485] Step-1: Synthesis of tert-butyl 3-oxo-3,4,5,7-tetrahydroisoxazolo[5,4-c]pyridine-6(2H)-carboxylate: To a solution of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3(2H)-one (250 mg, 1.785 mmol, 1 eq.) in DCM (10 mL) was added triethylamine (450 mg, 4.460 mmol, 2.5 eq.), DMAP (75.6 mg, 0.178 mmol, 0.1 eq.) and stirred for 5 minutes at 0 °C. 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 reach room temperature and stirred for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a 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.

[0486] 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: A mixture 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) -tert-butyl formate (240mg, 1.00mmol, 1 equivalent) and 2- (6- (bromomethyl) pyridin-3-yl) -5- (difluoromethyl) -1,3,4- oxadiazole (Int-I, 290mg, 1.00mmol, 1 equivalent) in acetonitrile (10mL) solution was added K2CO3 (414mg, 3.00mmol, 3 equivalents) and stirred for 5 minutes. The reaction mixture was heated at 80 ° C for 12 hours. After the starting material was completely consumed (monitored by TLC), the reaction mixture was cooled to room temperature and quenched with water (20mL), and extracted with ethyl acetate (3x20mL). The combined organic layer was washed with saline solution (20mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative HPLC to afford 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.

[0487] 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 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, 0.334 mmol, 1 eq.) in DCM (5 mL) was added TFA (0.5 mL) at 0° C. and stirred for 5 minutes. The resulting reaction mixture was allowed to reach room temperature and stirred for 1 hour. 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.

[0488] 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-pyridinyl]methoxy]-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (4, 100 mg, 0.286 mmol, 1 eq.) in methanol (2.5 mL) was added triethylamine (57.87 mg, 0.57 mmol, 2 eq.) at 0 °C and stirred for 5 min. At 0 ℃, formaldehyde (1mL) and acetic acid (0.02mL, 0.0286mmol, 0.1 equivalent) are added to the obtained reaction mixture and stirred for 5 minutes.The reaction mixture is made to reach room temperature and stirred for 12 hours.After 12 hours, sodium cyanoborohydride (36mg, 0.573mmol, 2 equivalents) is added to the reaction mixture at 0 ℃ and stirred for 2 hours.After the complete consumption of starting material (monitored by TLC), the reaction mixture is quenched with water (20mL), methanol is concentrated and extracted with ethyl acetate (3x20mL).The organic layer merged is washed with salt water (20mL), through anhydrous Na2SO4 is dried and concentrated under reduced pressure, and a crude product is obtained. The crude product was purified by reverse phase preparative HPLC to afford 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)δppm 9.21(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]. HPLC: 98.53% at 7.527 min.

[0489] 2-(Difluoromethyl)-5-(6-((4-(1-methyl-1H-pyrazol-5-yl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (199)

[0490]

[0491] 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 eq.) in acetonitrile (2.5 mL) was added KCO (358 mg, 2.595 mmol, 3.0 eq.) followed by 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-I, 250 mg, 0.8650 mmol, 1.0 eq.) at room temperature. The reaction mixture was heated and stirred at 60 °C for 12 hours. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and quenched with water (20 mL) and extracted with ethyl acetate (3x20 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 combiflash 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.

[0492] 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): To a stirred solution of 2-(6-((4-bromophenoxy)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (100 mg, 0.2616 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 for 10 min. Pd(PPh3)4(30mg, 0.0261mmol) was added to the obtained reaction mixture at room temperature. The reaction mixture was heated and stirred at 100°C for 12 hours. After the starting material was completely consumed (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mattress. The obtained filtrate was diluted with water (15mL) and extracted with ethyl acetate (3x15mL). The combined organic layer was washed with saline solution (15mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative HPLC to obtain 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-pyrazol-5-yl)phenoxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole (199, 100mg, 40%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.48-8.53 (m, 1H), 7.81 (d, J = 8.31 Hz, 1H), 7.38-7.73 (m, 4H), 7.18 (d, J = 8.80 Hz, 2H), 6.33 (s, 1H), 5.39 (s, 2H), 3.82 (s, 3H). LC-MS: m / z 383.93 [M+H]. HPLC: 95.03% at 7.959 min.

[0493] 2-(Difluoromethyl)-5-(6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)pyridin-3-yl)-1,3,4-oxadiazole(86)

[0494]

[0495] 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) were 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 minutes. The reaction mixture was heated at 60°C and stirred for 12 hours. 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 obtained residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x250 mL). The organic layer was washed with brine (100 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 methanol in DCM (0%-10%) gave methyl 5-fluoro-6-methylnicotinate (2.70 g, 75%) as an off-white solid. LC-MS: m / z 285.4 [M+H].

[0496] Step-2: Synthesis of 6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)nicotinamide: 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 hydrohydrazine (3.5 g, 110 mmol) at room temperature and stirred for 5 minutes. The reaction mixture was heated and stirred at 70°C for 12 hours. 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 give 6-((imidazo[1,2-a]pyrazin-8-yloxy)methyl)nicotinamide (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].

[0497] 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) were added imidazole (4.34 g, 62.5 mmol) and difluoroacetic anhydride (11.12 g) at 0°C. , 54.31mmol) and stirred for 5 minutes. The obtained reaction mixture was heated and stirred at 50°C for 4 hours. The reaction process was monitored by TLC. After the starting material was completely consumed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in water (100mL) and extracted with DCM (2x250mL). The organic layer was washed with brine (100mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Combi Flash column chromatography using methanol (0%-5%) in DCM to obtain 5-fluoro-6-methylnicotinate (86, 6.0g, 82% from 2 steps) as a pale 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=6.815min.

[0498] The following compounds were prepared in a similar manner to that used to prepare compound (86).

[0499]

[0500]

[0501]

[0502] 2-(2-(Bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J)

[0503]

[0504] 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 hours. 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].

[0505] 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-difluoroacetyl) 2,2-difluoroacetate (6.52 g, 37.49 mmol) at 0°C and stirred for 5 minutes. The reaction mixture was heated at 50°C for 12 hours. 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 residue obtained was dissolved in water (10 mL) and extracted with DCM (2x20 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 gave 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].

[0506] Step-4: Synthesis of 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J): To 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 NBS (503 mg, 2.82 mmol) and AIBN (38 mg, 0.226 mmol) at room temperature and stirred for 5 minutes. The reaction mixture was heated at 80°C and stirred for 12 hours. The progress of the reaction was monitored by TLC. After 12 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue obtained was dissolved in water (10 mL) and extracted with DCM (2x25 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 in n-heptane gave 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).

[0507] 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-ethoxyphosphonyloxyethane (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 reach 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 (2x25 mL). The organic layer was washed with brine (20 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%-10%) in n-heptane gave 2-(2-(dibromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Int-J, 200 mg, 36%) as an off-white solid. 1H NMR (400 Mhz, chloroform-d) δ ppm 9.41 (s, 1H), 7.71 (t, J=47.2 Hz, 1H), 4.81 (s, 2H).

[0508] 2-(Difluoromethyl)-5-(2-((4-fluorophenoxy)methyl)pyrimidin-5-yl)-1,3,4-oxadiazole(166)

[0509]

[0510] 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 KCO (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 hours. 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 (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous NaSO and concentrated under reduced pressure to obtain 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) δppm 9.44 (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.

[0511] Bioassay data and procedures

[0512] The enzyme activity of the disclosed compounds was determined in one of two biochemical assays described below. Both followed the same protocol. The first relied on caliper chip readings, while the second relied on fluorescence readings.

[0513] Caliper endpoint assay of HDAC enzyme activity

[0514] HDAC reactions were assembled in a 384-well plate (Greiner) in a total volume of 20 μL as follows: HDAC proteins (and their regulatory subunits, if applicable) were pre-diluted in assay buffer containing the following: 100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 25 mM KCl, and dispensed into a 384-well plate (10 μL per well). Examples of enzyme concentrations used in each assay are listed in the table below.

[0515]

[0516] Test compounds were serially pre-diluted in 100% DMSO using a 3-fold dilution step and added to protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO in all samples was equal to 1%. For the 12-point concentration-response format, the final compound concentration in the assay was typically in the range of 100 μM to 0.00056 μM.

[0517] The control samples (0% inhibition in the absence of inhibitors, DMSO only) and 100% inhibition (in the absence of enzymes) were assembled in quadruplicate (for each caliper pipette) and used to calculate the inhibition % in the presence of the compound. In this step, the compound was pre-incubated with the enzyme at room temperature (20°C-23°C) for 30 minutes. The reaction was initiated by adding 10 μL of a pre-diluted FAM-labeled substrate peptide (see table above) in the same assay buffer. The final concentration of the substrate peptide was 1 μM. The reaction was carried out at room temperature (20°C-23°C). Based on the predetermined enzyme progress curve, the typical incubation time for each HDAC is different and is listed in the table above.

[0518] After incubation, the reaction was quenched by adding 50 μL of stop buffer (100 mM HEPES (pH 7.5), 0.01% Triton X-100, 0.05% SDS). The terminated plates were analyzed on an ELISA (Caliper Life Sciences / Perkin Elmer) instrument that enables electrophoretic separation of deacetylated products from acetylated substrates. The change in relative intensity of the peptide substrate and product is the parameter measured. The activity of each test sample was determined as the product to sum ratio (PSR): P / (S+P), where P is the peak height of the product and S is the peak height of the substrate. The percentage of inhibition (P inh ) is determined using the following equation:

[0519] P inh =(PSR 0％inh -PSR 化合物 ) / (PSR0％inh -PSR 100％inh )*100, where: PSR 化合物 is the product / sum ratio in the presence of the compound, PSR 0％inh is the product / total ratio in the absence of the compound, and PSR 100％inh is the product / total ratio in the absence of enzyme. To determine the IC 50 (50% inhibition), %-inh data were fitted by a 4-parameter sigmoidal dose-response model using XLfit software (IDBS) (P inh Comparative compound concentration).

[0520] Nanosyn Biochemical HDAC6 Assay (Fluorescence Format)

[0521] The HDAC protein compositions and corresponding substrate peptides are summarized in the table below:

[0522]

[0523] 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 results in a cleavable bond between the fluorescent moiety of amino-methylcoumarin (AMC) and lysine. AMC is released by assisting treatment with trypsin, which is added to the stop buffer. Cracked AMC produces a detectable strong fluorescence signal (360nm excitation and 460nm emission).

[0524] HDAC reactions were assembled in black low binding 384-well plates (Corning) in a total volume of 20 mL as follows:

[0525] HDAC6 protein was pre-diluted in assay buffer containing: 100 mM HEPES (pH 7.5), 0.01% BSA, 0.01% Triton X-100, 25 mM KCl and dispensed into 384-well plates (10 uL per well).

[0526] Test compounds were serially pre-diluted in DMSO and added to protein samples by acoustic dispensing (Labcyte Echo).The concentration of DMSO in all samples was equal to 1%.

[0527] Control samples (0% inhibition in the absence of inhibitor, DMSO only) and 100% inhibition (in the absence of enzyme) were assembled in the same plate and used to calculate % inhibition in the presence of compound.

[0528] In this step, the compounds were pre-incubated with the enzyme for 30 min.

[0529] The reaction was initiated by adding 10 uL of LGK(Ac)-AMC substrate peptide pre-diluted in the same assay buffer.

[0530] The final concentration of hHDAC6 enzyme was 0.5 nM. The final concentration of mHDAC6 enzyme was 1 nM. The final concentration of substrate peptide was 1.25 uM.

[0531] The reaction was allowed to proceed at room temperature for 1 hour.

[0532] After incubation, the reaction was quenched by adding 20 mL of stop buffer containing trichostatin A (included as a stop agent) and trypsin (BPS catalog #50030). The stopped plates were read on a Synergy Neo2 luminometer. The change in relative luminescence intensity (RLU) was the parameter measured. The percentage of inhibition (P inh ) is determined using the following equation:

[0533] 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 the compound, and RLU 100％inh is the luminescence of the sample in the absence of enzyme. To determine the IC50 (50% inhibition) of the compound, the %-inh data (P inh Comparative compound concentration)

[0534] Exemplary compounds were evaluated for inhibitory activity against a panel of HDAC paralogs. The results in Table 1 demonstrate that the compounds of the present disclosure have potent activity against HDAC6, and many compounds selectively inhibit HDAC6 relative to the class I HDAC paralog HDAC8.

[0535] IC50 range: A: 0.001-0.1μM; B: >0.1-1μM; C: >1-10μM;

[0536] D: >10-100μM; E: >100μM.

[0537] Selectivity range (ratio of HDAC8 IC50 / HDAC6 IC50): I: 0.1-1; II: >1-10; III: >10-100; IV: >100-1000; V: >1000

[0538] Table 1. In vitro enzymatic IC of exemplary compounds 50 value

[0539]

[0540]

[0541]

[0542] Equivalents and scope

[0543] In the claims, unless indicated to the contrary or otherwise obvious from the context, articles such as "a", "an", and "the" may mean one or more than one. Claims or descriptions including "or" between one or more members of the group are considered satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or method, unless indicated to the contrary or otherwise obvious from the context. The invention includes embodiments in which only one member of the group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

[0544] In addition, the present invention includes all variations, combinations and arrangements, wherein one or more restrictions, elements, clauses and descriptive terms are introduced into another claim from one or more of the listed claims. For example, any claim attached to another claim can be modified to include one or more restrictions seen in any other claim belonging to the same basic claim. When the element is presented as a list, for example in the Markush group format, each subgroup of the element is also disclosed, and any one or more elements can be removed from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as comprising specific elements and / or features, some embodiments of the present invention or aspects of the present invention are composed of such elements and / or features or are substantially composed of such elements and / or features. For simplicity, those embodiments are not all specifically stated in this article. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow the inclusion of other elements or steps. When a range is given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, in various embodiments of the present invention, values ​​expressed as ranges may be assumed to be any specific value or sub-range within the stated range, to the tenth of the unit of the lower limit of the stated range, unless the context clearly dictates otherwise.

[0545] This application refers to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and this specification, the present specification shall prevail. In addition, any specific embodiment of the present invention within the prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if they are not explicitly set forth herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of the prior art.

[0546] Those skilled in the art will recognize or be able to determine using only routine experimentation many equivalents to the specific embodiments described herein. The scope of the embodiments of the present invention described herein is not intended to be limited to the above description, but is set forth as the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: X is N or CR 1 ;Y is CR 1 or N; provided that at least one of X and Y is N; R 1 is hydrogen or a halogen; R a and R b are each independently hydrogen or halogen; L is a bond or C optionally substituted by one or more halogens 1-4 Alkylene; A is an unsubstituted 5,6-bicyclic heteroaryl ring system or substituted by 1-3 independent substituents R 2 substituted 5,6-bicyclic heteroaryl ring systems; Each occurrence of R 2 R 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 two occurrences of R 2 are connected to their intervening atoms to form a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

2. The compound of claim 1, wherein: X is N; R 1 is hydrogen or fluorine; R a and R b each independently is hydrogen; L is the key; A is a 5,6-bicyclic heteroaryl ring system containing one or more nitrogen or oxygen heteroatoms; and A is optionally substituted by 1-3 independent substituents R 2 replace; and Each occurrence of R 2 are independently halogen, cyano, amine, amide, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, in which each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 The alkynyl group is optionally substituted with one or more amine, amide, halogen or cyano groups.

3. The compound of claim 2, wherein each R 2 are independently chlorine, fluorine, -CN, -CH2CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 haloalkyl, acyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amidoalkyl, optionally substituted by C 1-4 Alkyl-substituted amino or optionally C 1-4 Alkyl substituted amide.

4. The compound of claim 3, wherein each R 2 is independently C substituted with optionally substituted or unsubstituted amino 1-4 alkyl.

5. The compound of claim 4, wherein A is unsubstituted or replaced by a single R 2 replace.

6. The compound as claimed in claim 5, wherein R 2 It is C 1-4 alkyl.

7. The compound of claim 6, wherein R 2 It's methyl.

8. The compound of claim 7, wherein A is 9. The compound of claim 5, wherein A is unsubstituted.

10. The compound of claim 9, wherein A is 11. The compound of any one of claims 1 to 10, wherein Y is CR 1 .

12. The compound of claim 11, wherein R 1 It's hydrogen.

13. The compound of claim 11, wherein R 1 It's fluorine.

14. The compound of any one of claims 1-10, wherein Y is N.

15. The compound of claim 1, wherein the compound is 16. The compound of claim 1, wherein the compound is 17. The compound of claim 1, wherein the compound is 18. The compound of claim 1, wherein the compound is 19. The compound of claim 1, wherein the compound is 20. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

44. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

46. ​​The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound according to claims 1-46.

48. Use of a compound as claimed in any one of claims 1 to 46 in the manufacture of a medicament for treating a nervous system disorder.

49. The use of claim 48, wherein the neurological disorder is amyotrophic lateral sclerosis (ALS).

50. A method for impairing microtubule function by deacetylation of tubulin comprising administering a compound of claims 1-46.

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