Compounds for treatment of neurodegenerative diseases

Abstract

Herein, compounds, compositions, and methods for treating and preventing neurodegenerative diseases are described.

Description

Attorney Docket No.: AQN-030WO COMPOUNDS FOR TREATMENT OF NEURODEGENERATIVE DISEASES FIELD

[0001] The present disclosure relates to compounds, compositions, and methods of treating and preventing neurodegenerative diseases. BACKGROUND

[0002] One of the hallmarks of many neurodegenerative diseases is the accumulation of protein inclusions in the brain and central nervous system. These inclusions are insoluble aggregates of proteins and other cellular components that cause damage to cells and result in impaired function. Proteins such as tau (microtubule associate protein tau) have been found to form inclusions in the brain and are linked to the development of a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal lobar dementia (FTD), CorticoBasal Degeneration (CBD), and Traumatic Brain Injury (TBI).

[0003] Hyperphosphorylation of tau causes it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or “paired helical filaments”). Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated tau which are formed by self-polymerization of tau monomers.

[0004] An important aspect of the tau aggregation is its associated cytotoxicity which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms. A direct role of tau in disease onset has been established unequivocally by the elucidation of familial mutations in tau which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of tau that— directly or indirectly—promote neurotoxic aggregation.

[0005] Alzheimer’s disease (AD) is the best known tauopathy. It is characterized by thepresence of extracellular plaques consisting of insoluble amyloid beta (A ) and neurofibrillarytangles consisting of insoluble hyperphosphorylated tau. Neuronal death and progression of clinical symptoms correlates most strongly with the accumulation of tau neurofibrillary tangle.However, current FDA approved treatments of AD only target aggregated A (Aducanumab,Biogen / Eisai) or protofibrillar A (Lecanemab, Biogen).

[0006] Treatments aimed to suppress cytotoxic tau misfolding and / or aggregation in order to delay or halt the progression of disease are presently not available. Thus, there is a need for IPTS / 200079109.1Attorney Docket No.: AQN-030WO new treatments that target the underlying molecular mechanism of noxious tau misfolding and / or aggregation in order to reduce neuronal cell death and / or degeneration in patients suffering from tauopathies such as Alzheimer's disease. SUMMARY

[0007] Provided herein are compounds designed to function as modulators (e.g., inhibitors) of cytotoxic tau misfolding and aggregation. Such compounds can be useful as therapeutic agents for treating or preventing neurodegenerative diseases, such as Alzheimer’s disease or frontotemporal dementia.

[0008] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0009] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] Disclosed herein, in some embodiments, is a method of treating or preventing a neurodegenerative disease, wherein the method comprises administering a compound disclosed herein, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a timeline illustrating the dosing schedule of compounds of the present disclosure as described in Example 18. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0012] FIG. 2 depicts pellets being suspending in buffer and being used for biochemical analysis of tau-pathology via AlphaLISA.

[0013] FIG. 3 is a bar graph that show total tau signal (%) in mice after administration of compound 1-19 as compared to vehicle.

[0014] FIG. 4 is a bar graph that show MC-1 tau signal (%) in mice after administration of compound 1-19 as compared to vehicle.

[0015] FIG. 5 is a bar graph that show AT8 p.tau signal (%) in mice after administration of compound 1-19 as compared to vehicle.

[0016] FIG. 6 is a bar graph that show TOC1 o.tau signal (%) in mice after administration of compound 1-19 as compared to vehicle. DETAILED DESCRIPTION

[0017] The present compounds and compositions are useful for treating or preventing certain neurodegenerative disorders. Some neurodegenerative disorders are characterized by cytotoxic tau misfolding and / or aggregation, which misfolding and aggregation can be inhibited in order to delay or halt the progression of such diseases. Such diseases are summarized under the term tauopathy. The term “Tauopathy” refers to a disease characterized by dysfunctioning and / or toxicity of the tau protein, characterized by oligomers, aggregates or polymers of said protein. Such diseases include, but are not limited to, Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17).

[0018] Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated tau which are formed by self-polymerization of tau monomers. The precise molecular mechanisms involved in tau aggregation are not precisely known, but may involve a partial denaturation or misfolding of tau in conformations which have a high propensity to self-organize into higher order structures. The misfolding and aggregation may be triggered by hyperphosphorylation of tau, although at present it cannot be excluded that such aberrant phosphorylation is a consequence rather than the cause of aggregation. Tau is a protein with the ability to bind—and consequently stabilize and define—microtubule structure and function in neurons. The binding of tau to microtubules is regulated by phosphorylation of tau and several tau phosphorylation sites and their corresponding kinases have been identified which control phosphorylation status of tau and consequently modulate the affinity of tau- binding to microtubules. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0019] An important aspect of the tau aggregation is its associated cytotoxicity which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms. A direct role of tau in disease onset has been established unequivocally by the elucidation of familial mutations in tau which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of tau that— directly or indirectly—promote neurotoxic aggregation.

[0020] Alzheimer's disease (AD) is the best known of these, where tau protein is deposited within neurons in the form of neurofibrillary tangles (NFTs). They were first described by the eponymous Alois Alzheimer in one of his patients suffering from the disorder. The term “Alzheimer's disease” as used herein, refers to a chronic progressive nervous disease characterized by neurodegeneration with as most important (early) symptom being memory loss. As the disease advances, symptoms may include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline.

[0021] Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or “paired helical filaments”). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in the disease or play a more peripheral role. AD is also classified as an amyloidosis because of the presence of senile plaques.

[0022] Other conditions in which neurofibrillary tangles are commonly observed include: progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, similar to AD, but without plaques, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0023] The non-Alzheimer's tauopathies are sometimes grouped together as “Pick's complex”. In Pick's disease and corticobasal degeneration tau proteins are deposited in the form of inclusion bodies within swollen or “ballooned” neurons. Argyrophilic grain disease (AGD), another type of dementia, is marked by the presence of abundant argyrophilic grains and coiled bodies on microscopic examination of brain tissue Definitions IPTS / 200079109.1Attorney Docket No.: AQN-030WO Selected Chemical Definitions

[0024] At various places in the present specification, substituents of compounds disclosed herein are recited in groups or in ranges. It is specifically intended that the compounds disclosed herein include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0025] For compounds disclosed herein in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.

[0026] It is further appreciated that certain features of compounds disclosed herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the compounds disclosed herein which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0027] If a compound of the compounds disclosed herein is depicted in the form of a chemical name and as a formula, in case of any discrepancy, the formula shall prevail.

[0028] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure.

[0029] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0030] The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, purification, or use for one or more of the purposes disclosed herein.

[0031] Suitable substituents for an optionally substituted alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group include halogen, O, —CN, —ORcc, —NRddRee, —S(O)kkRcc, —NRccS(O)2Rcc, — IPTS / 200079109.1Attorney Docket No.: AQN-030WOS(O)2NRddRee, —C( O)ORcc, —OC( O)ORcc, —OC( O)Rcc, —OC( S)ORcc, —C( S)ORcc, —O(C S) Rcc, —C( O)NRddRee, —NRccC( O) Rcc, —C( S)NRddRee, —NRccC( S)Rcc, —NRcc(C O)ORcc, —O(C O)NRddRee, —NRcc (C S)ORcc, —O(C S)NRddRee, —NRcc(C O)NRddRee, —NRcc(C S)NRddRee, —C( S)Rcc, —C( O)Rcc,C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6- heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl and heteroarylare optionally substituted with one or more of halogen, ORcc, —NO2, —CN, —NRccC( O)W,—NRddRee, —S(O)kRcc, —C( O)ORcc, —C( O)NRddRee, —C( O)Rcc, C1-C6 alkyl, C1-C6haloalkyl, or C1-C6 heteroalkyl, and wherein Rccis hydrogen, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1- C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Rddand Reeare each independently selected from hydrogen, C1-C6 alkyl, or C1-C6heteroalkyl; and k is 0, 1 or 2. The compounds disclosed herein are not intended to be limited in any manner by the above exemplary listing of substituents.

[0032] As used herein, the term “optional substituent” refers to any of the suitable substituents for an alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group, including: halogen, O, —CN, —ORcc, —NRddRee,—S(O)kkRcc, —NRccS(O)2Rcc, —S(O)2NRddRee, —C( O)ORcc, —OC( O)ORcc, —OC( O)Rcc, —OC( S)ORcc, —C( S)ORcc, —O(C S) Rcc, —C( O)NRddRee, —NRccC( O)Rcc, —C( S)NRddRee, —NRccC( S)Rcc, —NRcc(C O)ORcc, —O(C O)NRddRee, —NRcc(C S)ORcc, —O(C S)NRddRee, —NRcc(C O)NRddRee, —NRcc(C S)NRddRee, —C( S)Rcc,—C( O)Rcc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl and heteroarylare optionally substituted with one or more of halogen, ORcc, —NO2, —CN, —NRccC( O)W,—NRddRee, —S(O)kRcc, —C( O)ORcc, —C( O)NRddRee, —C( O)Rcc, C1-C6 alkyl, C1-C6IPTS / 200079109.1Attorney Docket No.: AQN-030WO haloalkyl, or C1-C6 heteroalkyl, and wherein Rccis hydrogen, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1- C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Rddand Reeare each independently selected from hydrogen, C1-C6alkyl, or C1-C6heteroalkyl; and k is 0, 1 or 2. The compounds disclosed herein are not intended to be limited in any manner by the above exemplary listing of substituents.

[0033] As used herein, “alkyl” refers to a radical of a straight–chain or branched, saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6alkyl”). Examples of C1-C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3– pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n– hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C1–10 alkyl (e.g., –CH3). In some embodiments, the alkyl group is substituted C1–6 alkyl. As used herein, the term "alkylene” refers to an alkyl group with one additional open valence, i.e., a bivalent group. Exemplary alkylene groups include, but are not limited to -CH2CH2- and CH2-C(CH3)-CH2-.

[0034] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C2-C24 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6IPTS / 200079109.1Attorney Docket No.: AQN-030WO alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2-C4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is unsubstituted C2–10 alkenyl. In some embodiments, the alkenyl group is substituted C2–6 alkenyl.

[0035] As used herein, the term “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C2-C24 alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-C5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-C4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2-C4alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C4), 2–butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl group is unsubstituted C2–10 alkynyl. In some embodiments, the alkynyl group is substituted C2–6 alkynyl.

[0036] As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight-chain or branched, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen IPTS / 200079109.1Attorney Docket No.: AQN-030WO and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O- CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -NHCH2-, - C(O)NH-, -C(O)N(CH3), -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, -CH2-CH2- S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, - CH2-NH-OCH3and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like, it will be understood that the terms heteroalkyl and –CH2O or –NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like.

[0037] As used herein, the term "heteroalkylene” refers to a heteroalkyl group with one additional open valence, i.e., a bivalent group. Exemplary heteroalkylene groups include, but are not limited to: -CH2-CH2-O-CH2-, -CH2-O-,and -CH2-CH2-NH-CH2-.

[0038] As used herein, “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 electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (e.g., “unsubstituted aryl”) or substituted (e.g., “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted C6-C14 aryl. In some embodiments, the aryl group is substituted C6-C14 aryl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl.

[0039] As used herein, “heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 electrons shared in a cyclic array) having ring carbon atoms and one or more (e.g., 1–4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups IPTS / 200079109.1Attorney Docket No.: AQN-030WO that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). A heteroaryl group may be described as, e.g., a 5-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 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. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In some embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl. Exemplary heteroaryl groups include, but are not limited to, imidazolyl, pyridinyl, and quinolinyl.

[0040] As used herein, “cycloalkyl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring carbon atoms (“C3-C14 carbocyclyl”) and zero heteroatoms in the saturated or partially unsaturated, but not aromatic, ring system. In some embodiments, a IPTS / 200079109.1Attorney Docket No.: AQN-030WO cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8cycloalkyl groups include, without limitation, the aforementioned C3-C6cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, the cycloalkyl group is monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C3-C10cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-C10cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanyl, cyclohexenyl, cyclooctynyl, and bicyclo[4.4.0]decanyl.

[0041] “Heterocycloalkyl” as used herein refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring atoms including carbon and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (e.g., –S–, –S(O)–, and – S(O)2–), boron, phosphorus, and silicon (“3–14 membered heterocycloalkyl”). In heterocycloalkyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocycloalkyl group can either be monocyclic (“monocyclic heterocycloalkyl”) or polycyclic (“polycyclic heterocycloalkyl”), such as bicyclic (“bicyclic heterocycloalkyl”). A heterocycloalkyl group can be a fused, bridged or spiro ring system. Bicyclic heterocycloalkyl can include one or more heteroatoms IPTS / 200079109.1Attorney Docket No.: AQN-030WO in one or both rings. A heterocycloalkyl group may be described as, e.g., a 3-7-membered heterocycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocycloalkyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted (a “substituted heterocycloalkyl”) with one or more substituents. In some embodiments, the heterocycloalkyl group is unsubstituted 3–14 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl group is substituted 3–14 membered heterocycloalkyl. In some embodiments, a heterocycloalkyl group is a 5–10 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocycloalkyl”). In some embodiments, a heterocycloalkyl group is a 5–8 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocycloalkyl”). In some embodiments, a heterocycloalkyl group is a 5–6 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocycloalkyl”). In some embodiments, the 5–6 membered heterocycloalkyl has 1–3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocycloalkyl has 1–2 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 3,4-dihydro-2H-pyranyl, and octahydroindolyl.

[0042] As used herein, “carbocyclyl” refers to a radical of a polycyclic, partially unsaturated ring system having from 6 to 20 carbon atoms and at least one fused aryl ring. The term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a carbocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is unsubstituted 6-20 membered carbocyclyl. In some embodiments, the carbocyclyl group is a substituted 6-20 membered carbocyclyl. Exemplary carbocyclyl groups include, but are not limited to, indenyl and tetrahydronaphthyl.

[0043] As used herein, “heterocyclyl” refers to a radical of a polycyclic, partially unsaturated ring system having from 5 to 20 atoms (“5-20 membered heterocyclyl”) including carbon and IPTS / 200079109.1Attorney Docket No.: AQN-030WO 1 to 6 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and wherein the polycyclic, partially unsaturated ring system has at least one aromatic ring (e.g., aryl or heteroaryl). In some embodiments, a heterocyclyl group has 5 to 14 ring atoms (“5-14 membered heterocyclyl”). The term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a heterocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is unsubstituted 5-20 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 5-20 membered heterocyclyl. Exemplary heterocyclyl groups include, but are not limited to, 1,2,3,4- tetrahydroquinolyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 1,4,6,7-tetrahydropyrano[4,3- b]pyrrole, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 5,6,7,8-tetrahydroquinolinyl.

[0044] As used herein, “cyano” refers to the radical –CN.

[0045] As used herein, “halo” or “halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0046] As used herein, “haloalkyl” can include alkyl structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6 alkyl-CF3, -C1-C6 alkyl-C2F). Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluormethyl, and fluoroisopropyl.

[0047] As used herein, “alkoxy” refers to an alkyl group attached to the remainder of the molecule via an oxygen linker (–O–). Alkoxy groups of the present disclosure may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec- butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. In certain embodiments, alkoxy groups of the present disclosure are lower alkoxy groups, i.e. with between 1 and 6 carbon atoms. In certain embodiments, alkoxy groups of the present disclosure have between 1 and 4 carbon atoms.

[0048] As used herein, “hydroxy” refers to the radical –OH.

[0049] As used herein, “nitro” refers to –NO2.

[0050] As used herein, “oxo” (=O) refers to a carbonyl, in which both bonds from the oxygen are connected to the same atom. For example, a carbon atom substituted with oxo forms a carbonyl group C=O.

[0051] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carbocyclyl, or heterocyclyl groups. Such so-called ring-forming substituents IPTS / 200079109.1Attorney Docket No.: AQN-030WO are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non- adjacent members of the base structure.

[0052] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC); or preferred isomers can be prepared by asymmetric syntheses. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0053] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In some embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0054] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In some embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total IPTS / 200079109.1Attorney Docket No.: AQN-030WO weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In some embodiments, the enantiomerically pure S– compound in such compositions can, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0055] Compound disclosed herein may also comprise one or more isotopic substitutions. Isotopes include those atoms having the same atomic number but different mass numbers. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Further, unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least about 45% incorporation of deuterium).

[0056] One or more constituent atoms of the compounds of the present disclosure can be replaced or substituted with isotopes of the atoms in non-natural abundance. In some embodiments, the compound comprises one or more deuterium atoms. For example, one or more hydrogen atoms in a compound disclosed herein can be replaced or substituted by deuterium. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.

[0057] Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

[0058] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0059] Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit the formation of TDP-43 inclusions), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. IPTS / 200079109.1Attorney Docket No.: AQN-030WO In general, the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

[0060] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. As used herein, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted. Other Definitions

[0061] Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the disclosure. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0062] As used herein, the terms “compounds” and “agent” are used interchangeably to refer to the inhibitors / antagonists / agonists disclosed herein. In certain embodiments, the compounds are small organic or inorganic molecules, e.g., with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu. In certain embodiments, one class of small organic or inorganic molecules are non-peptidyl, e.g., containing 2, 1, or no peptide and / or saccharide linkages.

[0063] Unless otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages may mean ±1%.

[0064] The singular terms “a,” “an,” and “the” refer to one or to more than one, unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0065] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0066] As used herein, the term “administer” refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.

[0067] The terms “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount. In some embodiments, the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. absent level as compared to a reference sample), or any decrease between 1-100%, e.g., 10-100% as compared to a reference level.

[0068] The terms “increased”, ”increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount. In some embodiments, the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g. absent level as compared to a reference sample), or any increase between 1-100%, e.g., 10-100% as compared to a reference level.

[0069] By “treatment”, “prevention” or “amelioration” of a disease or disorder is meant delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder. In one embodiment, at least one symptom of a disease or disorder is alleviated by at IPTS / 200079109.1Attorney Docket No.: AQN-030WO least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.

[0070] As used herein, an amount of a compound or combination effective to treat a disorder (e.g., a disorder as described herein), “therapeutically effective amount” or “effective amount” refers to an amount of the compound or combination which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disorder (e.g., a disorder as described herein) beyond that expected in the absence of such treatment. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, a therapeutically effective amount can vary with the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents.

[0071] As used herein, a “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents. In certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “patient” and “subject” are used interchangeably herein. The terms, “patient” and “subject” are used interchangeably herein

[0072] The term "nucleic acid" as used herein refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide. The terms should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides.

[0073] The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present disclosure which is effective for producing some desired therapeutic effect, e.g., by inhibiting aggregation of tau, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0074] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0075] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0076] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0077] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition IPTS / 200079109.1Attorney Docket No.: AQN-030WO salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Compounds

[0078] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: IPTS / 200079109.1Attorney Docket No.: AQN-030WO Ringwhereineach of R1, R2, R3, R4, R5R9, R10, R11, R12, and R13is independently selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, and C2-6alkynyl; R6is hydrogen or C1-6alkyl; R7is selected from hydrogen, C1-6alkyl, –CH2OH, and –C(O)NH2; R8is hydrogen or C1-6alkyl; and R14is hydrogen or C1-6alkyl.

[0079] In some embodiments, each of R1, R2, R3, R4, and R5is, independently, hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl.

[0080] In some embodiments, each of R9, R10, R11, R12, and R13is, independently, hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0081] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: Ringeach of R1, R2, R3, R4, and R5is independently hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl; R6is hydrogen or C1-6alkyl; IPTS / 200079109.1Attorney Docket No.: AQN-030WO R7is selected from hydrogen, C1-6alkyl, –CH2OH, and –C(O)NH2; R8is hydrogen or C1-6alkyl; each of R9, R10, R11, R12, and R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and R14is hydrogen or C1-6alkyl.

[0082] In some embodiments, Ring A is, whereinis a bond to . In some embodiments, Ring A is, whereinis a bond to.

[0083] In some embodiments, R1is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl

[0084] In some embodiments, R1is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R1is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is C1-6alkyl. In some embodiments, R1is C1-6haloalkyl. In some embodiments, R1is C2-6alkynyl.In some embodiments, R1 is hydrogen, –F, –CF3, or –C CH.

[0085] In some embodiments, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R2is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-6haloalkyl. In some embodiments, R2is C2-6alkynyl.In some embodiments, R2 is hydrogen, –F, –CF3, or –C CH.

[0086] In some embodiments, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R3is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is C1-6haloalkyl. In some embodiments, R3is C2-6alkynyl.In some embodiments, R3 is hydrogen, –F, –CF3, or –C CH. In some embodiments, R3 ishydrogen, halogen, or C2-6alkynyl. In some embodiments, R3 is hydrogen, –F, or –C CH. Insome embodiments, R3 is –F. In some embodiments, R3 is –C CH.IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0087] In some embodiments, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R4is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is C1-6alkyl.In some embodiments, R4is C1-6haloalkyl. In some embodiments, R4is C2-6alkynyl.In some embodiments, R4 is hydrogen, –F, –CF3, or –C CH. In some embodiments, R4 is –CF3.

[0088] In some embodiments, R5is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R5is hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R5is hydrogen. In some embodiments, R5is halogen. I n some embodiments, R5is C1-6alkyl. In some embodiments, R5is C1-6haloalkyl. In some embodiments, R5is C2-6alkynyl. In some embodiments, R5 is hydrogen, –F, –CF3, or –C CH.

[0089] In some embodiments, R6is C1-6alkyl. In some embodiments, R6is –Me. In some embodiments, R6is hydrogen. In some embodiments, R6is hydrogen or –Me.

[0090] In some embodiments, R7is C1-6alkyl. In some embodiments, R7is –Me. In some embodiments, R7is hydrogen. In some embodiments, R7is hydrogen or –Me. In some embodiments, R7is –CH2OH or –C(O)NH2. In some embodiments, R7is –CH2OH. In some embodiments, R7is–C(O)NH2.

[0091] In some embodiments, R8is C1-6alkyl. In some embodiments, R8is –Me, –Et, or –nBu. In some embodiments, R8is hydrogen. In some embodiments, R8is hydrogen, –Me, –Et, or – nBu. In some embodiments, R8is hydrogen, –Et, or –nBu. In some embodiments, R8is –Et or –nBu. In some embodiments, R8is –Et. In some embodiments, R8is –nBu.

[0092] In some embodiments, R14is C1-6alkyl. In some embodiments, R14is –Me. In some embodiments, R14is hydrogen. In some embodiments, R14is hydrogen or –Me.

[0093] In some embodiments, R9is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R9is hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is halogen. In some embodiments, R9is C1-6alkyl. In some embodiments, R9is C1-6haloalkyl. In some embodiments, R9is C2-6alkynyl. In some embodiments, R9is hydrogen, –Me, or –CF3. In some embodiments, R9is hydrogen or C1- 6haloalkyl. In some embodiments, R9is hydrogen or –CF3. In some embodiments, R9is –CF3.

[0094] In some embodiments, R10is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2- 6alkynyl. In some embodiments, R10is hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is halogen. In some embodiments, R10is C1-6alkyl. In some embodiments, R10is C1-6haloalkyl. In some embodiments, R10is C2-6alkynyl. In some embodiments, R10is hydrogen, –Me, or –CF3. In some embodiments, R10is IPTS / 200079109.1Attorney Docket No.: AQN-030WO hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R10is hydrogen, –Me, or –CF3. In some embodiments, R10is –Me. In some embodiments, R10is –CF3.

[0095] In some embodiments, R11is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R11is hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R11is hydrogen. In some embodiments, R11is halogen. In some embodiments, R11is C1-6alkyl. In some embodiments, R11is C1-6haloalkyl. In some embodiments, R11is C2-6alkynyl. In some embodiments, R11is hydrogen, –Me, or –CF3. In some embodiments, R11is hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R11is hydrogen, –Me, or –CF3. In some embodiments, R10is –Me. In some embodiments, R11is –CF3.

[0096] In some embodiments, R12is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or C2-6alkynyl. In some embodiments, R12is hydrogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments, R12is hydrogen. In some embodiments, R12is halogen. In some embodiments, R12is C1-6alkyl. In some embodiments, R12is C1-6haloalkyl. In some embodiments, R12is C2- 6alkynyl. In some embodiments, R12is hydrogen, –Me, or –CF3.

[0097] In some embodiments, the compound is of Formula II:Formula II, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound is of Formula III: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the compound is of Formula I-a:Formula I-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the compound is of Formula II-a: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the compound is of Formula III-a:Formula III-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound is of Formula I-b: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula I-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the compound is of Formula I-c:Formula I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound is of Formula II-b: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the compound is of Formula II-c:Formula II-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is of Formula III-b: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound is of Formula III-c:Formula III-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound is of Formula I-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula I-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound is of Formula I-e:Formula I-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound is of Formula II-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound is of Formula II-e:Formula II-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, wherein the compound is of Formula III-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound is of Formula III-e:Formula III-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0114] Disclosed herein, in some embodiments, is a compound of Table 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the disclosureIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0115] In some embodiments, the compound is: 5-(4-ethynyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 3-((4-(5-propyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-((4-(5-ethyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-((4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; IPTS / 200079109.1Attorney Docket No.: AQN-030WO 3-((4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 5-(3-(trifluoromethyl)phenyl)-3-(1-(4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)ethyl)-1,2,4-oxadiazole; 3-(3-(trifluoromethyl)phenyl)-5-(1-(4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)ethyl)-1,2,4-oxadiazole; 3-(3-(trifluoromethyl)phenyl)-5-((4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(((2R,4R)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 5-(((2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-(((2R,4R)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-(((2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 5-(3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(((2R,4R)-2-methyl-4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(((2S,4S)-2-methyl-4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(1-methyl-4-(4-(trifluoromethyl)phenyl)- 1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-phenyl-1H-imidazol-2-yl)piperidin-1- yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(2-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(3-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; IPTS / 200079109.1Attorney Docket No.: AQN-030WO 3-((4-(4-(4-ethynyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-(((2R,4R)-2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 3-(((2S,4S)-2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; 5-(2-methyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 1-((5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-2-carboxamide; 3-((2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin- 1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole; (1-((5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-2-yl)methanol; 5-(4-chloro-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; 5-(4-methyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole; or 3-((4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole, or a stereoisomer, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions and Routes of Administration

[0116] Provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, (e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier. The pharmaceutical compositions disclosed herein are useful for treating or ameliorating or preventing a neurodegenerative disease described herein in a subject in need thereof.

[0117] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, (e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0118] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of Formula I, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0119] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of Formula II, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0120] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0121] The amount and concentration of a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, (e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof), in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of the compound(s) in the pharmaceutical composition, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0122] While it is possible for a compound of the present disclosure to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition), where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. The compounds according to the present disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.

[0123] Thus, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds IPTS / 200079109.1Attorney Docket No.: AQN-030WO disclosed herein, and stereoisomers, and a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula I, Formula II, and Formula III, and a subformula thereof, and stereoisomers, and pharmaceutically acceptable salts thereof), formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents.

[0124] As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960.

[0125] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the pharmaceutical compositions.

[0126] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0127] Pharmaceutical compositions of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will IPTS / 200079109.1Attorney Docket No.: AQN-030WO vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0128] Methods of preparing these formulations or pharmaceutical compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0129] Pharmaceutical compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. A compound of the present disclosure may also be administered as a bolus, electuary, or paste.

[0130] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0131] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0132] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using polymer matrices, liposomes and / or microspheres to provide the desired release profile. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0133] Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0134] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0135] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, IPTS / 200079109.1Attorney Docket No.: AQN-030WO microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0136] Formulations of the pharmaceutical compositions of the present disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0137] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port.

[0138] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated.

[0139] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection.

[0140] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this present disclosure suitable for parenteral administration comprise one or more compounds of the present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0141] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0142] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0143] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0144] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0145] When the compounds of the present disclosure are administered as pharmaceuticals, to a subject in need thereof, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier.

[0146] The addition of the active compound of the present disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).

[0147] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0148] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections.

[0149] In addition, the methods described herein can be used to treat domesticated animals and / or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder. Methods of Treatment

[0150] Without wishing to be bound by a theory, pharmaceutical compositions disclosed herein (e.g., pharmaceutical compositions comprising compounds disclosed herein, and stereoisomers, and a pharmaceutically acceptable salt thereof, e.g., compounds of Formula I, Formula II, and Formula III, and a subformula thereof, and stereoisomers, and pharmaceutically acceptable salts thereof), or compounds disclosed herein (e.g., compounds disclosed herein, and stereoisomers, and a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula I, Formula II, and Formula III, and a subformula thereof, and stereoisomers, and pharmaceutically acceptable salts thereof), can be used to delay the progression of neurodegenerative illnesses where the pathology incorporates tauopathy.

[0151] The term “neurodegenerative disease” as used herein, refers to a neurological disease characterized by loss or degeneration of neurons. The term “neurodegenerative disease” includes diseases caused by the involvement of genetic factors or the cell death (apoptosis) of neurons attributed to abnormal protein accumulation and so on. Additionally, IPTS / 200079109.1Attorney Docket No.: AQN-030WO neurodegenerative diseases include neurodegenerative movement disorders and neurodegenerative conditions relating to memory loss and / or dementia. Neurodegenerative diseases include tauopathies and -synucleopathies. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington's disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler- Scheinker syndrome, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) and autism.

[0152] As used herein, the term " -synucleopathy" refers to a neurodegenerative disorder ordisease involving aggregation of -synuclein or abnormal -synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci 19:5782:5791; Rideout, H.J., et al. (2004) J Biol Chem 279:46915-46920). -Synucleopathies include, but are not limited to, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Pick's disease, Down's IPTS / 200079109.1Attorney Docket No.: AQN-030WO syndrome, multiple system atrophy, amylotrophic lateral sclerosis (ALS), Hallervorden-Spatz syndrome, and the like.

[0153] As used herein, the term “tauopathy” refers to a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. Tauopathies include, but are not limited to, Alzheimer’s disease, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), progressive supranuclear palsy, Frontotemporal dementia, Frontotemporal lobar degeneration, or Pick's complex.

[0154] Provided herein are methods of treating or preventing a neurodegenerative disease in a subject in need thereof, the methods generally comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof).

[0155] Disclosed herein, in some embodiments, is a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, (e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula I, Formula II, or Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof).

[0156] Disclosed herein, in some embodiments, is a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0157] Disclosed herein, in some embodiments, is a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula II, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0158] Disclosed herein, in some embodiments, is a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula III, or a subformula thereof, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP- 17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis- parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), and autism. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0160] In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein, frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, a prion disease, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinobulbar muscular atrophy, post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay- Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety, an anxiety disorder, a sleep disorder, acute brain injury, and autism.

[0161] In some embodiments, FTD caused by mutations in the progranulin protein or tau proteinis progranulin-deficient FTLD.

[0162] In some embodiments, the prion disease is Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie.

[0163] In some embodiments, the spinal muscular atrophy (SMA) is SMA Type I, SMA Type II, SMA Type III, or congenital SMA with arthrogryposis.

[0164] In some embodiments, the SMA Type I is Werdnig-Hoffmann disease.

[0165] In some embodiments, the SMA Type III is Kugelberg-Welander disease. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0166] In some embodiments, the progressive spinobulbar muscular atrophy is Kennedy disease.

[0167] In some embodiments, the sleep disorder is narcolepsy or fatal familial insomnia.

[0168] In some embodiments, the acute brain injury is related to stroke or head injury.

[0169] In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle- predominant dementia with NFTs, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0170] In some embodiments, the neurodegenerative disease is Alzheimer’s disease or frontotemporal dementia. ENUMERATED EMBODIMENTS

[0171] In some embodiments, the present disclosure includes the following enumerated embodiments: 1. A compound of Formula I:Formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: IPTS / 200079109.1Attorney Docket No.: AQN-030WO Ringwhereinbondeach of R1, R2, R3, R4, and R5is, independently, hydrogen, halogen, C1-6haloalkyl, or C2-6alkynyl; R6is hydrogen or C1-6alkyl; R7is hydrogen or C1-6alkyl; R8is hydrogen or C1-6alkyl; each of R9, R10, R11, R12, and R13is, independently, hydrogen, C1-6alkyl, or C1- 6haloalkyl; and R14is hydrogen or C1-6alkyl. 2. The compound of embodiment 1, wherein Ring A isbond3. The compound of embodiment 1, wherein Ring A is, whereinabond4. The compound of embodiment 1, wherein the compound is of Formula II: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1, wherein the compound is of Formula III:Formula III, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 6. The compound of any one of embodiments 1-5, wherein R1is hydrogen. 7. The compound of any one of embodiments 1-6, wherein R2is hydrogen. 8. The compound of any one of embodiments 1-7, wherein R3is hydrogen, halogen, or C2-6alkynyl 9. The compound of any one of embodiments 1-8, wherein R3is hydrogen, –F, or –C CH.IPTS / 200079109.1Attorney Docket No.: AQN-030WO 10. The compound of any one of embodiments 1-9, wherein R4is C1-6haloalkyl. 11. The compound of any one of embodiments 1-10, wherein R4is –CF3. 12. The compound of any one of embodiments 1-11, wherein R5is hydrogen. 13. The compound of any one of embodiments 1-3, wherein the compound is of Formulaor a stereoisomer, or a pharmaceutically acceptable salt thereof. 14. The compound of any one of embodiments 1-4, wherein the compound is of Formula II-a:Formula II-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof. IPTS / 200079109.1Attorney Docket No.: AQN-030WO 15. The compound of any one of embodiments 1-3 and 5, wherein the compound is of Formula III-a:Formula III-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 16. The compound of any one of embodiments 1-15, wherein R6is C1-6alkyl. 17. The compound of any one of embodiments 1-16, wherein R6is –Me. 18. The compound of any one of embodiments 1-15, wherein R6is hydrogen. 19. The compound of any one of embodiments 1-18, wherein R7is C1-6alkyl. 20. The compound of any one of embodiments 1-19, wherein R7is –Me. 21. The compound of any one of embodiments 1-3, wherein the compound is of Formula I-b:IPTS / 200079109.1Attorney Docket No.: AQN-030WO Formula I-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 22. The compound of any one of embodiments 1-3, wherein the compound is of FormulaFormula I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 23. The compound of any one of embodiments 1-4, wherein the compound is of Formula II-b:Formula II-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 24. The compound of any one of embodiments 1-4, wherein the compound is of Formula II-c: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 25. The compound of any one of embodiments 1-3 and 5, wherein the compound is of Formula III-b:Formula III-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 26. The compound of any one of embodiments 1-3 and 5, wherein the compound is of Formula III-c: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 27. The compound of any one of embodiments 1-18, wherein R7is hydrogen. 28. The compound of any one of embodiments 1-29, wherein R8is C1-6alkyl. 29. The compound of any one of embodiments 1-30, wherein R8is –Et or –nBu. 30. The compound of any one of embodiments 1-29, wherein R8is hydrogen. 31. The compound of any one of embodiments 1-32, wherein R14is C1-6alkyl. 32. The compound of any one of embodiments 1-33, wherein R14is –Me. 33. The compound of any one of embodiments 1-32, wherein R14is hydrogen. 34. The compound of any one of embodiments 1-3, wherein the compound is of Formula I-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula I-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 35. The compound of any one of embodiments 1-3, wherein the compound is of Formula I-e:Formula I-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 36. The compound of any one of embodiments 1-4, wherein the compound is of Formula II-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 37. The compound of any one of embodiments 1-4, wherein the compound is of Formula II-e:Formula II-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 38. The compound of any one of embodiments 1-3 and 5, wherein the compound is of Formula III-d: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 39. The compound of any one of embodiment 1-3 and 5, wherein the compound is of Formula III-e:Formula III-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof. 40. The compound of any one of embodiments 1-41, wherein R9is hydrogen or C1-6haloalkyl. 41. The compound of any one of embodiments 1-42, wherein R9is hydrogen or –CF3. 42. The compound of any one of embodiments 1-43, wherein R10is hydrogen, C1-6alkyl, or C1-6haloalkyl. IPTS / 200079109.1Attorney Docket No.: AQN-030WO 43. The compound of any one of embodiments 1-44, wherein R10is hydrogen, –Me, or – CF3. 44. The compound of any one of embodiments 1-45, wherein R11is hydrogen or C1-6haloalkyl. 45. The compound of any one of embodiments 1-46, wherein R11is hydrogen or –CF3. 46. The compound of any one of embodiments 1-47, wherein R12is hydrogen. 47. A pharmaceutical composition comprising a compound of any one of embodiments 1- 48, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 48. A method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of embodiments 1-48, or an effective amount of a pharmaceutical composition of embodiment 49. 49. The method of embodiment 50, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), IPTS / 200079109.1Attorney Docket No.: AQN-030WO spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay- Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), and autism. 50. The method of embodiment 50 or 51, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden- Spatz disease, and lipofuscinosis. 51. The method of any one of embodiments 50-52, wherein the neurodegenerative disease is Alzheimer’s disease or frontotemporal dementia. EXAMPLES

[0172] Examples are provided below to facilitate a more complete understanding of the present disclosure. The following examples illustrate exemplary modes of making and practicing the compounds disclosed herein. However, the scope of the present disclosure is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. IPTS / 200079109.1Attorney Docket No.: AQN-030WO General

[0173] All oxygen and / or moisture sensitive reactions were carried out under N2 atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2 prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz1H, 75 MHz13C) or Varian (400 MHz1H, 75 MHz13C) spectrometer. Protonand carbon chemical shifts are reported in ppm ( ) referenced to the NMR solvent. Data arereported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant (s) in Hz). Unless otherwise indicated NMR data were collected at 25oC. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromatography / Mass Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO4) stain followed by heating. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Example 1. Preparation of 3-((4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (Compound I-4)Step 1 Synthesis of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate

[0174] A solution of tert-butyl 4-formylpiperidine-1-carboxylate (24 g, 0.1125 mol) in methanol (200 mL) was treated with 25% aqueous ammonium hydroxide (132. g, 0.945 mol), followed by 40% oxalaldehyde (16.3 g, 0.1125 mol). The contents were allowed to stir at room temperature for 16 h before it rotary evaporated to remove methanol. The remains were treated with brine and extracted with dichloromethane. The solvent was removed under reduced pressure to afford the tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (27 g crude, 85.6% yield) as a yellow solid.

[0175] LCMS (ESI) calculated for C13H21N3O2+ [M + H]+ m / z 252.16, found 252.10. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Step 2 Synthesis of tert-butyl 4-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate

[0176] To a solution of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (27 g, 0.107 mol) in THF (500 mL) was added NBS (38.1 g, 0.214 mol), the mixture was stirred at 50°C for 16 hrs. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / EtOAc = 2:1 as eluent to afford tert-butyl 4-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate (20.6 g, 46.92% yield) as a yellow solid.

[0177] LCMS (ESI) calculated for C13H19Br2N3O2+ [M + 2H -tBu]+ m / z 353.92, found 353.85. Step 3 Synthesis of tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

[0178] tert-butyl 4-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate (3 g, 0.0073 mol) and Na2SO3 (9.2 g, 0.073 mol) were dissolved in 40 mL of degassed EtOH / H2O(1:1), and the solution was refluxed for 16 h under nitrogen. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (1.6 g, 58.9% yield) as a white solid.

[0179] LCMS (ESI) calcd for C13H20BrN3O2+ [M + H]+ m / z 332.07, found 331.95. Step 4 Synthesis of tert-butyl 4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0180] To a solution of tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (500 mg, 1.5095 mmol), (3-methyl-4-(trifluoromethyl)phenyl)boronic acid (369 mg, 1.8114 mmol), Na2CO3 (480 mg, 4.5285 mmol) in EtOH / DME(20 mL, v / v = 1 / 1) was added Pd(PPh3)4 (174 mg, 0.1510 mmol), the mixture was stirred at 95 °C for 16 h. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford tert- butyl 4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (420 mg, 67.79% yield) as a yellow solid.

[0181] LCMS (ESI) calculated for C21H26F3N3O2+ [M + H]+ m / z 410.20, found 410.15. Step 5 Synthesis of 4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine

[0182] To a solution of tert-butyl 4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (420 mg, 1.0233 mmol) in EtOAc (5 mL) was added HCl-1,4- dioxane (10 mL, 4M), the mixture was stirred at 25 °C for 16 hours. After the reaction, the solvent was removed under reduced pressure to afford 4-(4-(3-methyl-4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine (410 mg, 94.33% yield) as a white solid.

[0183] LCMS (ESI) calculated for C16H18F3N3+ [M + H]+ m / z 310.15, found 310.10. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Step 6 Synthesis of 3-((4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin- 1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0184] To a solution of 3-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (150 mg, 0.5712 mmol) and 4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine (213 mg, 0.6854 mmol) in MeCN (5 mL) was added DIEA (369 mg, 2.856 mmol), the mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 3-((4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (160 mg, 52.12% yield) as a white solid.

[0185] LCMS (ESI) calcd for C26H23F6N5O+ [M + H]+ m / z 536.18, found 536.2.

[0186] 1H NMR (400 MHz, DMSO) 11.96 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 3.79 (s, 2H), 3.01 (d, J = 11.3 Hz, 2H), 2.69 (ddd, J = 14.7, 7.6, 3.5 Hz, 1H), 2.44 (s, 3H), 2.29 (t, J = 10.5 Hz, 2H), 1.93 (d, J = 10.9 Hz, 2H), 1.83 - 1.73 (m, 2H). Example 2. Preparation of 3-((4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (Compound I-5) IPTS / 200079109.1Attorney Docket No.: AQN-030WOStep 1 Synthesis of tert-butyl 4-(5-bromo-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate

[0187] To a solution of tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (6 g, 0.0151 mol) in THF (50 mL) was added NBS (5.4 g, 0.0302 mol), the mixture was stirred at 50 °C for 16 hrs. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / EtOAc = 2:1 as eluent to afford tert-butyl 4-(5-bromo-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.5 g, 34.44% yield) as a yellow solid.

[0188] LCMS (ESI) calculated for C20H23BrF3N3O2+ [M + H]+ m / z 474.09, found 474.00. Step 2 Synthesis of tert-butyl 4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0189] To a solution of tert-butyl 4-(5-bromo-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (500 mg, 1.0497 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (659 mg, 5.2485 mmol) and K2CO3 (435 mg, 3.1491 mmol) in 1,4- dioxane / H2O (11 mL, v / v = 10 / 1) was added Pd(dppf)Cl2DCM (86 mg, 0.1049 mmol), the mixture was stirred at 95 °C for 16 h. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to afford tert-butyl 4-(5-methyl- 4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (230 mg, 53.25% yield) as a yellow oil.

[0190] LCMS (ESI) calculated for C21H26F3N3O2+ [M + H]+ m / z 410.20, found 410.15. Step 3 Synthesis of 4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine

[0191] To a solution of tert-butyl 4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (230 mg, 0.5590 mmol) in EtOAc (2 mL) was added HCl-1,4- dioxane (5 mL, 4M), the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure to afford 4-(5-methyl-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine (230 mg, 96.62% yield) as a white solid.

[0192] LCMS (ESI) calculated for C16H18F3N3+ [M + H]+ m / z 310.15, found 310.1. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Step 4 Synthesis of 3-((4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin- 1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0193] To a solution of 3-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (150 mg, 0.5712 mmol) and 4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine (213 mg, 0.6854 mmol) in MeCN (5 mL) was added DIEA (369 mg, 2.856 mmol), the mixture was stirred at 70 for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 3-((4-(5-methyl-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (122 mg, 39.74% yield) as a white solid.

[0194] LCMS (ESI) calcd for C26H23F6N5O+ [M + H]+ m / z 536.18, found 536.6.

[0195] 1H NMR (400 MHz, DMSO) 11.75 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 3.79 (s, 2H), 3.00 (d, J = 11.5 Hz, 2H), 2.68 – 2.60 (m, 1H), 2.40 (s, 3H), 2.29 (dd, J = 11.9, 9.0 Hz, 2H), 1.92 (d, J = 10.5 Hz, 2H), 1.77 (ddd, J = 15.4, 12.5, 3.6 Hz, 2H). Example 3. Preparation of Additional Compounds

[0196] The following compounds were prepared analogously to the steps described in the previous example: IPTS / 200079109.1Attorney Docket No.: AQN-030WO Table 2IPTS / 200079109.1Attorney Docket No.: AQN-030WO Example 4. Preparation of 5-(((2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (Compound I-10)Step 1 Synthesis of methyl 2-methylisonicotinate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0197] To a solution of 2-methylpyridine-4-carboxylic acid (32 g, 0.2333 mol) in MeOH (300 mL) was added H2SO4 (60 mL), the mixture was stirred at 80 °C for 16 hrs. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford methyl 2-methylisonicotinate (33 g, 93.57% yield) as a yellowish solid.

[0198] LCMS (ESI) calculated for C8H9NO2+ [M + H]+ m / z 152.06, found 152.05. Step 2 Synthesis of methyl 2-methylpiperidine-4-carboxylate

[0199] To a solution of methyl 2-methylpyridine-4-carboxylate (33 g, 0.2183 mol) in EtOAc (500 mL) was added Pd / C (3.5 g, 10 wt% on carbon). The mixture was stirred at 50 °C for 48 h under H2 atmosphere. After completion of the reaction, the mixture was filtered and the solvent was removed under reduced pressure to afford methyl 2-methylpiperidine-4- carboxylate (37 g crude, 75.45% yield) as a colorless oil.

[0200] LCMS (ESI) calculated for C8H15NO2+ [M + H]+ m / z 158.11, found 158.1.Step 3 Synthesis of 1-(tert-butyl) 4-methyl 2-methylpiperidine-1,4-dicarboxylate

[0201] To a solution of methyl 2-methylpiperidine-4-carboxylate (56 g, 0.3562 mol) in DCM (1 L) was added DIEA (92.1 g, 0.7124 mol) and Boc2O (93.3 g, 0.4274 mol) at 0 , the reaction mixture was stirred at 25 for 3 hours. After completion of the reaction, the mixture IPTS / 200079109.1Attorney Docket No.: AQN-030WO was diluted with water and extracted with ethyl acetate for 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to get crude, which was purified by flash chromatography (PE / EtOAc=5 / 1,v / v)) to afford 1-(tert-butyl) 4-methyl 2-methylpiperidine-1,4-dicarboxylate (95.5 g, 93.4% yield) as a colorless oil.

[0202] LCMS (ESI) calcd for C9H16NO4+ [M –tBu + 2H]+ m / z 202.34, found 202.10. Step 4 Synthesis of 1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid

[0203] To a solution of 1-(tert-butyl) 4-methyl 2-methylpiperidine-1,4-dicarboxylate (95.5 g, 0.3697 mol) in MeOH / H2O (1.5 L, v / v = 2 / 1) was added LiOH (54.3 g, 1.294 mol), the mixture was stirred at 25 for 16 hours. After completion of the reaction, the mixture was adjusted pH = 3 - 4 by using 6M HCl aq. The resulting mixture was extracted with EtOAc for 3 times, the combined organic phases were washed with brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford 1-(tert-butoxycarbonyl)-2- methylpiperidine-4-carboxylic acid (95.8 g, 95.46% yield) as a yellow oil.

[0204] LCMS (ESI) calcd for C12H22NO4+ [M –tBu + 2H]+ m / z 188.15, found 188.1. Step 5 Synthesis of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) 2- methylpiperidine-1,4-dicarboxylate

[0205] To a solution of 1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (30 g, 0.1228 mol) and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (36.2 g, 0.1351 mol) in DCM (1 L) was added DIEA (47.6 g, 0.3684 mol), the reaction mixture was stirred at 25 for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and IPTS / 200079109.1Attorney Docket No.: AQN-030WO concentrated to get crude, which was purified by flash chromatography (PE / EtOAc=20 / 1, v / v) to afford 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) 2-methylpiperidine-1,4- dicarboxylate (32.2 g, 60.75% yeild) as a yellowish solid.

[0206] LCMS (ESI) calcd for C17H19F3NO5+ [M -tBu + 2H]+ m / z 374.34, found 374.1. Step 6 Synthesis of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) (2S,4S)-2- methylpiperidine-1,4-dicarboxylate (7A) and 1-(tert-butyl) 4-(2-oxo-2-(4- (trifluoromethyl)phenyl)ethyl) (2R,4R)-2-methylpiperidine-1,4-dicarboxylate

[0207] 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) (2S,4S)-2- methylpiperidine-1,4-dicarboxylate (3.76 g, 7A) and 1-(tert-butyl) 4-(2-oxo-2-(4- (trifluoromethyl)phenyl)ethyl) (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (4.08 g, 7B) were obtained by chiral HPLC separation (raw material: 10.23 g). The conditions were shown as below:

[0208] First chiral separation: Column: Chiral ART Amylose-KSC (10 m). Column size:0.46 cm I.D. × 25 cm L. Mobile phase: n-Hexane / IPA=90% / 10%(V / V). Flow rate: 1.0 ml / min. HPLC equipment: Shimadzu LC 20CNZ with UV detector SPD-M20A.7A, Rt = 17.034 min. 7B, Rt = 12.094 min

[0209] Second chiral separation: Column: Chiral ART Cellulose-KCZ (10 m). Column size:0.46 cm I.D. × 25 cm L. Mobile phase: n-Hexane / IPA=90% / 10%(V / V). Flow rate: 1.0 ml / min. HPLC equipment: Shimadzu LC 20CNZ with UV detector SPD-M20A. Rt = 14.194 min. Step 7 Synthesis of tert-butyl (2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol- 2-yl)piperidine-1-carboxylate

[0210] To a solution of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) (2S,4S)-2- methylpiperidine-1,4-dicarboxylate (3.75 g, 8.7 mmol) in toluene (50 mL) was added NH4OAc IPTS / 200079109.1Attorney Docket No.: AQN-030WO (5.36g, 70 mmol), the mixture was stirred at 110 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography by using 30% EtOAc / PE as an eluent to afford tert-butyl (2S,4S)-2- methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.55 g, 68% yield) as a yellow solid.

[0211] LCMS (ESI) calcd for C21H26F3N3O2+ [M + H] + m / z 410.20, found 410.6. Step 8 Synthesis of (2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine hydrochloride

[0212] To a solution of tert-butyl (2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidine-1-carboxylate (2.55 g, 6.2 mmol) in HCl / dioxane (20 mL, 4M) was stirred at 25 for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to afford (2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine hydrochloride (3.4 g, 97% yield) as a yellow solid.

[0213] LCMS (ESI) calcd for C16H18F3N3 + [M + H]+ m / z 310.15, found 310.1. Step 9 Synthesis of N-hydroxy-3-(trifluoromethyl)benzimidamide

[0214] To a solution of 3-(trifluoromethyl)benzonitrile (15 g, 0.0877 mol) in MeOH (50 mL) was added NH2OH aq. (29 g, 0.877 mol), the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the mixture was diluted with H2O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford N-hydroxy-3- (trifluoromethyl)benzimidamide (18 g, 95.55% yield) as a white solid.

[0215] LCMS (ESI) calculated for C8H7F3N2O+ [M + H+ m / z 205.05, found 205.00. Step 10 Synthesis of 5-(chloromethyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0216] To a solution of N-hydroxy-3-(trifluoromethyl)benzimidamide (10 g, 0.049 mol) and TEA (9.9 g, 0.098 mol) in toluene (100 mL) was added 2-chloroacetyl chloride (6.6 g, 0.0588mol) at 0 , the mixture was stirred at 110 for 16 hours. After completion of the reaction,the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 5-(chloromethyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (10.3 g, 80% yield) as a yellow oil.

[0217] 1H NMR (400 MHz, DMSO) 8.33 (d, J = 7.8 Hz, 1H), 8.25 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 5.25 (s, 2H). Step 11 Synthesis of 5-(((2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0218] To a solution of 5-(chloromethyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (150 mg, 0.569 mmol) and (2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine hydrochloride (211 mg, 0.6828 mmol) in MeCN (5 mL) was added DIEA (368 mg, 2.845 mmol), the mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 5-(((2S,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H- IPTS / 200079109.1Attorney Docket No.: AQN-030WO imidazol-2-yl)piperidin-1-yl)methyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (179 mg, 58.75% yield) as a white solid.

[0219] LCMS (ESI) calcd for C26H23F6N5O+ [M + H]+ m / z 536.18, found 536.85.

[0220] 1H NMR (400 MHz, DMSO) 12.00 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.28 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.86 (t, J = 7.8 Hz, 1H), 7.67 (dd, J = 16.2, 5.0 Hz, 3H), 4.22 (d, J = 2.6 Hz, 2H), 3.09 – 3.02 (m, 1H), 2.75 (ddd, J = 12.4, 8.8, 3.7 Hz, 1H), 2.47 (d, J = 9.0 Hz, 2H), 1.96 (d, J = 12.8 Hz, 2H), 1.76 (tt, J = 12.6, 6.4 Hz, 1H), 1.53 (dd, J = 24.0, 12.5 Hz, 1H), 1.22 (d, J = 6.1 Hz, 3H). Example 5. Preparation of Additional Compounds

[0221] The following compounds were prepared analogously to the steps described in the previous example: Table 3.IPTS / 200079109.1Attorney Docket No.: AQN-030WO Example 6. Preparation of 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(((2R,4R)-2- methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4- oxadiazole (Compound I-14)Step 1 Synthesis of tert-butyl (2R,4R)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol- 2-yl)piperidine-1-carboxylate

[0222] To a solution of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) (2R,4R)-2- methylpiperidine-1,4-dicarboxylate (2 g, 0.0046 mol) in toluene (20 mL) was added ammonium acetate (3.6 g, 0.046 mol), the mixture was stirred at 110 °C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / EtOAc = 1:1 as eluent to afford tert-butyl (2R,4R)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (1.6 g, 84.78% yield) as a yellow solid.

[0223] LCMS (ESI) calculated for C21H26F3N3O2+ [M + H]+ m / z 410.20, found 410.15. Step 2 Synthesis of (2R,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0224] To a solution of tert-butyl (2R,4R)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidine-1-carboxylate (1.6 g, 0.0039 mol) in EtOAc (5 mL) was added HCl- 1,4-dioxane (20 mL, 4M), the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure to afford (2R,4S)-2-methyl-4-(4- (4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine (1.4 g, 97.44% yield) as a white solid.

[0225] LCMS (ESI) calculated for C16H18F3N3+ [M + H]+ m / z 310.15, found 310.10. Step 3 Synthesis of 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(((2R,4R)-2-methyl-4-(4-(4-

[0226] To a solution of 3-(chloromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4- oxadiazole (200 mg, 0.7127 mmol) and (2R,4S)-2-methyl-4-(4-(4-(trifluoromethyl)phenyl)- 1H-imidazol-2-yl)piperidine (221 mg, 0.7127 mmol) in MeCN (5 mL) was added DIEA (461 mg, 3.5635 mmol), the mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(((2R,4R)-2- methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4- oxadiazole (154 mg, 38.96% yield) as a white solid.

[0227] LCMS (ESI) calcd for C26H22F7N5O+ [M + H]+ m / z 554.17, found 554.15. IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0228] 1H NMR (400 MHz, DMSO) 11.97 (s, 1H), 8.54 – 8.49 (m, 1H), 8.40 (d, J = 6.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 – 7.80 (m, 1H), 7.66 (dd, J = 13.0, 5.0 Hz, 3H), 4.00 (dd, J = 35.1, 15.1 Hz, 2H), 3.00 (d, J = 11.3 Hz, 1H), 2.71 (t, J = 12.3 Hz, 1H), 1.92 (s, 2H), 1.75 – 1.66 (m, 1H), 1.51 (dd, J = 23.9, 12.5 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H). Example 7. Preparation of Additional Compounds

[0229] The following compounds were prepared analogously to the steps described in the previous example: Table 4.Example 8. Preparation of 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole (Compound I-19) IPTS / 200079109.1Attorney Docket No.: AQN-030WOStep 1 Synthesis of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) piperidine-1,4- dicarboxylate

[0230] To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, 13.1 mmol) in DCM (20 mL) was added DIEA (5.1 g, 39.3 mmol) and 2-bromo-1-(4- (trifluoromethyl)phenyl)ethan-1-one (3.5 g, 13.1 mmol) at 0 °C, the reaction mixture was allowed to stir at room temperature for about 16 hours. After completion of the reaction, the mixture was diluted with DCM, washed with water and brine, dried over Na2SO4and filtered. The organic layer was concentrated under reduced pressure to afford 1-(tert-butyl) 4-(2-oxo- 2-(4-(trifluoromethyl)phenyl)ethyl) piperidine-1,4-dicarboxylate (3.57 g, 65.65% yield) as a yellow solid, which was used without further purification.

[0231] LCMS (ESI) calculated for C20H24F3NO5+ [M + H -tBu]+ m / z 360.10, found 360.05. Step 2 Synthesis of tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1- carboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0232] A solution of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) piperidine- 1,4-dicarboxylate (3.58 g, 8.6 mmol) and ammonium acetate (6.6 g, 084 mmol) in toluene (50 mL) was stirred at 110 for 16 h. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / ethyl acetate = 1 / 1 as eluent to afford tert-butyl 4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.8 g, 81.4% yield) as a yellow solid.

[0233] LCMS (ESI) calculated for C20H24F3N3O2+ [M + H]+ m / z 396.18, found 396.15. Step 3 Synthesis of 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine

[0234] To a solution of tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (300 mg, 0.7204 mmol) in EtOAc (2 mL) was added HCl-1,4- dioxane (5 mL), the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure to afford 4-(4-(4-(trifluoromethyl)phenyl)- 1H-imidazol-2-yl)piperidine (200 mg, 93.7% yield) as yellowish solid, which was used without further purification.

[0235] LCMS (ESI) calculated for C15H16F3N3+ [M + H]+ m / z 296.13, found 296.10.IPTS / 200079109.1Attorney Docket No.: AQN-030WO Step 4 Synthesis of 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole

[0236] To a solution of 3-(chloromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4- oxadiazole (220 mg, 0.7840 mmol) and 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine (256 mg, 0.8624 mmol) in MeCN (5 mL) was added DIEA (203 mg, 1.568 mmol), the mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole (133 mg, 31.39% yield) as a white solid.

[0237] LCMS (ESI) calcd for C25H20F7N5O+ [M + H]+ m / z 540.16, found 540.20.

[0238] 1H NMR (400 MHz, DMSO) 11.99 (s, 1H), 8.53 – 8.49 (m, 1H), 8.40 (dd, J = 6.6, 1.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.82 (t, J = 9.6 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 3.78 (s, 2H), 3.00 (d, J = 11.3 Hz, 2H), 2.73 – 2.66 (m, 1H), 2.28 (t, J = 10.6 Hz, 2H), 1.94 (d, J = 10.7 Hz, 2H), 1.83 – 1.73 (m, 2H). Example 9. Preparation of Additional Compounds

[0239] The following compounds were prepared analogously to the steps described in the previous example: IPTS / 200079109.1Attorney Docket No.: AQN-030WO Table 5.IPTS / 200079109.1Attorney Docket No.: AQN-030WOIPTS / 200079109.1Attorney Docket No.: AQN-030WO Example 10. Preparation of 5-(4-methyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole

[0240] To a solution of 4-methyl-3-(trifluoromethyl)benzoic acid (500 mg, 2.5 mmol), (Z)-2- chloro-N'-hydroxyacetimidamide (292 mg, 2.7 mmol) and NMI (7.4 mg, 8.6 mmol) in 10 mL MeCN was added TCFH (1031 mg, 3.7 mmol), and the mixture was stirred at 25 °C for 16 h. After the reaction, the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (Z)-2-chloro-N'-((4-methyl-3- (trifluoromethyl)benzoyl)oxy)acetimidamide (720 mg, 95% yield) as a yellow oil.

[0241] LCMS (ESI) calculated for C11H10ClF3N2O2+[M + H]+m / z 295.04, found 295.0. IPTS / 200079109.1Attorney Docket No.: AQN-030WO Step 2 Synthesis of 3-(chloromethyl)-5-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0242] A solution of (Z)-2-chloro-N'-((4-methyl-3- (trifluoromethyl)benzoyl)oxy)acetimidamide (720 mg, 2.44 mmol) in AcOH (10 mL) was stirred at 120 °C for 4 h. After cooling to rt, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 3-(chloromethyl)-5-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,4- oxadiazole (330 mg, 46% yield) as a white solid.

[0243] 1H NMR (400 MHz, DMSO) 8.33 – 8.25 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 4.99 (s, 2H), 2.57 (d, J = 1.2 Hz, 3H). Step 3 Synthesis of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) piperidine-1,4- dicarboxylate

[0244] To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, 0.0131 mol) in DCM (20 ml) was added DIEA (5.1 g, 0.0393 mol) at 0 °C and after 10 minutes, 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (3.5 g, 0.0131 mol) was added and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction, the reaction mixture was diluted with DCM, washed with water followed by saturated brine and the organic layer was concentrated under reduced pressure to afford 1-(tert- butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) piperidine-1,4-dicarboxylate (3.57 g, 65.65% yield) as yellow solid.

[0245] LCMS (ESI) calculated for C20H24F3NO5+[M + H - tBu]+m / z 360.10, found 360.05. Step 4 Synthesis of tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1- carboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0246] A solution of 1-(tert-butyl) 4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) piperidine- 1,4-dicarboxylate (3.58 g, 0.0086 mol) and ammonium acetate (6.6 g, 0.084 mol) in 50 mL toluene was stirred at 110 °C for 16 h. After the reaction, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / EtOAc = 1:1 as eluent to afford tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)- 1H-imidazol-2-yl)piperidine-1-carboxylate (2.8 g, 81.4% yield) as a yellow solid.

[0247] LCMS (ESI) calculated for C20H24F3N3O2+[M + H]+m / z 396.18, found 396.15. Step 5 Synthesis of 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride

[0248] To a solution of tert-butyl 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (300 mg, 0.7204 mmol) in EtOAc (2 mL) was added HCl-1,4- dioxane (5 mL, 4M), the mixture was stirred at 25 °C for 16 hours. After the reaction, the solvent was removed under reduced pressure to afford 4-(4-(4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidine hydrochloride (200 mg, 93.7% yield) as a yellowish solid.

[0249] LCMS (ESI) calculated for C15H16F3N3+[M + H]+m / z 296.13, found 296.10. Step 6 Synthesis of 5-(4-methyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0250] To a solution of 4-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride (100 mg, 0.30 mmol) in MeCN (3 mL) was added 3-(chloromethyl)-5-(4- methyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (83 mg, 0.30 mmol) and DIEA (195 mg, 1.5 mmol). The mixture was stirred at 70 °C for 16 hours. After the reaction finished, the solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (0.05% NH4OH) to afford 5-(4-methyl-3-(trifluoromethyl)phenyl)-3-((4-(4-(4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-1,2,4-oxadiazole (70 mg, 42% yield) as a white solid.

[0251] LCMS (ESI) calcd for C26H23F6N5O+[M + H]+m / z 536.18, found 536.4.

[0252] 1H NMR (400 MHz, DMSO) 11.98 (s, 1H), 8.32 – 8.28 (m, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 3.77 (s, 2H), 3.00 (d, J = 11.2 Hz, 2H), 2.74 – 2.64 (m, 1H), 2.57 (s, 3H), 2.32 – 2.24 (m, 2H), 1.97 – 1.89 (m, 2H), 1.84 – 1.82 (m, 2H). Example 11. Preparation of Additional Compounds

[0253] The following compounds were prepared analogously to the steps described in the previous example: IPTS / 200079109.1Attorney Docket No.: AQN-030WO Table 6.IPTS / 200079109.1Attorney Docket No.: AQN-030WOExample 12. Preparation of 3-((4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol- 2-yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (CompoundStep 1 Synthesis of 2-bromo-1-(3-bromo-4-(trifluoromethyl)phenyl)ethan-1-one

[0254] To a solution of 3-bromo-4-(trifluoromethyl)benzoic acid (5 g, 18.5 mmol) in DCM (50 mL) was added oxalyl chloride (11.74 g, 92.5 mmol) and a drop of DMF at 0 °C. The mixture was stirred at 0 °C for 4 h. The solvent was removed and the residue was dried in vacuo to give 3-bromo-4-(trifluoromethyl)benzoyl chloride as a yellow solid, which was dissolved in MeCN (50 mL) and cooled to 0 °C. TMSCHN2(11 mL, 22.2 mmol, 2M in hexane) was added, followed by TEA (4.12 g, 40.7 mmol). The mixture was stirred at 25 °C for 18 h, then poured IPTS / 200079109.1Attorney Docket No.: AQN-030WO into NaHCO3 (sat, 50 mL) and extracted with EA (30 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude 1-(3-bromo-4- (trifluoromethyl)phenyl)-2-diazoethan-1-one as a yellow solid, which was dissolved in 50 mL DCM and cooled to 0 °C. HBr / HOAc (22.68 g, 33% HBr in acetic acid) was added slowly. After addition, the mixture was stirred for 1 h at 0 °C, then the mixture was concentrated under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 20 / 1 as eluent to afford 2-bromo-1-(3-bromo-4- (trifluoromethyl)phenyl)ethan-1-one (3.6 g, 54% yield) as a yellow oil.

[0255] 1H NMR (400 MHz, DMSO) 8.41 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H). Step 2 Synthesis of 4-(2-(3-bromo-4-(trifluoromethyl)phenyl)-2-oxoethyl) 1-(tert-butyl) piperidine-1,4-dicarboxylate

[0256] To a solution of 2-bromo-1-(3-bromo-4-(trifluoromethyl)phenyl)ethan-1-one (3.6 g, 10.4 mmol) in DCM (50 mL) was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.63 g, 11.4 mmol) and DIEA (4.03 g, 31.2 mmol). The mixture was stirred at 25 °C for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by by column chromatography using petroleum ether / ethyl acetate = 20 / 1 as eluent to afford 4-(2-(3-bromo-4-(trifluoromethyl)phenyl)-2-oxoethyl) 1-(tert-butyl) piperidine-1,4- dicarboxylate (2.4 g, 44% yield) as a yellow oil.

[0257] LCMS (ESI) calculated for C20H23BrF3NO5+[M + H Boc]+m / z 394.02, found 393.9. Step 3 Synthesis of tert-butyl 4-(4-(3-bromo-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0258] To a solution of 4-(2-(3-bromo-4-(trifluoromethyl)phenyl)-2-oxoethyl) 1-(tert-butyl) piperidine-1,4-dicarboxylate (2.4 g, 48 mmol) in toluene (30 mL) was added NH4OAc (3.7 g, 4.8 mmol) and stirred at 110 °C for 16 hours. After reaction, the reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography by using 30% EtOAc / PE as an eluent to afford tert-butyl 4-(4-(3- bromo-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.55 g, 94% yield) as yellow solid.

[0259] LCMS (ESI) calculated for C20H23BrF3N3O2+[M + H]+m / z 474.09, found 474.0. Step 4 Synthesis of tert-butyl 4-(4-(4-(trifluoromethyl)-3-vinylphenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate

[0260] To a solution of tert-butyl 4-(4-(3-bromo-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (500 mg, 1.05 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (194 mg, 1.26 mmol) and K2CO3(436 mg, 3.16 mmol) in 1,4-dioxane / H2O (11 mL, v / v = 10 / 1) was added Pd(dppf)Cl2DCM (86 mg, 0.105 mmol), the mixture was stirred at 100 °C under N2for 16 hours. After the reaction finished, the solvent was removed under IPTS / 200079109.1Attorney Docket No.: AQN-030WO reduced pressure, the residue was purified by column chromatography using petroleum ether / ethyl acetate = 2 / 3 as eluent to afford tert-butyl 4-(4-(4-(trifluoromethyl)-3-vinylphenyl)- 1H-imidazol-2-yl)piperidine-1-carboxylate (338 mg, 72% yield) as a yellow solid.

[0261] LCMS (ESI) calculated for C22H26F3N3O2+[M + H]+m / z 422.20, found 422.1. Step 5 Synthesis of tert-butyl 4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate

[0262] To the solution of tert-butyl 4-(4-(4-(trifluoromethyl)-3-vinylphenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (338 mg, 0.80 mmol) in MeOH (10 mL) was added Pd / C (34 mg). The mixture was stirred at 25 °C under H2for 16 h. After reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(4-(3-ethyl-4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (368 mg, 98% yield) as a yellow oil.

[0263] LCMS (ESI) calculated for C22H28F3N3O2+[M + H]+m / z 424.21, found 424.2. Step 6 Synthesis of 4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride

[0264] A solution of tert-butyl 4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine-1-carboxylate (368 mg, 0.87 mmol) in HCl (5 mL, 2M in EtOAc) was stirred at IPTS / 200079109.1Attorney Docket No.: AQN-030WO 25 °C for 16 h. After the reaction, the mixture was concentrated under reduced pressure afford 4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride (310 mg, 94% yield) as a white solid.

[0265] LCMS (ESI) calculated for C17H20F3N3+[M + H]+m / z 324.16, found 324.1. Step 7 Synthesis of 3-((4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0266] To a solution of 4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride (100 mg, 0.28 mmol) in MeCN (3 mL) was added 3-(chloromethyl)-5-(3- (trifluoromethyl)phenyl)-1,2,4-oxadiazole (88 mg, 0.33 mmol) and DIEA (180 mg, 1.4 mmol). The mixture was stirred at 70 °C for 16 hours. After the reaction finished, the solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (0.05% NH4OH) to afford the 3-((4-(4-(3-ethyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (74 mg, 47% yield) as a yellowish solid.

[0267] LCMS (ESI) calculated for C27H25F6N5O+[M + H]+m / z 550.20, found 550.1.

[0268] 1H NMR (400 MHz, DMSO) 11.96 (s, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.37 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.79 (s, 2H), 3.01 (d, J = 11.6 Hz, 2H), 2.80 – 2.65 (m, 3H), 2.32 – 2.24 (m, 2H), 1.93 (d, J = 10.8 Hz, 2H), 1.87 – 1.72 (m, 2H), 1.23 (t, J = 7.8 Hz, 3H). IPTS / 200079109.1Attorney Docket No.: AQN-030WO Example 13. Preparation of Additional Compounds

[0269] The following compounds were prepared analogously to the steps described in the previous example: Table 7.Example 14. Preparation of 3-((2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)- 1H-imidazol-2-yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (Compound I-27)Step 1 Synthesis of 1-(tert-butyl) 4-(2-(3-methyl-4-(trifluoromethyl)phenyl)-2-oxoethyl) 2- methylpiperidine-1,4-dicarboxylate IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0270] To a solution of 1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (2 g, 0.0082 mol) in 10 mL DCM was added 2-bromo-1-(3-methyl-4-(trifluoromethyl)phenyl)ethan- 1-one(2.31 g, 0.0082 mol) and DIEA (3.18 g, 0.0246 mol) . The mixture was stirred at 25 °C for 6 hours. After the reaction finished, the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / EtOAc = 3 / 1 as eluent to afford 1-(tert-butyl) 4-(2-(3-methyl-4-(trifluoromethyl)phenyl)-2-oxoethyl) 2- methylpiperidine-1,4-dicarboxylate (3 g, 78.05% yield) as a colorless oil.

[0271] LCMS (ESI) calculated for C22H29F3NO5+[M + H]+m / z 444.0, found 444.0. Step 2 Synthesis of tert-butyl 2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidine-1-carboxylate

[0272] To a solution of 1-(tert-butyl) 4-(2-(3-methyl-4-(trifluoromethyl)phenyl)-2-oxoethyl) 2-methylpiperidine-1,4-dicarboxylate (3 g, 0.0067 mol) in 40 mL toluene, NH4OAc (5.16 g, 0.067 mol) was added. The mixture was stirred at 110 °C for 16 hours. After the reaction finished, the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / EtOAc = 1 / 1 as eluent to afford tert-butyl 2-methyl-4- (4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.5 g, 83.58% yield) as a colorless oil.

[0273] LCMS (ESI) calculated for C22H29F3N3O2+[M + H]+m / z 424.2, found 424.2. Step 3 Synthesis of 2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine hydrochloride IPTS / 200079109.1Attorney Docket No.: AQN-030WO5

[0274] A solution of tert-butyl 2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidine-1-carboxylate (2.5 g, 0.0059 mol) in 10 mL HCl in EtOAc was stirred at 25 °C for 2 hours. After the reaction, the solvent was removed under reduced pressure to afford 2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride (1.8 g, 84.75% yield) as a white solid.

[0275] LCMS (ESI) calculated for C17H21F3N3+[M + H]+m / z 324.1, found 324.1. Step 4 Synthesis of 3-((2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole

[0276] To a solution of 2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidine hydrochloride (100 mg, 0.3093 mmol) and 3-(chloromethyl)-5-(3- (trifluoromethyl)phenyl)-1,2,4-oxadiazole (81 mg, 0.3093 mmol) in MeCN (5 mL) was added DIEA (119 mg, 0.9279 mmol). The mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the mixture was concentrated and the residue was purified by column chromatography using petroleum ether / EtOAc = 1 / 1 as eluent to afford 3-((2-methyl-4-(4-(3- IPTS / 200079109.1Attorney Docket No.: AQN-030WO (d, (4-Step 13-(((2S,4S)-2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (I-24) & 3- (((2R,4R)-2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1- yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (I-23) 104 IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0279] 3-((2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin- 1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (180 mg) was further separated by chiral-SFC to afford 3-(((2S,4S)-2-methyl-4-(4-(3-methyl-4-(trifluoromethyl)phenyl)-1H- imidazol-2-yl)piperidin-1-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (I-24, stereochemistry depicted has been arbitrarily assigned) (31.1 mg, 96% purity, > 99% ee, 17.27% yield, Rt = 6.688 min) as a white solid and 3-(((2R,4R)-2-methyl-4-(4-(3-methyl-4- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)methyl)-5-(3- (trifluoromethyl)phenyl)-1,2,4-oxadiazole (I-23, stereochemistry depicted has been arbitrarily assigned ) (33.2 mg, 96% purity, > 99% ee, 17.27% yield, Rt = 8.565 min) as a white solid.

[0280] I-24

[0281] LCMS (ESI) calcd. for C27H26F6N5O+[M + H]+m / z 550.2, found 550.2.

[0282] 1H NMR (400 MHz, DMSO) 11.96 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.66 – 7.56 (m, 2H), 4.01 (dd, J = 35.2, 15.1 Hz, 2H), 3.01 (d, J = 11.2 Hz, 1H), 2.70 (dd, J = 19.9, 7.7 Hz, 1H), 2.44 (s, 5H), 1.92 (d, J = 10.4 Hz, 2H), 1.76 – 1.66 (m, 1H), 1.52 (dd, J = 23.9, 12.0 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H).

[0283] SFC conditions:

[0284] Method: IC-15%B-2.5

[0285] Column: DAICEL IC 4.6mmI.D.*250mmL 5 m

[0286] Mobile Phase:CO2 / IPA[0.1%NH3(7M Solution in MeOH)]=85 / 15

[0287] Oven: 40 °C

[0288] Flow rate:2.5ml / min IPTS / 200079109.1Attorney Docket No.: AQN-030WO

[0289] Instrument: SHIMADZU LC-30AD SFC

[0290] I-23

[0291] LCMS (ESI) calcd. for C27H26F6N5O+[M + H]+m / z 550.2, found 550.2.

[0292] 1H NMR (400 MHz, DMSO) 11.96 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 13.7 Hz, 2H), 4.01 (dd, J = 35.2, 15.1 Hz, 2H), 3.01 (d, J = 11.2 Hz, 1H), 2.70 (dd, J = 20.3, 7.9 Hz, 1H), 2.44 (s, 5H), 1.92 (d, J = 9.7 Hz, 2H), 1.71 (dd, J = 21.2, 12.3 Hz, 1H), 1.52 (dd, J = 23.8, 12.5 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H).

[0293] SFC conditions:

[0294] Method: IC-15%B-2.5

[0295] Column: DAICEL IC 4.6mmI.D.*250mmL 5 m

[0296] Mobile Phase:CO2 / IPA[0.1%NH3(7M Solution in MeOH)]=85 / 15

[0297] Oven: 40 °C

[0298] Flow rate:2.5ml / min

[0299] Instrument: SHIMADZU LC-30AD SFC Example 16. SH-SY5Y-tT1 Cell Assay

[0300] Exemplary compounds disclosed herein were evaluated for efficacy in inhibiting stress granules compounded of tau and TIA1 in cellular imaging-based assays.

[0301] Human neuroblastoma SH-SY5Y cells (ATCC, cat# CRL-2266) were engineered to stably express a tetracycline repressor protein (Blasticidin resistance, designated as TREx- SY5Y cells, customer cell line development by ThermoFisher). Trex-SY5Y cells were sequentially stably transfected with pcDNA5 / TO[tauP301S::eGFP] (Hygromycin B resistance) then pT-REx-DEST30[TIA1::mKate2] (Neomycin resistance). The resulting line was designated “SH-SY5Y-tT1”, in which exposure to tet induces expression of human tau with a P301S mutation fused to eGFP and human TIA1 fused to mKate2.

[0302] Following induction, exposure to stress (by treatment with arsenite or thapsigargin) triggered the formation of cytoplasmic tau / TIA1 stress granules (SGs). Compounds were screened against this line to explore their efficacy in reducing stress granules. High-content imaging was used to detect and quantify TIA1::mKate2-positive stress granules. To determine potency of novel compound, the inhibition of SGs was observed over a dilution curve and the IC50 against specific stressors was calculated from fitted non-linear regression curves.

[0303] The tau stress granule inhibition per cell-arsenite (IC50) for each compound tested was determined and is summarized in the table below. In the table, “A” indicates an IC50 of less IPTS / 200079109.1Attorney Docket No.: AQN-030WO than 1000 nM, “B” indicates an IC50 range from 1000 nM to 3000 nM; “C” indicates an IC50 range from 3000 nM to 5000 nM; and “D” indicates an IC50 greater than 5000 nM. Table 8. Stress Granules Per Cell-Arsenite: Average IC50(nM)

[0304] The tau stress granule inhibition per cell-thapsigargin (IC50) for each compound tested was determined and is summarized in the table below. In the table, “A” indicates an IC50of less than 500 nM, “B” indicates an IC50range from 500 nM to 1000 nM; “C” indicates an IC50range from 1000 nM to 2000 nM; and “D” indicates an IC50 greater than 2000 nM. Table 9. Stress Granules Per Cell- Thapsigargin: Average IC50 (nM)IPTS / 200079109.1Attorney Docket No.: AQN-030WOExample 17. DMPK Characteristics

[0305] Compounds I-1 19 exhibited good potency, efficacy, and DMPK characteristics, asshown in the table below. Table 10.IPTS / 200079109.1Attorney Docket No.: AQN-030WOExample 18. PS19 Mouse Model for Investigation of In Vivo Efficacy PS19 Transgenic Mouse Line

[0306] The PS19 transgenic mouse line (strain name: C57BL / 6;C3-Tg(Prnp-MAPT*P301S) PS19Vle / J) constitutively expresses human 1N4R tau protein carrying the familial FTD- causing mutation P301S (Yoshiyama et al., Neuron, 2007, 53(3), 337–351). In an age- dependent manner, heterozygous (+ / -) PS19 mice develop tau pathologies; by 8 to 9 months, these pathologies include a) neurofibrillary tangles of misfolded and phosphorylated tau in the neocortex, hippocampus, amygdala and brain stem; b) neuron loss in the hippocampus and the entorhinal cortex (EC); c) microgliosis in the white and grey matter of the hippocampus, amygdala and EC; d) decreased synaptophysin immunoreactivity in the hippocampus.

[0307] 4R tau includes the alternatively spliced exon 10 and thus contains 4 repeated microtubule domains. It is the predominant isoform in the pathologies of the neurodegenerative conditions progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and argyrophilic grain disease (AGD). Whereas Alzheimer’s disease (AD) pathology consists of both 4R and 3R tau isoforms (the latter lacking exon 10) (Wang & Mandelkow, Nature Reviews Neuroscience, 2016, 17(1), 5–21). As such, the PS19 mouse model is an excellent platform for characterization of therapeutics targeting 4R tauopathies, and may be an appropriate model for conditions exhibiting 3R tauopathy (such as AD and Pick’s disease) or secondary tau pathology (such as Huntington’s disease (HD) and in Parkinson’s disease and related Lewy body dementias) (Fernández-Nogales et al., Nature Medicine, 2014, 20(8), 881–885; Pan et al., Journal of Molecular Neuroscience : MN, 2021, 71(11), 2179–2191). The PS19 model has been used extensively to understand the etiology of tauopathies and for investigation of the in IPTS / 200079109.1Attorney Docket No.: AQN-030WO vivo efficacy of anti-tauopathy therapeutics (Makani et al., Acta Neuropathologica Communications, 2016, 4(106), 1-12).

[0308] PS19 mice used in in vivo efficacy studies are aged greater than 7 months of age and are treated with compounds daily (QD) by oral gavage (PO) for 28 days. Hence, administration of compounds in >7-month-old mice, once pathologies have developed, aims to ameliorate or prevent the worsening of existing tau pathology. Upon completion of dosing mice are ~9- months old. Tissues were then collected for analysis of pharmacokinetics and pharmacodynamic effects. Frontocortical (F.Ctx) tissue is biochemically partitioned (Apicco etal., Nature Neuroscience, 2018, 21(1), 72–82; Ramsden et al., The Journal of Neuroscience :The Official Journal of the Society for Neuroscience, 2005, 25(46), 10637–10647) and the resulting fractions assayed for total tau (tau12), misfolded tau (MC-1) and phosphorylated tau (AT8 and pT181). AlphaLISA Detection of Pathological Tau Species

[0309] Reduction of pathogenic tau species is quantified by AlphaLISA immunodetection assay (PerkinElmer, Revvity). These immunodetection assays employ a biotinylated-HT7 anti- tau mouse monoclonal antibody that interacts with streptavidin-conjugated donor beads, and acceptor beads conjugated to antibodies that detect total tau (Tau12), misfolded (MC-1) or phosphorylated (AT8, pT181) tau. In the presence of analyte, the sandwich antibody pair brings the donor and acceptor beads into close proximity. Under 680nm light, Phthalocynanine within the donor beads converts ambient oxygen into singlet oxygen. Acceptor beads that are within close proximity emit 615nm light from chemiluminescence in the presence of singlet oxygen resulting in production of a sensitive highly specific signal. For examples of use of AlphaLISA for quantitative detection of analytes in multiple biological samples and across many disease conditions see the following publications (Baldo et al., ENeuro, 2018, 5(4), 1-16; Bielefeld- Sevigny, Assay and Drug Development Technologies, 2009, 7(1), 90–92; Cauchon et al., Analytical Biochemistry, 2009, 388(1), 134–139; Dehdashti et al., Current Alzheimer Research, 2013, 10(7), 679–687; Medda et al., Journal of Biomolecular Screening, 2016, 21(8), 804–815; Szekeres et al., Journal of Biomolecular Screening, 2008, 13(2), 101–111).

[0310] Misfolded (MC-1) and phosphorylated (AT8) tau is elevated in the brains of individuals affected with AD and several related dementias (Holtzman et al., Science Translational Medicine, 2011, 3(77), 77sr1-77sr1; Wang & Mandelkow, Nature Reviews Neuroscience, 2016, 17(1), 5–21). The levels of tau pathologies strongly correlate with Braak stage disease progression and multiple declining cognitive measures (Koss et al., Acta Neuropathologica, IPTS / 200079109.1Attorney Docket No.: AQN-030WO 2016, 132(6), 875–895). Preclinical studies showed that immunotherapy with MC-1 reduced tau pathologies in tau transgenic mice (Chai et al., The Journal of Biological Chemistry, 2011, 286(39), 34457–34467). Between April 2016 and April 2018, Lilly conducted two Phase 1 (NCT02754830 and NCT03019536) and a Phase 2 trial of a humanized MC-1 Zagotenemab (LY3303560) as a passive immunotherapeutic intravenous infusion. LY3303560 was dropped (October 2021) when Lilly disclosed that the Phase 2 trial missed its primary endpoint: change from baseline on Lilly’s integrated Alzheimer's Disease Rating Scale (iADRS). A potential explanation for lack of efficacy of Zagotenemab, may be poor penetration of high molecular weight antibodies into neurons of the CNS, providing opportunity for small molecules that can more readily reach to the site of action. Tau phosphorylated at Serine 202 / Threonine 205 (AT8) and at Threonine 181 (pT181) is increased in affected brains and plasma of AD patients (Koss et al., Acta Neuropathologica, 2016, 132(6), 875–895; Murray et al., Global neuropathologic severity of Alzheimer’s disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels, 2022, 17(1), 85). Plasma and CSF pT181 tau correlates with predictive positive tau positron emission tomography (PET) in the diagnosis of AD; and plasma pT181 tau levels are diagnostic of AD (versus non-AD neurodegenerative conditions) and predictive progression from mild-cognitive impairment (MC-I) to AD (Janelidze et al., Nature Medicine, 2020, 26(3), 379–386). Due to these findings, biofluid pT181 levels have been used as pharmacodynamic markers in several clinical trials, including in those of the FDA-approved anti-amyloid immunotherapeutic Lecanamab (Biogen) (van Dyck et al., The New England Journal of Medicine, 2023, 388(1), 9-21).

[0311] Hence, quantitative detection of misfolded (MC-1) and phosphorylated (AT8, pT181) tau by AlphaLISA are selected as these are recognized pharmacodynamic markers that correlate with improvement in response to treatment (in either transgenic mice or AD patients), and significant reduction in one or more of these biomarkers in the PS19 mouse study, provides good evidence for assessment and efficacy in patients. Treatment with Compound

[0312] For PS19 mice treated for 1 month with compound, pathological tau levels were observed. Compound I-19 rescued tau pathology in the PS19 P301S MAPT mouse model of Alzheimer’s disease. PS19 mice were aged (9 mo) and then given compound (or vehicle) orally every day for 28 days (FIG. 1). There was no effect of drug on survival or change in weight by the end of the study (day 28: p>0.5, n.s.). Brains were lysed and fractionated to obtain the pellet from the ultra-centrifuged 100K soluble fraction. This pellet was resuspended in buffer IPTS / 200079109.1Attorney Docket No.: AQN-030WO and used for biochemical analysis of tau-pathology via AlphaLISA (FIG.2). Compound I-19 significantly reduced misfolded tau (MC-1), phosphorylated tau (AT8) and oligomeric tau (TOC1) relative to vehicle control (FIG.3, FIG.4, FIG.5, and FIG.6). EQUIVALENTS

[0313] It will be recognized that one or more features of any embodiments disclosed herein may be combined and / or rearranged within the scope of the present disclosure to produce further embodiments that are also within the scope of the present disclosure.

[0314] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the present disclosure. Such equivalents are intended to be within the scope of the present disclosure.

[0315] Although the present disclosure has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the present disclosure can be made without departing from the spirit and scope of the present disclosure, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and / or rearranged in various ways within the scope and spirit of the present disclosure to produce further embodiments that are also within the scope of the present disclosure. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

[0316] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. * * * * * IPTS / 200079109.1

Claims

Attorney Docket No.: AQN-030WO CLAIMS What is claimed:

1. A compound of Formula I:Formula I, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: Ringwhereinbondeach of R1, R2, R3, R4, and R5is independently selected from hydrogen, halogen, C1-6haloalkyl, and C2-6alkynyl; R6is hydrogen or C1-6alkyl; R7is selected from hydrogen, C1-6alkyl, –CH2OH, and –C(O)NH2; R8is hydrogen or C1-6alkyl; each of R9, R10, R11, R12, and R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and R14is hydrogen or C1-6alkyl. IPTS / 200079109.1Attorney Docket No.: AQN-030WO The compound of claim 1, wherein Ring A is, whereinis a bond3. The compound of claim 1, wherein Ring A is, wherein is a bond to.

4. The compound of claim 1, wherein the compound is of Formula II:Formula II, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is of Formula III: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein R1is hydrogen.

7. The compound of any one of claims 1-6, wherein R2is hydrogen.

8. The compound of any one of claims 1-7, wherein R3is hydrogen, halogen, or C2-6alkynyl9. The compound of any one of claims 1-8, wherein R3 is hydrogen, –F, or –C CH.

10. The compound of any one of claims 1-9, wherein R4is C1-6haloalkyl.

11. The compound of any one of claims 1-10, wherein R4is –CF3.

12. The compound of any one of claims 1-11, wherein R5is hydrogen.

13. The compound of any one of claims 1-3, wherein the compound is of Formula I-a: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula I-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-4, wherein the compound is of Formula II-a:Formula II-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula III-a: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-a, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-15, wherein R6is C1-6alkyl.

17. The compound of any one of claims 1-16, wherein R6is –Me.

18. The compound of any one of claims 1-15, wherein R6is hydrogen.

19. The compound of any one of claims 1-18, wherein R7is C1-6alkyl.

20. The compound of any one of claims 1-19, wherein R7is –Me.

21. The compound of any one of claims 1-18, wherein R7is –CH2OH.

22. The compound of any one of claims 1-18, wherein R7is –C(O)NH2.

23. The compound of any one of claims 1-3, wherein the compound is of Formula I-b:IPTS / 200079109.1Attorney Docket No.: AQN-030WO Formula I-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-3, wherein the compound is of Formula I-c:Formula I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1-4, wherein the compound is of Formula II-b:Formula II-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-4, wherein the compound is of Formula II-c: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula III-b:Formula III-b, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula III-c: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1-18, wherein R7is hydrogen.

30. The compound of any one of claims 1-29, wherein R8is C1-6alkyl.

31. The compound of any one of claims 1-30, wherein R8is –Et or –nBu.

32. The compound of any one of claims 1-29, wherein R8is hydrogen.

33. The compound of any one of claims 1-32, wherein R14is C1-6alkyl.

34. The compound of any one of claims 1-33, wherein R14is –Me.

35. The compound of any one of claims 1-32, wherein R14is hydrogen.

36. The compound of any one of claims 1-3, wherein the compound is of Formula I-d:IPTS / 200079109.1Attorney Docket No.: AQN-030WO Formula I-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1-3, wherein the compound is of Formula I-e:Formula I-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 1-4, wherein the compound is of Formula II-d:Formula II-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 1-4, wherein the compound is of Formula II-e: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula II-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula III-d:Formula III-d, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula III-e: IPTS / 200079109.1Attorney Docket No.: AQN-030WOFormula III-e, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 1-41, wherein R9is hydrogen or C1-6haloalkyl.

43. The compound of any one of claims 1-42, wherein R9is hydrogen or –CF3.

44. The compound of any one of claims 1-43, wherein R10is hydrogen, C1-6alkyl, or C1-6haloalkyl.

45. The compound of any one of claims 1-44, wherein R10is hydrogen, –Me, or –CF3.

46. The compound of any one of claims 1-45, wherein R11is hydrogen or C1-6haloalkyl.

47. The compound of any one of claims 1-46, wherein R11is hydrogen or –CF3.

48. The compound of any one of claims 1-47, wherein R12is hydrogen.

49. A pharmaceutical composition comprising a compound of any one of claims 1-48, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

50. A method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-48, or an effective amount of a pharmaceutical composition of claim 49. IPTS / 200079109.1Attorney Docket No.: AQN-030WO 51. The method of claim 50, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay- Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), and autism.

52. The method of claim 50 or 51, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, parkinsonism IPTS / 200079109.1Attorney Docket No.: AQN-030WO linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden- Spatz disease, and lipofuscinosis.

53. The method of any one of claims 50-52, wherein the neurodegenerative disease is Alzheimer’s disease or frontotemporal dementia. IPTS / 200079109.1

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