(2-OXO-2h-chromen-3-YL) scaffold based carboxamide analogs as potent inhibitors of TAU protein fibrils

Abstract

Disclosed herein are compounds of the formula as well as pharmaceutical compositions thereof, wherein the variables are defined herein. In some aspects, the compounds and compositions provided herein may be used to treat neurodegenerative disorders, such as Alzheimer's disease. Also provided are methods of administering compounds and compositions provided herein to a patient in need thereof.

Description

DESCRIPTION (2-OXO-2H-CHROMEN-3-YL) SCAFFOLD BASED CARBOXAMIDE ANALOGS AS POTENT INHIBITORS OF TAU PROTEIN FIBRILS

[0001] This application claims the benefit of priority to United States Provisional Application No. 63 / 681,541, filed August 9, 2024, the entire contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION I. Field of the Invention

[0002] The present invention relates generally to the field of chemistry, particularly organic chemistry and medicinal chemistry. More particularly, it concerns compounds, compositions, and methods for the treatment and prevention of neurodegenerative diseases and disorders, such as Alzheimer’s disease. II. Description of Related Art

[0003] Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative brain disorder. AD is considered as the third leading cause of death, following cardiovascular disease and cancer (Huang et al., 2016). Owing to AD’s complex pathophysiological characteristics, and complicated interactions with related genes and proteins, no effective drugs which can obtain a long-term treatment effect for AD or even cure AD are available (Liu et al., 2017).

[0004] AD is defined by the accumulation of protein aggregates, specifically plaques of aggregated Aß and intraneuronal fibrils of aggregated tau (neurofibrillary tangles, or NFTs). In recent years, the Food and Drug Administration (FDA) has approved three disease- modifying anti-amyloid antibodies that target pathological Aß aggregates, demonstrating the therapeutic benefits of clearing protein aggregates from the brain. Currently, there are only five marketed drugs, including the inhibitors of acetylcholinesterase (AChEIs) such as Tacrine, Donepezil, Galantamine, Rivastigmine, and N-methyl- D-aspartate (NMDA) receptor antagonist Memantine as approved by the FDA to treat AD (Reitz et al., 2011; Guzior et al., 2015). However, relying solely on Aß monotherapy is insufficient for treating AD, as tau NFTs continue to spread despite Aß therapy. In addition, no AD therapeutic that targets tau fibrils is currently available (Lane-Donovan and Boxer, 2024). Furthermore, existing tau fibrildisaggregators are not blood brain barrier penetrable (e.g., EGCG which is highly polar), and thus exhibit poor brain penetration (Seidler et al., 2022). Given that tau aggregation progresses independently of Aß, there is a pressing need for tau-targeted therapies in order to more effectively limit AD.SUMMARY

[0005] The present disclosure provides novel compounds, including (2-oxo-2H- chromen-3-yl) scaffold based carboxamide analogs, pharmaceutical compositions thereof, and methods for their use. In some embodiments, the compounds are further defined as:wherein: R1, R2, R3, R4and R12are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X1 and X2 are each independently −NH−, −NCH3− or −C(O)−, provided X1 and X2are not both-C(O)-;Y is O or NH; Z is a group of the formula:, wherein: R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12),cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula: , wherein: X3 is absent, −N− or −S−; and X4and X5are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11 and R11' are each independently:absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound is further defined as:wherein: R1, R2, R3and R4are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X1 and X2 are each independently −NH−, −NCH3− or −C(O)−, provided X1 and X2 are not both -C(O)-; Y is O or NH;Z is a group of the formula:, wherein: R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently:hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3 is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the compound is further defined as:wherein:R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X1and X2are each independently −NH−, −NCH3− or −C(O)−, provided X1and X2are not both-C(O)-;Z is a group of the formula:, wherein: R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2is not −NH− when R5is alkyl(C≤8); andR6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the compound is further defined as:wherein: R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; Z is a group of the formula:, wherein: R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9is hydrogen, hydroxy, halo, amino, or mercapto; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; and provided X2is not −NH− when R5is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3 is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; oralkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound is further defined as:wherein: R1, R2, R3and R4are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; Z is a group of the formula:, wherein: R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12),cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3 is absent, −N− or −S−; and X4and X5are each independently absent, −N−, −NH−, −O− or −S−; or−CR11R11'−, wherein R11 and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound is further defined as:wherein: R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or−C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; provided X2is not −NH− when R5is alkyl(C≤8); and R6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound is further defined as:wherein:R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X3is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, R1is hydrogen, hydroxy or alkoxy(C≤12). In certain embodiments, R1is hydrogen. In some embodiments, R2is hydrogen, hydroxy, nitro or amino. In certain embodiments, R2is hydrogen. In other embodiments, R2is nitro. In yet other embodiments, R2is hydroxy. In some embodiments, R3is hydrogen, halo, hydroxy or amino. In certain embodiments, R3 is halo such as chloro. In other embodiments, R3 is hydrogen. In yet other embodiments, R3 is hydroxy. In still other embodiments, R3 is amino. In some embodiments, R4 is hydrogen, hydroxy or alkoxy(C≤12). In certain embodiments, R4 is hydrogen. In other embodiments, R4 is alkoxy(C≤12), such as methoxy. In some embodiments, R12 is hydrogen or hydroxy.

[0013] In some embodiments, X1 is −NH− and X2 is −C(O)−. In other embodiments, X1 is −C(O)− and X2 is −NH−. In still other embodiments, X1 is −C(O)− and X2 is −NCH3−. In some embodiments, Y is O. In some embodiments, Z is a group of the formula:.

[0014] In other embodiments, wherein Z is a group of the formula:.

[0015] In some embodiments, R5is cyano, nitro, alkyl(C≤12), substituted alkyl(C≤12), alkoxy(C≤12), substituted alkoxy(C≤12)or heteroaryl(C≤12). In certain embodiments, R5is cyano. In other embodiments, R5is alkyl(C≤12)or substituted alkyl(C≤12). In certain embodiments, R5 is substituted alkyl(C≤12), such as −CF3. In some embodiments, R5 is heteroaryl(C≤12), such as 1H-tetrazol-5-yl. In other embodiments, R5 is −C(O)R9, wherein R9 is hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8). In certain embodiments, R5 is hydroxy. In some embodiments, R5 is amino. In certain embodiments, R5 is hydrazinyl. In some embodiments, R6 is hydrogen or halo. In certain embodiments, R6 is hydrogen. In other embodiments, R6 is fluoro. In some embodiments, R7 is hydrogen. In some embodiments, R8 is hydrogen.

[0016] In some embodiments, X3 is −N−. In other embodiments, X3 is −S−. In still other embodiments, X3 is absent. In some embodiments, X4 is −N−. In some embodiments, X4 is −CR11R11'−, wherein R11 and R11' are each independently absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups.

[0017] In some embodiments, R11is absent. In some embodiments, R11' is hydrogen. In other embodiments, R11' is −CN. In some embodiments, X4is absent. In some embodiments, X5 is −N−. In other embodiments, X5 is −CR11R11'−, wherein R11 and R11' are each independently absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups.

[0018] In some embodiments, R11 is absent. In some embodiments, R11' is hydrogen. In other embodiments, R11' is −CN. In some embodiments, the compound is further defined as:, ,or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the present disclosure provides a compound of the formula:or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present disclosure provides a pharmaceutical composition comprising: (A) a compound described herein or shown above; and (B) an excipient.

[0021] In some embodiments, the pharmaceutical composition is formulated for administration orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for administration via injection. In some embodiments, the pharmaceutical composition is formulated for intraarterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration. In some embodiments, wherein the pharmaceutical composition is formulated as a unit dose.

[0022] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition according any of the embodiments described herein. In some embodiments, the patient is a mammal, such as a human. In some embodiments, the disease or disorder is a disease or disorder associated with tau aggregation. In some embodiments, the disease or disorder is a tauopathy. In some embodiments, the disease or disorder is a neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, corticobasal degeneration, or Huntington’s disease. In certain embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the patient has been diagnosed with Alzheimer's disease by behavioral testing or by a brain scan. In some embodiments, the patient is over 40 years of age. In some embodiments, the method further comprises administering the compound of composition to the patient more than once. In some embodiments, the patient is treated with at least a second anti-Alzheimer’s disease therapy that reduces risk of developing Alzheimer’s disease and / or reduces symptoms of Alzheimer’s disease.Brief Description of The Figures

[0024] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description.

[0025] FIG. 1 shows the biological cell-based activity measure of tau aggregation catalysis by prionogenic seeding using crude AD brain homogenate. Tau biosensor cells expressing K18 tau fused with GFP (Green Fluorescent Protein) were seeded with AD brain homogenates (Fibrils Only). Each subsequent condition contains the addition of carboxamide tau ligands from the CNS-16 series pre-incubated with crude AD brain homogenate to assay inhibited prionogenic seeding. EGCG (Epigallocatechin gallate) was included as a control due to its strong in vitro inhibitory effect on tau aggregation, despite its inability to pass the Blood-Brain Barrier (BBB), unlike carboxamide tau ligands from the CNS- 16 series, which exhibit BBB permeability.

[0026] FIG.2 shows representative images of tau biosensor cells seeded using crude AD brain homogenate. White puncta reflect template-induced assembly of tau seeded by fibrils from AD brain. At left is provided a representative image showing inhibited seeding (puncta formation) by M4 (N-(6-cyanopyridin-2-yl)-2-oxo-2H-chromene-3-carboxamide).

[0027] FIG. 3 depicts the reduction in purified AD fibril quantity through quantitative Electron Microscopy (qEM). Fibrils incubated with M4 are compared to fibrils alone. FIG.3 at left depicts a representative electron micrograph of the purified fibrils without treatment with a compound disclosed herein. FIG. 3 in the center depicts a representative electron micrograph of purified fibrils that were treated with M4, as indicated. Fibrils that do remain upon treatment with M4 appear to be fragmented compared to the ones with no treatment. At right is shown the quantity of fibrils observed through quantitative electron microscopy imaging (qEM) using samples of AD brain-purified tau fibrils treated with M4 versus untreated fibrils. A marked reduction in the average number of observed fibrils / image is seen with M4 incubation. The distorting effects by M4 on tau fibrils in addition to reduced fibril counts shown in Figure 3 indicate, without being bound by theory, that inhibited templated-based prionogenic seeding by M4 occurs by mechanisms that the disrupt fibril structure.

[0028] FIG.4 shows biological cell-based activity measure of tau aggregation catalysis by prionogenic seeding similar to FIG. 1, except using crude CorticobasalDegeneration (CBD) brain homogenate as a template. K18 Biosensor cells show seeding when exposed to Corticobasal Degeneration (CBD) brain homogenate as well. Similarly to AD, M4 shows potential in inhibiting the presence of these fibrils in the cells as well. Similar results to those shown in FIG. 1 for AD brain homogenate are seen with M4, effectively inhibiting seeding. FIG.4 shows representative images from tau biosensor cells comparing seeding levels seen in non-treated cells seeding with CBD brain homogenate (left) versus seeding induced by M4-treated CBD brain homogenate (right). Thus, M4 shows potential as an inhibitor of AD and tauopathy brain homogenates.

[0029] FIG. 5 quantifies the reduction in seeding in tau biosensor cells by carboxamide tau ligands from the CNS-16 series using traumatic brain injury related tau from Chronic Traumatic Encephalopathy (CTE) as a seed. K18 Biosensor cells show seeding when exposed to Chronic Traumatic Encephalopathy (CTE) brain homogenate as well. Similarly to AD, M4 and M12 show potential in inhibiting the presence of these fibrils in the cells as well.

[0030] FIGS. 6A-6B shows changes in seeding in representative cells without inhibitor treatment (Control) versus using CTE brain homogenate treated with M4. FIG. 6 compares the K18 cells transfected with CTE crude brain homogenate alone (FIG. 6A) with CTE crude brain incubated with M4 overnight (FIG.6B).

[0031] FIG.7 provides evidence that compounds disclosed herein possess brain permeability. Pilot studies show the compound M4 reaches the brain at submicromolar levels near the biochemically measured IC50. C57BL mice injected with 5 mg / kg M4 by intraperitoneal (IP) and subcutaneous (SC) injection. M4 concentrations from brain at various time points post-injection are shown.

[0032] FIGS. 8A-8C demonstrate that compounds disclosed herein show seeding inhibition of tauopathies derived from crude brain tissue of PS19 tauopathy mouse model. Seeding represented as puncta is quantified in FIG.8A. FIG.8B and FIG.8C visualize the reduction in seeding between the control (FIG. 8B) and Crude brain tissue incubated with M4 overnight (FIG.8C).

[0033] FIGS. 9A-9D show that disrupting ligand stacking interferes with anti- tau propagation activity. Results of tau biosensor aggregation assays using (FIG. 9A) Crude Brain Homogenate or (FIG. 9B) Recombinant tau oligomers as seeds. (FIG. 9C) Chemical structures of the ligands used in FIG. 9A and FIG. 9B. (FIG. 9D) Representative images of seeded cells from FIG.9B. Red arrows highlight representative tau aggregates (puncta); white arrows indicate cells without detectable tau aggregation.

[0034] FIGS. 10A-10E demonstrate that repeated injections of presently disclosed compounds at 15 mg / kg are tolerated in the mice, as observed from their weight (FIGS. 10A-C), food (FIG. 10D), and water intake (FIG. 10E). N / A indicates mice receiving no injection.Description of Illustrative Embodiments

[0035] Disclosed herein are compounds and compositions that may be used to target pathological Aß aggregates and may thus be useful in the treatment of neurodegenerative disorders, such as Alzheimer’s disease (AD). The compounds and compositions disclosed herein may also be useful in the treatment of tauopathies. In some embodiments, the compounds and compositions may be useful in the treatment of Parkinson’s disease, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, corticobasal degeneration, and / or Huntington’s disease. In certain aspects, the compounds or compositions provided herein may prevent, delay or slow down the progression of AD, Parkinson’s disease, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, corticobasal degeneration, and / or Huntington’s disease, or other tauopathies.

[0036] In some aspects, the present disclosure provides small molecule tau disaggregants which inhibit tau seeding and are able to pass cell membranes and the blood- brain barrier. In certain aspects, the compounds or compositions provided herein may be carboxamide ligands that inhibit tau aggregation catalyzed by AD brain homogenates. In certain aspects, the compounds or compositions provided herein are (2-oxo-2H-chromen-3-yl) scaffold based carboxamide analogs, which may be used for the treatment of tau aggregation. A structure-activity relationship points to the determinants of carboxamides that drive potency. Amino- and hydroxy- substituted carboxamides offer potential to expand the series by PROTAC design, which fuses tau inhibitor carboxamides with E3 ubiquitin ligases to enhance the biological degradation of tau fibrils by proteasomes. In some aspects, the carboxamide series provided herein offers multiple avenues with the potential to revolutionize the management of tau aggregation by inhibiting catalytic tau aggregation and enhancing tau disaggregation and degradation.

[0037] In some aspects, the present disclosure provides compounds or compositions that are non-polar in nature, with lower polar surface area in order to improve brain penetration and an adequate exposure. In some aspects, the compounds or compositions provided herein exhibit excellent permeability and efflux ratio in MDCK-MDR1 cells. In some embodiments, the present compounds inhibit seeding of Alzheimer’s disease. In some embodiments, the compounds or compositions provided herein may target tau fibrils. In some embodiments, the compounds or compositions provided herein may effectively penetrate the blood brain barrier.

[0038] These and other aspects of the disclosure are described in detail below.I. Compounds of the Present Invention

[0039] The compounds of the present invention (also referred to as “compounds of the present disclosure”) are shown, for example in the summary of the invention section, in the examples section, and in the claims. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry. Such principles and techniques are taught, for example, in Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development – A Guide for Organic Chemists (2012), which is incorporated by reference herein. Table 1: Examples of (2-Oxo-2H-Chromen-3-yl) Scaffold Based Carboxamide Analogs Provided Herein

[0040] All the compounds of the present invention may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and / or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all the compounds of the present invention are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.

[0041] In some embodiments, the compounds of the present invention have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.

[0042] Compounds of the present invention may contain one or more asymmetrically-substituted carbon, nitrogen, sulfur, or phosphorus atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.

[0043] Chemical formulas used to represent compounds of the present invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardlessof which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

[0044] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0045] In some embodiments, compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

[0046] In some embodiments, compounds of the present invention exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0047] It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present invention.II. Indications A. Diseases Associated with Tau Misfolding and Aggregation

[0048] The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau). They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

[0049] Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease are associated with tau proteins that have become hyperphosphorylated insoluble aggregates called neurofibrillary tangles. The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly, and since then they have been characterized as intrinsically disordered proteins.

[0050] Tau proteins are found more often in neurons than in non-neuronal cells in humans. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system microtubule-associated proteins (MAPs) may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.

[0051] Although tau is present in dendrites at low levels, where it is involved in postsynaptic scaffolding, it is active primarily in the distal portions of axons, where it provides microtubule stabilization but also flexibility as needed. Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation. In addition to its microtubule-stabilizing function, Tau has also been found to recruit signaling proteins and to regulate microtubule-mediated axonal transport.

[0052] Tau is a negative regulator of mRNA translation in Drosophila, mouse, and human brains, through its binding to ribosomes, which results in impaired ribosomal function, reduction of protein synthesis and altered synaptic function. Tau interacts specifically with several ribosomal proteins, including the crucial regulator of translation rpS6.

[0053] The primary non-cellular function of tau is to negatively regulate long- term memory and to facilitate habituation (a form of non-associative learning), two higher and more integrated physiological functions. Since regulation of tau is critical for memory, this could explain the linkage between tauopathies and cognitive impairment.

[0054] In mice, while the reported tau knockout strains present without overt phenotype when young, when aged, they show some muscle weakness, hyperactivity, and impaired fear conditioning. However, neither spatial learning in mice, nor short-term memory (learning) in Drosophila seems to be affected by the absence of tau. In addition, tau knockout mice have abnormal sleep-wake cycle, with increased wakefulness periods and decreased non- rapid eye movements (NREM) sleep time.

[0055] Other typical functions of tau include cellular signaling, neuronal development, neuroprotection and apoptosis. Atypical, non-standard roles of tau are also under current investigation, such as its involvement in chromosome stability, its interaction with the cellular transcriptome, its interaction with other cytoskeletal or synaptic proteins, its involvement in myelination or in brain insulin signaling, its role in the exposure to chronic stress and in depression, etc.

[0056] Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. Tau is a phosphoprotein with 79 potential serine (Ser) and threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.

[0057] Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine / threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization. Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau. The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases. Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396. The binding of these phosphatases to tau affects tau's association with microtubules. Phosphorylation of tau has also been suggested to be regulated by O- GlcNAc modification at various Ser and Thr residues.

[0058] The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration. The actual mechanism of how tau propagates from one cell to another is not well identified. Also, other mechanisms, including tau release and toxicity, are unclear. As tau aggregates, it replaces tubulin, which in turn enhances fibrilization oftau. Several propagation methods have been proposed that occur by synaptic contact such as synaptic cell adhesion proteins, neuronal activity and other synaptic and non-synaptic mechanisms. The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.

[0059] Tau involves in uptake and release process, which is known as seeding. Uptake of tau protein mechanism requires the presence of heparan sulfate proteoglycans at the cell surface, which happens by macropinocytosis. On the other hand, tau release depends on neuronal activity. Many factors influence tau release, for example, type of isoforms or MAPT mutations that change the extracellular level of tau. According to Asai and his colleagues, the spreading of tau protein occurs from the entorhinal cortex to the hippocampal region in the early stages of the disease. They also suggested that microglia were also involved in the transport process, and their actual role is still unknown.

[0060] Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanisms such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activatation other kinases (GSK- 3 and CDK5) that cause disease-associated phosphoepitopes. The degree of toxicity is affected by different factors, such as the degree of microtubule binding. Toxicity could also happen by neurofibrillary tangles (NFTs), which leads to cell death and cognitive decline.

[0061] Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease, frontotemporal dementia and other tauopathies. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases. Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses.

[0062] Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies. Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.

[0063] The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into paired-helical-filament (PHF) tau and neurofibrillary tangles (NFTs). The stage of the disease determines NFTs' phosphorylation.In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 199, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231. Through its isoforms and phosphorylation, tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments (PHFs) in the AD brain.

[0064] Tau mutations have many consequences, including microtubule dysfunction and alteration of the expression level of tau isoforms. Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1 (microtubule associated protein tau 1), MAPT 2 and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.

[0065] Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients. It has been well demonstrated that regions of tau six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK), can form tau PHF aggregation in AD. Apart from the PHF6, some other residue sites like Ser285, Ser289, Ser293, Ser305 and Tyr310, located near the C-terminal of the PHF6 sequences, play key roles in the phosphorylation of tau. Hyperphosphorylated tau differs in its sensitivity and its kinase as well as alkaline phosphatase activity and is, along with beta-amyloid, a component of the pathologic lesion seen in Alzheimer disease. A recent hypothesis identifies the decrease of reelin signaling as the primary change in Alzheimer's disease that leads to the hyperphosphorylation of tau via a decrease in GSK3^ inhibition.

[0066] “Tauopathies”, including AD, represent a broad spectrum of neurodegenerative diseases involving tau misfolding and aggregation as a causative factor in neuron death and cognitive decline. Approximately 30 million people are estimated to be affected by tauopathies today (Chang et al., 2018). No approved clinical therapies have reversed tauopathy-associated neurodegeneration; very few have demonstrated that they can slow cognitive decline by even a minor amount. While tau pathology is largely intracellular, one of the most significant events in disease progression is the propagation of disease- associated tau oligomers across the extracellular matrix from affected to healthy neurons in a prion-like manner, where propagated oligomers induce disease states by templating the formation of similarly detrimental aggregates (Frost and Diamond, 2010). This processfacilitates an epidemic spread of disease pathology among communicating neurons, validating extracellular tau aggregates as important, sometimes even predictive, readouts of local neuron health. While tauopathies, in reality, exist on a wide-ranging, multi-dimensional continuum of pathology and clinical presentation, tauopathies can be binned into common diagnoses based largely on (1) whether tau misfolding and aggregation is the primary pathology (termed “primary” tauopathies) or occurs as the result of, or in concert with, other pathological mechanisms (termed “secondary” tauopathies); on (2) disease-specific tau pathology archetypes, especially in isoform content; and finally on (3) clinically-relevant symptoms exhibited by the affected individual. Per Sexton et al., 2022, an up-to-date list of commonly- accepted tauopathies is: Alzheimer’s disease; amyotrophic lateral sclerosis / parkinsonism- dementia complex; anti-IgLON5-related tauopathy; Caribbean parkinsonism; chronic traumatic encephalopathy; diffuse neurofibrillary tangles with calcification; Down syndrome; familial British dementia; familial Danish dementia; Niemann-Pick disease, Type C; non- Guamanian motor neuron disease with neurofibrillary tangles; postencephalitic parkinsonism; primary age-related tauopathy; progressive ataxia and palatal tremor; tangle-only dementia; Pick’s disease; familial frontotemporal dementia; argyrophilic grain disease; corticobasal degeneration; Guadeloupean parkinsonism; globular glial tauopathy; Huntington’s disease; progressive supranuclear palsy; SLC9a-related Parkinsonism; and tau astrogliopathy. Subtopics C1-3 outline general features of tauopathies and supplies a non-exhaustive list of example tauopathies corresponding to each feature, while subtopic C4 describes each tauopathy individually in terms of the features outlined in C1-3. It should be restated that, despite the diagnostic reality, tauopathies exist on a continuum — the pathology and clinical presentation of most tauopathies vary greatly, even between individuals with the same diagnosis.

[0067] Primary and Secondary Tauopathies. Primary and secondary tauopathies differ in the primacy afforded to tau pathology as neurodegenerative hallmarks: primary tauopathies center tau aggregation as the main pathological feature; secondary tauopathies see tau aggregation happening either because of, or in concert with, other disease mechanisms (e.g. AD is characterized by both aggregated amyloid-beta and aggregated tau). As reviewed by Sexton et al., 2022, primary and secondary tauopathies are heterogenous with respect to tau pathology and clinical manifestation. Some examples of primary tauopathies are frontotemporal dementia, corticobasal degeneration, Pick’s disease, and certain parkinsonisms. Examples of secondary tauopathies are AD, Down syndrome, chronic traumatic encephalopathy (CTE), Huntington’s disease, and Parkinson’s disease.

[0068] Tau Isoform Content. In the CNS, tau is expressed as one of six predominant isoforms varying based on whether the first and second N-terminal “insert” domains and the second C-terminal “repeat” domain is spliced out of pre-mRNA transcribed from the MAPT locus. Tau isoforms containing both the first and second insert are termed “2N” isoforms, those containing only the first insert are “1N” isoforms, and those with neither the first nor second insert are “0N” isoforms. Similarly, isoforms with all four repeat domains are “4R” isoforms, while isoforms lacking the second repeat domain are “3R” isoforms. Splicing at tau repeats do not preclude splicing at inserts, and vice-versa. Thus, splicing of MAPT pre-mRNA results in 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, and 0N3R isoforms when translated. While humans indeed express all six isoforms of tau in the CNS, tauopathies are oftentimes characterized by a dysregulation in relative isomer content, being broadly divided into 3R, 4R, and 3R+4R (“mixed”) tauopathies. 3R tauopathies see a predominance of 3R tau isoforms; the two currently identified 3R tauopathies are Pick’s disease and certain types of frontotemporal dementia. 4R tauopathies, then, see a predominance of 4R tau isoforms; some examples of 4R tauopathies include Huntington’s disease, types of frontotemporal dementia that are not 3R tauopathies, and corticobasal degeneration. Examples of mixed tauopathies are AD, CTE, and Down syndrome. In fact, differences in certain tau properties among individual tauopathies, especially isomer content, cause differential seeding and propagation, leading to differences in the spatial distribution of tau pathology, in neuronal death, and in clinical presentation (Sanders et al., 2014).

[0069] Clinical Presentation. The clinical presentation of tauopathies is highly variable and dependent on the underlying neurodegenerative condition, including both cognitive and functional symptoms such as memory loss, decline in reasoning skills, disinhibition, tremor, ataxia, and bradykinesia (Zhang et al., 2022).

[0070] Pathology and Clinical Presentation of Individual Tauopathies. Amylotrophic Lateral Sclerosis / Parkinsonism-dementia complex. Amylotrophic Lateral Sclerosis / Parkinsonism-dementia complex (ALS / PDC) is a mixed secondary tauopathy biochemically characterized by the aggregation of alpha-synuclein, tau, amyloid-beta, FUS, SOD1, and / or TDP-43 (Condello et al., 2023). Individuals with ALS / PDC (primarily in or around the island of Guam) present most often with symptoms related to motor control and dementia consistent with ALS and Parkinson’s disease (Condello et al., 2023). Anti-IgLON5- related tauopathy. Anti-IgLON5-related tauopathy is recently-discovered secondary mixed tauopathy with an autoimmune disease mechanism — autoantibodies against the neural cell adhesion molecule IgLON5 cause neuron stress and death; repeated insults lead to taumisfolding and aggregation (Gelpi et al., 2016). Individuals with Anti-IgLON5-related tauopathy present primarily with sleep and movement disorders (Luo et al., 2024). Caribbean parkinsonism. Caribbean parkinsonism is a mixed tauopathy. It is debated whether tau pathology in Caribbean parkinsonism is secondary to some other pathological mechanism, but foci of high disease incidence in certain locations with tropical climates suggest an environmental origin, potentially a plant-derived toxin (Lefebvre et al., 2019). Individuals with Caribbean parkinsonism present with rapidly developing motor symptoms characteristic of parkinsonisms, such as bradykinesia, tremor, and dementia (Tolosa et al., 2004). Chronic traumatic encephalopathy. Chronic traumatic encephalopathy, whose pathology and diagnostic criteria are just beginning to be standardized, is understood as mixed tauopathy, with tau pathology (alongside amyloid-beta and TDP43 pathology) secondary to one or more traumatic brain injuries (Smith et al., 2019). Individuals with chronic traumatic encephalopathy present in the clinic with symptoms falling largely into one of two groups: those exhibiting behavior and mood dysregulation, and others with cognitive impairment (Stern et al., 2013). Diffuse neurofibrillary tangles with calcification. Diffuse neurofibrillary tangles with calcification is a mixed primary tauopathy with seemingly sporadic onset; individuals presenting with diffuse neurofibrillary tangles with calcification exhibit symptoms consistent with dementia. (Haraguchi et al., 2001). Down syndrome. Down syndrome is an inherited condition resulting from trisomy of chromosome 21. Among other difficulties (e.g. an increased chance of leukemia and cerebellar hypoplasia), individuals with Down syndrome exhibit early-onset Alzheimer’s-like pathology — a mixed secondary tauopathy including amyloid-beta aggregates contributing to intellectual impairment (Antonarakis et al., 2020). Familial British dementia and familial Danish dementia. Both familial British dementia and familial Danish dementia are inherited neurodegenerative conditions that resemble Alzheimer’s pathology — a mixed secondary tauopathy characterized by amyloid aggregates, tau aggregates, and cerebral amyloid angiopathy (Garringer et al., 2009). Individuals with familial British or Danish dementia present largely with early-onset Alzheimer’s symptoms: loss of hearing and vision, ataxia, paranoia, and dementia (Holton et al., 2002). Niemann-Pick disease, type C. Niemann- Pick disease type C is a highly variable and multifaceted lysosomal storage disease involving, in part, the buildup of gangliosides leading to mixed (secondary) tauopathy; individuals with Niemann-Pick disease type C exhibit ataxia, loss of hearing, and dementia (Las Heras et al., 2023). Non-Guamanian motor neuron disease with neurofibrillary tangles. Non-Guamanian motor neuron disease with neurofibrillary tangles is a primary mixed tauopathy which results in movement deficits and dementia (Hilton et al., 1995). Postencephalitic parkinsonism.Postencephalitic parkinsonism is a rare secondary mixed tauopathy caused by prior infection with von Economo’s disease (Casals et al., 1998; Bigman and Bobrin, 2018). Individuals with postencephalitic parkinsonism oftentimes exhibit common symptoms of parkinsonisms, such as bradykinesia and myoclonus, complemented by kinesia paradoxical (Hoffman and Vilensky, 2017). Primary age-related tauopathy. Primary age-related tauopathy manifests in older individuals much like AD, except that it lacks any observable amyloid pathology; that is, primary age-related tauopathy is a mixed primary tauopathy. The clinical manifestation of primary age-related tauopathy, when not entirely asymptomatic, is noticeably more docile than most other symptomatic neurodegenerative diseases, and extreme cases of impairment due to primary age-related tauopathy oftentimes meet the criteria for other, more drastic, neurodegenerative diseases (Crary et al., 2014). Progressive ataxia and palatal tremor. Progressive ataxia and palatal tremor is considered by some to be a mixed tauopathy due to tau aggregation being present in the olivary nucleus (Marrakchi et al., 2024). It manifests clinically with gait disorders and myoclonus (Pradeep et al., 2020). Tangle-only dementia. Tangle-only dementia is a mixed tauopathy closely resembling Alzheimer’s disease, but either almost entirely or entirely lacking amyloid plaques (Noda et al., 2006). As such, tangle-only dementia is most closely mirrored by primary age-related tauopathy in biochemical form; the factor distinguishing tangle-only dementia from primary age-related tauopathy is that individuals with tangle-only dementia present with more drastic symptoms than those with primary age- related dementia (Crary et al., 2014). Pick’s disease. Pick’s disease is a 3R primary tauopathy closely related to frontotemporal dementia with characteristic “Pick bodies” (Irwin, 2015). Individuals with Pick’s disease present with behavioral abnormalities and cognitive decline, including language deficits (Dickson, 1998). Familial frontotemporal dementia. Frontotemporal dementia can either be a 3R- or 4R-predominant primary tauopathy, and oftentimes is due to inherited genetic mutations (Morris et al., 2001) and presents through behavioral or specific aphasic variants (Weder et al., 2007). Argyrophilic grain disease. Argyrophilic grain disease is the second most prevalent neurodegenerative condition, after Alzheimer’s disease. It is a 4R primary tauopathy with enriched occurrence in elderly individuals and has no distinct clinical presentation, although psychiatric and mild cognitive symptoms are common (Rodriguez and Grinberg, 2015). Corticobasal degeneration. Corticobasal degeneration is a primary 4R tauopathy leading to diverse cognitive and behavioral symptoms, including parkinsonian traits, such as myoclonus (reviewed in Constantinides et al., 2019). Guadeloupean parkinsonism. Guadeloupean parkinsonism is a 4R primary tauopathy with high incidence in Guadeloupe; individuals with Guadeloupeanparkinsonism have diverse clinical presentations centered around parkinsonian movement deficits and cognitive decline (Lannuzel et al., 2007). Globular glial tauopathy. Globular glial tauopathies are 4R primary tauopathies characterized by globular phosphorylated tau inclusions in glia (Ahmed et al., 2013). Huntington’s disease. Huntington’s disease is an early- onset genetic 4R tauopathy, with tau inclusions secondary to disease mechanisms initiated by mutant huntingtin protein (Tabrizi et al., 2020). Individuals suffering from Huntington’s disease present with dementia, psychiatric disturbances, and movement disorders, such as chorea (Roos et al., 2010). Progressive supranuclear palsy. Progressive supranuclear palsy is a 4R primary tauopathy with tau inclusions mainly in the brainstem and basal nuclei (Stamelou et al., 2021). Individuals with progressive supranuclear palsy present with limitations in eye movement, bodily instability when in static positions, and cognitive decline (Currens and Pantelyat, 2024). Tau astrogliopathy. Tau astrogliopathy is a 4R primary tauopathy marked by tau pathology in astrocytes across various regions of the brain (Kovacs et al., 2018). Tau astrogliopathy is perceived currently to be less harmful than many other tauopathies, but more research into the clinical manifestation of tau astrogliopathy is required to make this perception more concrete (Kovacs et al., 2016). B. Alzheimer’s Disease

[0071] Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–80% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

[0072] The cause of Alzheimer's disease is poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of APOE. Other risk factors include a history of head injury, clinical depression, and high blood pressure. The disease process is largely associated with amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain. A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging. Examination of brain tissue is needed for a definite diagnosis, but thiscan only take place after death. Good nutrition, physical activity, and engaging socially are known to be of benefit generally in aging, and these may help in reducing the risk of cognitive decline and Alzheimer's; in 2019 clinical trials were underway to look at these possibilities. There are no medications or supplements that have been shown to decrease risk.

[0073] No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit and an increased risk of early death.

[0074] As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. It most often begins in people over 65 years of age, although up to 10% of cases are early-onset affecting those in their 30s to mid-60s. It affects about 6% of people 65 years and older, and women more often than men. The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion. Alzheimer's disease is currently ranked as the seventh leading cause of death in the United States.

[0075] The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. The three stages are described as early or mild, middle or moderate, and late or severe. The disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment. Proteins fail to function normally. This disrupts the work of the brain cells affected and triggers a toxic cascade, ultimately leading to cell death and later brain shrinkage.

[0076] Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (A^), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases.

[0077] Advances in brain imaging techniques allow researchers to see the development and spread of abnormal amyloid and tau proteins in the living brain, as well aschanges in brain structure and function. Beta-amyloid is a fragment of a larger protein. When these fragments cluster together, a toxic effect appears on neurons and disrupts cell-to-cell communication. Larger deposits called amyloid plaques are thus further formed.

[0078] Tau proteins are responsible in neuron's internal support and transport system to carry nutrients and other essential materials. In Alzheimer's disease, the shape of tau proteins is altered and thus organize themselves into structures called neurofibrillary tangles. The tangles disrupt the transport system and are toxic to cells.

[0079] The cause for most Alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the two predominant hypotheses are the amyloid beta (A^) hypothesis and the cholinergic hypothesis.

[0080] The oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis, which proposes that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (A^) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.

[0081] Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Degeneration is also present in brainstem nuclei, particularly the locus coeruleus in the pons. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison, with similar images from healthy older adults.

[0082] Both A^ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles inthe neocortex. Plaques are dense, mostly insoluble deposits of beta- amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulates inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with Alzheimer's disease.

[0083] Alzheimer's disease has been identified as a protein misfolding disease (proteopathy) caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (A^). Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques.

[0084] Alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated and is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation.

[0085] Exactly how disturbances of production and aggregation of the beta- amyloid peptide give rise to the pathology of Alzheimer's disease is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that A^ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilization of glucose by neurons.

[0086] Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease and may be either secondary to tissue damage in Alzheimer's disease or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.

[0087] Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease. III. Pharmaceutical Formulations and Routes of Administration

[0088] In another aspect, for administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medicinal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and / or drug carriers appropriate to the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner amenable for the treatment of human and / or veterinary patients. In some embodiments, formulation comprises admixing or combining one or more of the compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulations may be subjected to pharmaceutical operations, such as sterilization, and / or may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0089] Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, and intraperitoneal).Depending on the route of administration, the compounds disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. In some embodiments, the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.

[0090] The compounds disclosed herein may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0091] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0092] The compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compounds and other ingredients may also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the patient’s diet. For oral therapeutic administration, the compounds disclosed herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may,of course, be varied. The amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained.

[0093] The therapeutic compound may also be administered topically to the skin, eye, ear, or mucosal membranes. Administration of the therapeutic compound topically may include formulations of the compounds as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When the therapeutic compound is formulated for topical administration, the compound may be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered. In other embodiments, it is contemplated that the topical administration is administered to the eye. Such administration may be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by any theory, it is believed that administration to the surface of the eye allows the therapeutic compound to reach the posterior portion of the eye. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration may also include administration to the mucosa membranes such as the inside of the mouth. Such administration can be directly to a particular location within the mucosal membrane such as a tooth, a sore, or an ulcer. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.

[0094] In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal.

[0095] In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg canbe calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference): HED (mg / kg) = Animal dose (mg / kg) × (Animal Km / Human Km)

[0096] Use of the Kmfactors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. Km values for humans and various animals are well known. For example, the Kmfor an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Kmof 25. Kmfor some relevant animal models are also well known, including: mice Kmof 3 (given a weight of 0.02 kg and BSA of 0.007); hamster Kmof 5 (given a weight of 0.08 kg and BSA of 0.02); rat Kmof 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Km of 12 (given a weight of 3 kg and BSA of 0.24).

[0097] Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.

[0098] The actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication.

[0099] In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 250 mg / kg, from about 10 mg / kg to about 150 mg / kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day.[000100] In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent.[000101] Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, patients may be administered two doses daily at approximately 12-hour intervals. In some embodiments, the agent is administered once a day.[000102] The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the invention provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of when the patient has eaten or will eat.IV. Chemical Definitions[000103] When used in the context of a chemical group: “hydrogen” means -H; “hydroxy” means -OH; “oxo” means =0; “carbonyl” means -C(=O)-; “carboxy” means -C(=O)OH (also written as -COOH or -CO2H); “halo” means independently -F, -Cl, -Br or -I; “amino” means -NH2; “hydroxyamino” means -NHOH; “nitro” means -NO2; “hydrazinyl” means -NH2NH2; imino means =NH; “cyano” means -CN; “isocyanyl” means -N=C=O; “azido” means -N3; in a monovalent context “phosphate” means -OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means -OP(O)(OH)O- or a deprotonated form thereof; “mercapto” means -SH; and “thio” means =S; “thiocarbonyl” means -C(=S)-; “sulfonyl” means -S(O)2~; and “sulfinyl” means -S(O)-.[000104] In the context of chemical formulas, the symbol means a single bond, “=” means a double bond, and “=” means triple bond. The symbol “ - ” represents an optional bond, which if present is either single or double. The symbol “==” represents asingle bond or a double bond. Thus, the formulacovers, for example,,. And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “−”, when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry.Instead, it covers all stereoisomers as well as mixtures thereof. The symbol “ ”, whendrawn perpendicularly across a bond (e.g., for methyl) indicates a point of attachmentof the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point ofattachment. The symbol “means a single bond where the group attached to the thick endof the wedge is “out of the page.” The symbol “ ” means a single bond where the groupattached to the thick end of the wedge is “into the page”. The symbol “ ” means a singlebond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper. [000105] When a variable is depicted as a “floating group” on a ring system, for example, the group “R” in the formula:, then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula:, then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., ahydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals −CH−), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter “y” immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system. [000106] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group / class. “C≤n” defines the maximum number (n) of carbon atoms that can be in the group / class, with the minimum number as small as possible for the group / class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl(C≤8)”, “alkanediyl(C≤8)”, “heteroaryl(C≤8)”, and “acyl(C≤8)” is one, the minimum number of carbon atoms in the groups “alkenyl(C≤8)”, “alkynyl(C≤8)”, and “heterocycloalkyl(C≤8)” is two, the minimum number of carbon atoms in the group “cycloalkyl(C≤8)” is three, and the minimum number of carbon atoms in the groups “aryl(C≤8)” and “arenediyl(C≤8)” is six. “Cn-n&” defines both the minimum (n) and maximum number (n&) of carbon atoms in the group. Thus, “alkyl(C2-10)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “C1-4-alkyl”, “C1-4-alkyl”, “alkyl(C1-4)”, and “alkyl(C^4)” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(C12)group; however, it is not an example of a dialkylamino(C6)group. Likewise, phenylethyl is an example of an aralkyl(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(C1-6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.[000107] The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon- carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present in the group replacing the hydrogen atom, as discussed below. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine / enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution. [000108] The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds / groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, that is joined by single carbon-carbon bonds (alkanes / alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes / alkenyl) or with one or more carbon-carbon triple bonds (alkynes / alkynyl). [000109] The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n +2 electrons in a fully conjugated cyclic ' system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:is also taken to refer to[000110] The term “alkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups −CH3(Me), −CH2CH3(Et), −CH2CH2CH3(n-Pr or propyl), −CH(CH3)2(i-Pr,iPr or isopropyl), −CH2CH2CH2CH3(n-Bu), −CH(CH3)CH2CH3(sec-butyl), −CH2CH(CH3)2(isobutyl), −C(CH3)3(tert-butyl, t-butyl, t-Bu ortBu), and −CH2C(CH3)3 (neo-pentyl) are non-limiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups −CH2− (methylene),−CH2CH2−, −CH2C(CH3)2CH2−, and −CH2CH2CH2− are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group =CRR& in which R and R& are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. An “alkane” refers to the class of compounds having the formula H−R, wherein R is alkyl as this term is defined above. [000111] The term “cycloalkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. Non-limiting examples include: −CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term “cycloalkanediyl” refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groupis a non- limiting example of cycloalkanediyl group. A “cycloalkane” refers to the class of compounds having the formula H−R, wherein R is cycloalkyl as this term is defined above. [000112] The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include:−CH=CH2 (vinyl), −CH=CHCH3, −CH=CHCH2CH3, −CH2CH=CH2(allyl), −CH2CH=CHCH3, and −CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups −CH=CH−, −CH=C(CH3)CH2−, −CH=CHCH2−, and −CH2CH=CHCH2− are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H−R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “(-olefin” are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.[000113] The term “alkynyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups −C%CH, −C%CCH3, and −CH2C%CCH3 are non-limiting examples of alkynyl groups. An “alkyne” refers to the class of compounds having the formula H−R, wherein R is alkynyl. [000114] The term “aryl” refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, −C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:. An “arene” refers to the class of compounds having the formula H−R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.[000115] The term “aralkyl” refers to the monovalent group −alkanediyl−aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. [000116] The term “heteroaryl” refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term “N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as the point of attachment. A “heteroarene” refers to the class of compounds having the formula H−R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. [000117] The term “heterocycloalkyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydropyridinyl, pyranyl, oxiranyl, and oxetanyl. The term “N-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group.[000118] The term “acyl” refers to the group −C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, −CHO, −C(O)CH3 (acetyl, Ac), −C(O)CH2CH3, −C(O)CH(CH3)2, −C(O)CH(CH2)2, −C(O)C6H5, and −C(O)C6H4CH3are non-limiting examples of acyl groups. A “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group −C(O)R has been replaced with a sulfur atom, −C(S)R. The term “aldehyde” corresponds to an alkyl group, as defined above, attached to a −CHO group. [000119] The term “alkoxy” refers to the group −OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −OCH3(methoxy), −OCH2CH3(ethoxy), −OCH2CH2CH3, −OCH(CH3)2 (isopropoxy), or −OC(CH3)3 (tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as −OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term “alkylthio” and “acylthio” refers to the group −SR, in which R is an alkyl and acyl, respectively. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group. [000120] The term “alkylamino” refers to the group −NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −NHCH3and −NHCH2CH3. The term “dialkylamino” refers to the group −NRR&, in which R and R& can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: −N(CH3)2and −N(CH3)(CH2CH3). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group −NHR, in which R is acyl, as that term is defined above. A non- limiting example of an amido group is −NHC(O)CH3. [000121] When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by −OH, −F, −Cl, −Br, −I, −NH2, −NO2, −CO2H, −CO2CH3, −CO2CH2CH3, −CN, −SH, −OCH3, −OCH2CH3,−C(O)CH3,−NHCH3,−NHCH2CH3,−N(CH3)2,−C(O)NH2,−C(O)NHCH3,−C(O)N(CH3)2,−OC(O)CH3, −NHC(O)CH3, −S(O)2OH, or −S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: −CH2OH, −CH2Cl, −CF3, −CH2CN, −CH2C(O)OH, −CH2C(O)OCH3, −CH2C(O)NH2, −CH2C(O)CH3, −CH2OCH3, −CH2OC(O)CH3, −CH2NH2, −CH2N(CH3)2, and −CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. −F,−Cl, −Br, or −I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, −CH2Cl is a non-limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups −CH2F, −CF3, and −CH2CF3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, −C(O)CH2CF3, −CO2H (carboxyl), −CO2CH3(methylcarboxyl), −CO2CH2CH3, −C(O)NH2(carbamoyl), and −CON(CH3)2, are non-limiting examples of substituted acyl groups. The groups −NHC(O)OCH3and −NHC(O)NHCH3are non-limiting examples of substituted amido groups. [000122] The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” [000123] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients. [000124] An “active ingredient” (AI) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically active. [000125] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. [000126] The term “effective,” as that term is used in the specification and / or claims, means adequate to accomplish a desired, expected, or intended result. “Effective amount,” “Therapeutically effective amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to the patient or subject, is sufficient to effect such treatment or prevention of the disease as those terms are defined below. [000127] An “excipient” is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, tobulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors. [000128] The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound. [000129] An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs. [000130] As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses. [000131] As generally used herein “pharmaceutically acceptable” refers 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, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. [000132] “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid,4,4&-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). [000133] A “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and / or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and / or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers. [000134] A “pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug, agent, or preparation) is a composition used to diagnose, cure, treat, or prevent disease,which comprises an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (defined above). [000135] “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and / or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease. [000136] “Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical ingredient of the present invention. The prodrug itself may or may not have activity in its prodrug form. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Non-limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene- bis-β-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, and esters of amino acids. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound. [000137] A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetryfrequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains ^ 15%, more preferably ^ 10%, even more preferably ^ 5%, or most preferably ^ 1% of another stereoisomer(s). [000138] “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. [000139] The term “unit dose” refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations. [000140] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention. [000141] The term “heteroaralkyl” refers to the monovalent group −alkanediyl−heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl. [000142] The term “heteroarenediyl” refers to a divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and onearomatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroarenediyl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroarenediyl groups include:[000143] The term “heterocycloalkanediyl” refers to a divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. As used herein, the term heterocycloalkanediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include:[000144] The terms “alkylsulfonyl” and “alkylsulfinyl” refers to the groups −S(O)2R and −S(O)R, respectively, in which R is an alkyl, as that term is defined above. The terms “cycloalkylsulfonyl”, “alkenylsulfonyl”, “alkynylsulfonyl”, “arylsulfonyl”, “aralkylsulfonyl”, “heteroarylsulfonyl”, and “heterocycloalkylsulfonyl” are defined in an analogous manner. [000145] The terms “cycloalkylamino”, “alkenylamino”, “alkynylamino”, “arylamino”, “aralkylamino”, “heteroarylamino”, “heterocycloalkylamino”, and “alkoxyamino” when used without the “substituted” modifier, refers to groups, defined as −NHR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is −NHC6H5. Theterms “dicycloalkylamino”, “dialkenylamino”, “dialkynylamino”, “diarylamino”, “diaralkylamino”, “diheteroarylamino”, “diheterocycloalkylamino”, and “dialkoxyamino”, refers to groups, defined as −NRR&, in which R and R& are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. Similarly, the term alkyl(cycloalkyl)amino refers to a group defined as −NRR&, in which R is alkyl and R& is cycloalkyl. V. Examples [000146] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example which follows represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Example 1: Materials and Methods [000147] General Experimental Methods: The reactions were performed under a dry argon atmosphere and reaction temperatures were measured externally. Anhydrous solvents over molecular sieves were purchased from Aldrich and used as such in reactions. Microwave (MW) reactions were performed in CEM Discover Labmate System with Intelligent Technology for Focused™ Microwave Synthesizer (Explorer 48) or Biotage Initiator+ equipped with Robot Eight microwave system. The reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel (60F254) aluminium plates (0.25 mm) from E. Merck and visualized using UV light (254 nm). Purification of compounds was performed on an Isco Teledyne Combiflash Rf200. Universal RediSep solid sample loading pre-packed cartridges (5.0 g silica) were used to absorb crude product and purified on 12 g silica RediSep Rf Gold Silica (20–40 µm spherical silica) columns using appropriate solvent gradients. Pure samples were dried overnight under high vacuum before analyses. The high resolution electrospray ionization mass spectral data (HR-ESIMS) were obtained on an Agilent LC-MSTOF.1H NMR spectra were recorded at 400 MHz on Agilent / Varian MR-400 spectrometer in CDCl3, CD3OD, or DMSO-d6 as solvents. The chemical shifts ()) are in ppm downfield from standard tetramethylsilane (TMS). HPLC of final compounds were run on anAgilent 1100 LC equipped with a diode array UV detector and were monitored at 254 nm using the following using Sunfire C18 column (5µm, 4.6 × 150 mm) using H2O-CH3CN (both containing 0.1% formic acid) 5-95% in 20 min with flow rate 1.0 mL / min. Example 2: BOP-Cl Coupling Method Scheme 1.[000148] BOP-Cl coupling method: To a solution of carboxylic acid (1 mmol) in anhydrous DCM (10 mL) under nitrogen atmosphere at room temperature, BOP-Cl (1.5 mmol) was added followed by the addition of triethylamine (3 mmol) and the reaction mixture was stirred at same temperature for 5 min. corresponding amine (1 mmol) was added to the reaction mixture and refluxed for 20 h. After completion of the reaction. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, followed by purification using pre-packed Silica gel column on ISCO gave the pure product. Scheme 2[000149] Synthesis of 6-methyl-N-(2-oxo-2H-chromen-3-yl)picolinamide (M1): This compound was synthesized by using the BOP-Cl Coupling method. Purification on pre- packed silica gel column using Teledyne Isco system (0-10 % EtOAc in Hexanes, 30 min) togive the title compound as a yellow-white solid (140 mg, 38%).1H NMR (400 MHz, CDCl3) ) 10.81 (s, 1H), 8.90 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 7.46 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.39 – 7.28 (m, 3H), 2.67 (s, 3H).13C NMR (101 MHz, CDCl3) ) 163.76, 158.56, 157.90, 150.21, 148.25, 137.69, 129.60, 127.79, 126.75, 125.05, 124.20, 123.34, 119.97, 119.43, 116.39, 31.92, 29.70, 24.33, 22.69, 14.12. HR- ESIMS: Exact m / z 281.0921 [M+H]+calc-d. for C16H12N2O3,found 281.09161. HPLC Purity: 99.9% (Retention Time = 15.70 min). Scheme 3(trifluoromethyl)picolinamide (M3): This compound was synthesized by using the BOP-Cl Coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0- 0,2% MeOH in CH2Cl2, 4 min) to give the title compound as a white flakey solid (226.5 mg, 61.4%)1H NMR (400 MHz, CDCl3) ) 10.55 (s, 1H), 8.88 (s, 1H), 8.47 (ddq, J = 7.9, 0.9, 0.5 Hz, 1H), 8.15 (tt, J = 7.8, 0.6 Hz, 1H), 7.91 (dd, J = 7.9, 1.0 Hz, 1H), 7.57 (ddt, J = 7.7, 1.7, 0.4 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.40 – 7.30 (m, 2H).13C NMR (101 MHz, cdcl3) ) 162.00, 158.30, 150.35, 149.32, 147.92, 147.57, 147.21, 139.58, 130.01, 127.92, 125.14, 125.07, 124.98, 124.09, 123.77, 123.58, 123.56, 123.53, 123.50, 122.25, 119.66, 119.52, 116.79, 116.51, 77.22. HR-ESIMS: m / z 335.063803 [M+H]+calcd. for C16H9F3N2O3,found 335.0633. HPLC Purity = 99.9% (Retention Time = 12.4 min). Scheme 4[000151] General Procedure for Amide Methylation: To a solution of amide (1 mmol) in 3 mL DMF under nitrogen atmosphere, NaH (1.14 mmol) was added at 0 °C, reaction mixture was allowed to stir at the same temperature for about 30 minutes, then iodomethane (0.95 mmol) was added by using a glass syringe and the reaction was allowed to stir at room temperature overnight. After completion of the reaction monitored by TLC, 25 mL of water was added dropwise to quench the reaction, followed by extraction with EtOAc (3 X 50 mL) combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and the solvent was evaporated. [000152] Synthesis of N-methyl-N-(6-methylpyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M13): This compound was synthesized by using the Amide Methylation method. The crude material was purified on silica gel column using Teledyne Isco system (0- 40 % EtOAc in Hexanes, 24 min) to give the title compound as an off-white solid (7.2 mg, 8.7%).1H NMR (400 MHz, CDCl3) ) 7.94 (s, 1H), 7.62 – 7.46 (m, 3H), 7.28 (t, J = 7.4 Hz, 3H), 6.92 (d, J = 7.6 Hz, 1H), 3.56 (s, 3H), 2.28 (s, 3H). HR-ESIMS: Exact m / z 295.1077 [M+H]+calcd. for C17H14N2O3, found 295.1072. HPLC Purity = 99.9% (Retention Time = 10.07 min). [000153] Synthesis of N-(6-cyanopyridin-2-yl)-N-methyl-2-oxo-2H-chromene-3- carboxamide (M42): This compound was synthesized by using the Amide Methylation method. The crude material was purified on silica gel column using Teledyne Isco system (0- 40 % EtOAc in Hexanes, 21 min) to give the title compound as an off-white solid (11.3 mg, 14.7%).1H NMR (400 MHz, CDCl3) ) 8.13 (s, 1H), 7.83 (dd, J = 8.4, 7.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.60 (td, J = 7.4, 1.6 Hz, 2H), 7.47 (dd, J = 7.3, 0.9 Hz, 1H), 7.38 – 7.29 (m, 2H), 3.57 (s, 4H).13C NMR (101 MHz, CDCl3) ) 165.55, 157.55, 155.99, 154.22, 144.74, 139.02, 133.29, 131.38, 128.95, 125.52, 125.29, 125.07, 121.79, 118.20, 116.78, 116.45, 35.41. HR-ESIMS: Exact m / z 306.0864 [M+H]+calcd. for C17H11N3O3, found 306.0863. HPLC Purity = 99.9% (Retention Time = 10.36 min). Example 3 - Microwave (MW) mediated BOP-Cl coupling method Scheme 5[000154] Microwave (MW) mediated BOP-Cl coupling method: To a solution of carboxylic acid (1 mmol) in anhydrous 1,2-dichloroethane (5 mL) in a 20 mL oven dried MW- vial under nitrogen atmosphere at room temperature, BOP-Cl (1.5 mmol) was added followed by the addition of triethylamine (3 mmol), followed by the addition of corresponding amine (1 mmol), and the MW-vial was placed in Biotage-Microwave system for 2 hours at 85 °C. After completion of the reaction. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4 filtered, and evaporated to dryness under reduced pressure to give a residue, followed by purification using pre-packed Silica gel column on ISCO gave the pure product. [000155] Synthesis of 2-oxo-N-(6-(trifluoromethoxy)pyridin-2-yl)-2H-chromene- 3-carboxamide (M7): This compound was synthesized by using the Microwave mediated BOP-Cl Coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-0.4% MeOH in CH2Cl2, 30 min) to give the title compound as a white powder (22.5 mg, 23%).1H NMR (400 MHz, CDCl3) ) 8.92 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.74 – 7.60 (m, 2H), 7.43 – 7.30 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 161.12, 160.00, 154.74, 149.60, 149.54, 142.16, 134.82, 130.07, 125.53, 121.32, 118.72, 118.50, 117.98, 116.89, 112.20, 108.51, 108.49. HR-ESIMS: Exact m / z349.0444 [M-H] calc-d. for C16H7F3N2O4, found 349.0453. HPLC Purity = 99.9% (Retention Time = 16.57 min). [000156] Synthesis of: N-(1-cyanocyclopropyl)-2-oxo-2H-chromene-3- carboxamide (M18): This compound was synthesized by using the Microwave mediated BOP- Cl Coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-60% EtOAc in Hexanes, 36 min) to give the title compound as a white powder (40 mg, 50%).1H NMR (400 MHz, CDCl3) ) 9.26 (s, 1H), 8.95 (s, 1H), 7.72 (ddd, J = 11.2, 7.2, 1.8 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 1.69 – 1.64 (m, 2H), 1.41 – 1.33 (m, 2H).13C NMR (101 MHz, cdcl3) ) 162.55, 161.35, 154.59, 149.67, 134.83, 130.13, 125.62, 119.65, 118.36, 117.29, 116.80, 29.69, 20.67, 16.87. HR-ESIMS: Exact m / z 255.0764 [M+H]+calcd. for C14H10N2O3, found 255.0756. HPLC Purity = 99.9% (Retention Time = 9.566 min). [000157] Synthesis of N-(6-cyanopyridin-2-yl)-5-hydroxy-4-oxo-4H-chromene-2- carboxamide (M39): This compound was synthesized by using the Microwave mediated BOP- Cl Coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-24% EtOAc in Hexanes, 23 min) to give the title compound as a yellow solid (28.4 mg, 29.8%).1H NMR (400 MHz, CDCl3) ) 12.15 (s, 1H), 9.25 (s, 1H), 8.64 (dd, J = 8.6, 0.8 Hz, 1H), 7.97 (dd, J = 8.6, 7.5 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.58 (dd, J = 7.5, 0.9 Hz, 1H), 7.23 (s, 1H), 7.11 (dd, J = 8.5, 0.9 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 183.21, 161.04, 157.06, 155.23, 154.00, 150.98, 140.04, 136.83, 131.93, 125.55, 118.38, 116.44, 112.90, 112.17, 111.48, 107.20. HR-ESIMS: Exact m / z 306.0520 [M-H]- calc-d. for C16H9N3O4,found 306.0570. HPLC Purity = 99.9% (Retention Time = 12.80 min). Example 4 - T3P-mediated coupling method Scheme 6Scheme 7[000158] T3P-mediated coupling method: Carboxylic acid (1 mmol) was taken in an oven dried 50 mL round bottom flask which was equipped with a small stir bar, to this 5mL of anhydrous DMF was added under nitrogen atmosphere, followed by the addition of corresponding amine (1.1 mmol), DIPEA (5 mmol), and T3P 50% in DMF (1.5 mmol). The reaction mixture was stirred at room temperature for 4 hours to overnight. After completion of reaction monitored by TLC, reaction was quenched with 10 mL of ice-cold water, and the resultant precipitate was filtered through a Buchner funnel, further washed with 25 mL of water. The precipitate was then collected and purified by flash column chromatography. [000159] Synthesis of N-(6-cyanopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M4): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-60%EtOAc in Hexanes, 35 min) to give the title compound as a white, flakey solid (156 mg, 52%).1H NMR (400 MHz, CDCl3) ) 11.43 (s, 1H), 9.02 (d, J = 0.8 Hz, 1H), 8.63 (dd, J = 8.5, 0.9 Hz, 1H), 7.88 (ddd, J = 8.5, 7.4, 0.6 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.52 – 7.40 (m, 3H).13C NMR (101 MHz, CDCl3) ) 161.13, 160.31, 154.79, 152.17, 149.93, 139.24, 135.06, 132.02, 130.14, 125.63, 124.77, 118.58, 118.43, 117.70, 116.94, 116.78. HR-ESIMS: Exact m / z 292.0717 [M+H]+calcd. for C16H9N3O3,found 292.0713. HPLC Purity = 99.9% (Retention Time = 13.34 min). [000160] Synthesis of N-(2-cyanothiazol-5-yl)-2-oxo-2H-chromene-3- carboxamide (M23): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-0.5% MeOH in CH2Cl2, 30 min) to give the title compound as a yellow solid (84.3 mg, 24%).1H NMR (400 MHz, CDCl3) ) 9.02 (s, 1H), 7.91 (s, 1H), 7.80 – 7.75 (m, 3H), 7.50 – 7.43 (m, 2H). ESIMS: Exact m / z 296.0135 [M-H]- calcd. for C14H7N3O3S, found 296.018. [000161] Synthesis of N-(4-cyanopyrimidin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M24): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-44% EtOAc in Hexanes, 30 min) to give the title compound as a brown solid (46.8 mg, 27.5%).1H NMR (400 MHz, CDCl3) ) 9.04 (s, 1H), 8.89 (d, J = 4.8 Hz, 1H), 7.79 – 7.68 (m, 2H), 7.46 – 7.37 (m, 3H).13C NMR (101 MHz, CDCl3) ) 161.50, 160.65, 159.12, 157.98, 154.79, 150.78, 142.35, 135.26, 130.36, 125.74, 119.78, 118.47, 117.69, 116.92, 114.99. HR-ESIMS: Exact m / z 293.0669 [M+H]+calcd. for C15H8N4O3, found 293.06692. HPLC Purity = 99.9% (Retention Time = 10.48 min). [000162] Synthesis of N-(5,6-dibromopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M14): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-60% EtOAc in Hexanes, 30 min) to give the title compound as a white-orange solid (203 mg, 41.3%).1H NMR (400 MHz, CDCl3) ) 11.30 (s, 1H), 9.00 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.74 (t, J = 8.5 Hz, 2H), 7.44 (dd, J = 17.7, 8.5 Hz, 2H). HR-ESIMS: Exact m / z 422.8972 [M+H]+calcd. for C15H8Br2N2O3, found 424.8954. HPLC Purity = 99.9% (Retention Time = 17.44 min). [000163] Synthesis of N-((3s,5s,7s)-adamantan-1-yl)-2-oxo-2H-chromene-3- carboxamide (M17): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-38% EtOAc in Hexanes, 30 min) to give the title compound as a white solid (179 mg, 63.7%).1HNMR (400 MHz, CDCl3) ) 8.85 (d, J = 0.6 Hz, 1H), 8.65 (s, 1H), 7.71 – 7.58 (m, 2H), 7.42 – 7.33 (m, 2H), 2.19 – 2.07 (m, 9H), 1.78 – 1.64 (m, 6H).13C NMR (101 MHz, CDCl3) ) 161.63, 159.90, 154.34, 147.66, 133.71, 129.67, 125.15, 119.60, 118.76, 116.52, 52.30, 41.38, 36.38, 29.42. HR-ESIMS: Exact m / z 346.1414 [M+Na] calcd. for C20H21NO3found 346.1430. HPLC Purity = 99.9% (Retention Time = 18.30 min). [000164] Synthesis of N-(6-bromopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M43) This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-65% EtOAc in Hexanes, 42 min) to give the title compound as a white-yellow solid (183 mg, 24.8%).1H NMR (400 MHz, CDCl3) ) 11.24 (s, 1H), 9.00 (s, 1H), 8.32 (dd, J = 8.1, 0.7 Hz, 1H), 7.79 – 7.68 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.28 (s, 1H). HR- ESIMS: Exact m / z 344.9867 [M+H]+calcd. for C15H10BrN2O3, found 344.9869. HPLC Purity = 99.9% (Retention Time = 15.53 min). [000165] Synthesis of N-(6-cyanopyridin-2-yl)chromane-3-carboxamide (M40) This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-50% EtOAc in Hexanes, 24 min) to give the title compound as a white solid (34 mg 14.46%). HR-ESIMS: Exact m / z 280.1041 [M+H] calcd. for C16H13N3O2found 280.098. HPLC Purity = 99.9% (Retention Time = 13.237 min). Scheme 8[000166] Synthesis of 6-cyano-N-(2-oxo-2H-chromen-3-yl)picolinamide (M2): This compound was synthesized by using the T3P-mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-45% EtOAc in Hexanes, 30 min) to give the title compound as a white solid (43.2 mg, 16.4%).1H NMR (400 MHz, CDCl3) ) 10.43 (s, 1H), 8.87 (s, 1H), 8.49 (dd, J = 8.0, 1.1 Hz, 1H), 8.12 (t, J = 7.9 Hz, 1H), 7.92 (dd, J = 7.7, 1.1 Hz, 1H), 7.57 (dd, J = 7.7, 1.6 Hz, 1H), 7.49 (ddd, J = 8.3, 7.3, 1.6 Hz, 1H), 7.41 – 7.31 (m, 2H).13C NMR (101 MHz, CDCl3) ) 161.38, 158.31, 150.47, 150.38, 139.19, 132.71, 131.23, 130.19, 127.97, 125.61, 125.22, 124.44, 123.61, 119.57, 116.56, 116.17. HR-ESIMS:Exact m / z 290.0571 [M-H]- calcd. for C16H9N3O3, found 290.0571. HPLC Purity = 99.9% (Retention Time = 13.753). Example 5 - Trimethyl aluminum mediated coupling method Scheme 9[000167] General Synthetic Procedure: Substituted aryl or heteroaryl amine (1 mmol) was taken in an oven dried 50 mL round bottom flask equipped with a small stir bar, to this 5 mL of anhydrous toluene was added using syringe under nitrogen atmosphere, and at 0 °C 2M trimethyl aluminum solution (3 mmol) was added dropwise, reaction was allowed to continue at the same temperature for about 20 minutes after which corresponding ester (1.1 mmol) was added and the reaction stirred at reflux temperature for overnight. After completion of reaction monitored by TLC, excess of trimethyl aluminum was quenched by the dropwise addition of 5 mL MeOH at 0 °C, crude reaction mixture was concentrated under reduced pressure, diluted with 100 mL of water and then extracted with EtOAc ( 3 X 100 mL) combined organic layer was washed with brine (200 mL), organic layer was separated and dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure followed by purification. [000168] Synthesis of 6-chloro-N-(4-fluorophenyl)-2-oxo-2H-chromene-3- carboxamide (M35): This compound was synthesized by using the Trimethyl aluminum mediated coupling method. Purification on pre-packed silica gel column using Teledyne Iscosystem (0-10% EtOAc in Hexanes, 30 min) to give the title compound as an orange solid (18.7 mg, 12%).1H NMR (400 MHz, CDCl3) ) 13.10 (s, 1H), 8.52 (s, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.34 – 7.31 (m, 1H), 7.29 – 7.23 (m, 2H), 7.16 – 7.09 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 163.12, 161.03, 161.02, 160.67, 159.56, 144.11, 144.08, 132.98, 131.21, 123.74, 122.73, 122.64, 119.83, 118.85, 116.47, 116.24. HR-ESIMS: Exact m / z 318.0328 [M+H]+calc-d. for C16H9ClFN3O3, found 318.0327. HPLC Purity = 99.9% (Retention Time = 17.83 min). [000169] Synthesis of 6-chloro-N-(3-fluorophenyl)-2-oxo-2H-chromene-3- carboxamide (M36): This compound was synthesized by using Trimethyl aluminum mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0- 10% EtOAc in Hexanes, 30 min) to give the title compound as an orange solid (29.1 mg, 18.8%).1H NMR (400 MHz, CDCl3) ) 12.93 (s, 1H), 8.54 (s, 1H), 7.45 – 7.30 (m, 3H), 7.09 – 6.96 (m, 4H).13C NMR (101 MHz, CDCl3) ) 164.57, 162.31, 162.11, 159.67, 149.79, 149.70, 133.36, 131.43, 130.77, 130.68, 123.83, 119.65, 118.94, 117.13, 117.10, 114.22, 114.01, 108.56, 108.33. HR-ESIMS: Exact m / z 318.0328 [M+H]+calcd. for C16H9ClFN3O3, found 318.0327. HPLC Purity = 99.9% (Retention Time = 17.97 min). [000170] Synthesis of N-(6-cyanopyridin-2-yl)-4-oxo-1,4-dihydroquinazoline-2- carboxamide (M38): This compound was synthesized by using the Trimethyl aluminum mediated coupling method. Purification on pre-packed silica gel column using Teledyne Isco system (0-58% EtOAc in Hexanes, 58 min) to give the title compound as a cream-colored solid (56.2 mg, 23.4%).1H NMR (400 MHz, CDCl3) ) 8.59 (dd, J = 8.5, 0.9 Hz, 1H), 8.34 (dt, J = 7.9, 1.1 Hz, 1H), 7.94 (dd, J = 8.6, 7.5 Hz, 1H), 7.89 – 7.85 (m, 2H), 7.66 – 7.60 (m, 1H), 7.54 (dd, J = 7.4, 0.9 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 157.72, 150.97, 146.77, 139.86, 135.31, 131.96, 129.33, 128.49, 126.96, 125.25, 122.95, 117.87, 116.52. HR-ESIMS: Exact m / z 290.0683 [M-H]- calcd for C15H9N5O2, found 290.0690. HPLC Purity = 99.9% (Retention Time = 10.93 min). Scheme 10[000171] Synthesis of 2-oxo-N-(2,2,2-trifluoroethyl)-2H-chromene-3- carboxamide (M19): 2-oxo-2H-chromene-3-carboxylic acid (100 mg, 0.526 mmol) was taken in an oven dried 50 mL round bottom flask equipped with a small stir bar, to this 5 mL of anhydrous DMF was added under nitrogen atmosphere followed by the addition of COMU (337.5 mg, 0.788 mmol) and DIPEA (0.274 mL, 1.577 mmol) were added The reaction was stirred at room temperature for 5 minutes. Then 2,2,2-trifluoroethan-1-amine (52.07 mg, 0.526) was added. and the reaction stirred at room temperature overnight. After completion of reaction monitored by TLC, reaction mixture was diluted with 50 mL of ice-cold water followed by extraction with EtOAc (3 X 50 mL) combined organic layer was washed with brine (100 mL), organic layer was separated and dried over anhydrous Na2SO4, concentrated under reduced pressure followed by purification on pre-packed silica gel column using Teledyne Isco system (0-0.4% MeOH in CH2Cl2, 30 min) to give the title compound as a white solid (30.5 mg, 18%).1H NMR (400 MHz, CDCl3) ) 8.92 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.72 – 7.62 (m, 2H), 7.42 – 7.31 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 162.40, 161.37, 154.47, 149.74, 134.78, 130.07, 128.08, 125.55, 125.31, 122.54, 118.30, 117.10, 116.64. HR-ESIMS: Exact m / z 272.0529 [M+H]+calc-d. for C12H8F3NO3 found 272.0529. HPLC Purity = 99.9% (Retention Time = 11.984 min). Scheme 11[000172] Synthesis of N-(6-cyanopyridin-2-yl)-2-imino-2H-chromene-3- carboxamide (M37): Step.1: 6-aminopicolinonitrile (400 mg, 3.36 mmol) was taken in an oven dried 100 mL round bottom flask with a magnetic stir bar, to this 15 mL of anhydrous toluene was added, followed by the addition of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile (548 mg, 3.36) and then flask was sealed with water condenser, rubber septum and nitrogen balloon, reflux for 6 hours. Once the first reaction ran to completion, the material was filtered through a Buchner funnel and washed with 50 mL of hexanes. Once material was dried, it was used for the second step reaction to form the coumarin ring through Knoevenagel condensation.Step.2 in a dry 50 mL round bottom flask with a magnetic stir bar, 0.885 mmol 2-cyano-N-(6- cyanopyridin-2-yl)acetamide (165 mg, 0.885 mmol) was taken up and dissolved in 5 mL absolute Ethanol, followed by the addition of salicylaldehyde (108 mg, 0.885 mmol) and 5 drops of piperidine with a syringe. Reaction was stirred at room temperature for overnight. After completion of reaction monitored by TLC, the crude product was filtered through silica funnel coupled to vacuum to remove solids and material was washed with 50 mL ethyl acetate. Filtrate was transferred to a 250 mL separatory funnel, diluted with 100 mL water and extracted with EtOAc (3 X 100 mL). The combined organic layer was washed with brine. The organic layer was dried over anhydrous Na2SO4filtered, concentrated under reduced pressure followed by purification on a pre-packed silica gel column using Teledyne Isco system (0-28% EtOAc in Hexanes, 30 min) to give the title compound as an off-white solid (14.7 mg, 5.3%).P1H NMR (400 MHz, CDCl3) ) 13.33 (s, 1H), 8.64 (dd, J = 8.6, 0.9 Hz, 1H), 8.57 (dd, J = 1.8, 0.7 Hz, 1H), 7.91 – 7.80 (m, 2H), 7.58 – 7.49 (m, 2H), 7.45 (dd, J = 7.4, 0.9 Hz, 1H), 7.24 (dd, J = 7.5, 1.1 Hz, 1H), 7.18 (dd, J = 8.1, 1.0 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 161.13, 157.08, 154.09, 152.88, 143.23, 139.06, 133.52, 131.96, 129.83, 124.46, 124.36, 119.80, 118.64, 118.54, 116.95, 115.55. HR-ESIMS: Exact m / z 289.0731[M-H]- calcd. for C16H10N4O2, found 289.073. Example 6 - General Synthetic Procedure Scheme 12[000173] Step 1. (trans cyanoacetamidation): Aryl or heteroaryl amine (1 mmol) was taken in an oven dried 100 mL round bottom flask with a magnetic stir bar, to which 15 mL of anhydrous toluene was added using syringe, followed by the addition of 3-(3,5-dimethyl- 1H-pyrazol-1-yl)-3-oxopropanenitrile (1 mmol) and the reaction reflux for 6 hours. After completion of reaction monitored by TLC, the material was filtered through a Buchner funnel coupled to a vacuum pump and washed with 50 mL of hexanes. Once material was dried, it was used for the second step to form the coumarin ring through Knoevenagel condensation. [000174] Step 2. (Knoevenagel condensation): The product of first step which was substituted cyanoacetamide intermediate compound (1 mmol) was placed in an oven dried 100 mL round bottom flask with a magnetic stir bar, to this 15 mL glacial acetic acid was added. The flask was sealed with water condenser, rubber septum and nitrogen balloon. The reaction stirred in oil bath as sodium acetate was added as 3 / 4thof the weight of the starting material. Followed by the addition of appropriate salicylaldehyde, and the reaction reflux for overnight. After completion of reaction, the material was filtered through a Buchner funnelcoupled to a vacuum pump and washed with 50 mL of hexanes. The crude solid material was collected and purified by flash column chromatography. [000175] Synthesis of N-(5-cyanopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M5): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-0.2% MeOH in CH2Cl2, 30 min) to give the title compound as a white solid (32.5 mg, 39%).1H NMR (400 MHz, CDCl3) ) 8.97 (d, J = 0.6 Hz, 1H), 8.60 (dd, J = 2.3, 0.9 Hz, 1H), 8.44 (dd, J = 8.7, 0.9 Hz, 1H), 7.96 (dd, J = 8.7, 2.3 Hz, 1H), 7.77 – 7.65 (m, 2H), 7.47 – 7.32 (m, 2H).13C NMR (101 MHz, CDCl3) ) 161.23, 160.31, 154.80, 153.66, 151.94, 150.17, 141.57, 135.20, 130.21, 125.71, 118.41, 117.59, 116.94, 116.83, 114.35, 105.45, 77.21. HR-ESIMS: Exact m / z 292.0717 [M+H]+calcd. for C16H9N3O3, found 292.0574. HPLC Purity = 99.9% (Retention Time = 13.02 min). [000176] Synthesis of N-(4-cyanopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M6): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on ACCQ-PrepHP-150 reverse- phase column (0-95% ACN in water, 65 min) to give the title compound as a cream-colored solid (37.6 mg, 15%).1H NMR (400 MHz, CDCl3) ) 11.50 (s, 1H), 9.04 (d, J = 0.7 Hz, 1H), 8.69 (t, J = 1.1 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H), 7.81 – 7.71 (m, 2H), 7.50 – 7.42 (m, 2H), 7.31 (dd, J = 5.0, 1.4 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 161.24, 160.23, 154.77, 151.94, 150.02, 149.49, 135.07, 130.21, 125.67, 122.26, 121.52, 118.45, 117.63, 116.89, 116.64, 116.60. HR-ESIMS: Exact m / z 292.0717 [M+H]+calc-d. for C16H9N3O3,found 290.057. HPLC Purity = 99.9% (Retention Time = 13.188 min). [000177] Synthesis of Methyl 6-(2-oxo-2H-chromene-3-carboxamido)picolinate (M8): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on ACCQ-PrepHP-150 reverse-phase column (0-95% ACN in water, 65 min) to give the title compound as a cream-colored solid (37.6 mg, 15%).1H NMR (400 MHz, CDCl3) ) 11.33 (s, 1H), 9.01 (d, J = 0.7 Hz, 1H), 8.57 (dd, J = 6.9, 2.4 Hz, 1H), 7.98 – 7.84 (m, 2H), 7.78 – 7.67 (m, 2H), 7.52 – 7.38 (m, 2H), 4.01 (s, 3H).13C NMR (101 MHz, CDCl3) ) 165.37, 160.93, 160.25, 154.77, 151.12, 149.59, 146.58, 139.22, 134.77, 130.05, 125.48, 121.60, 118.72, 118.52, 118.07, 116.87, 52.88. HR-ESIMS: Exact m / z 325.0819 [M+H]+calcd. for C17H12N2O5,found 325.0819. HPLC Purity = 99.9% (Retention Time = 12.7 min). [000178] Synthesis of N-(3-cyanophenyl)-2-oxo-2H-chromene-3-carboxamide (M20): This compound was synthesized by using the method described in Step 1 and Step 2 ofExample 6 above. Purification on pre-packed silica gel column using Teledyne Isco system (0- 2% MeOH in CH2Cl2, 30 min) to give the title compound as a yellow solid (117.4 mg, 47%).1H NMR (400 MHz, CDCl3) ) 9.02 (d, J = 0.7 Hz, 1H), 8.24 (ddd, J = 2.2, 1.4, 0.6 Hz, 1H), 7.82 (ddd, J = 7.8, 2.3, 1.6 Hz, 1H), 7.79 – 7.68 (m, 2H), 7.51 – 7.39 (m, 4H). HR-ESIMS: Exact m / z 291.0764 [M+H]+calcd. for C17H10N2O3, found 291.0764. HPLC Purity 99.9% (Retention Time = 13.62 min). [000179] Synthesis of N-(6-cyanopyridin-2-yl)-6-nitro-2-oxo-2H-chromene-3- carboxamide (M25): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-0.2% MeOH in CH2Cl2, 30 min) to give the title compound as an off-white solid (95.2 mg, 35.8%).1H NMR (400 MHz, CDC l3) ) 9.21 (s, 1H), 8.85 (d, J = 2.7 Hz, 1H), 8.74 – 8.66 (m, 2H), 8.05 (dd, J = 8.6, 7.5 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 7.5, 0.9 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 159.67, 159.00, 157.67, 151.79, 148.52, 144.75, 139.45, 132.10, 129.11, 125.71, 125.10, 120.02, 118.62, 118.34, 118.29, 117.64, 116.63. Exact m / z 335.0425 [M-H]- calc-d. for C16H7N4O5, found 335.0420. HPLC Purity = 95.23% (Retention Time = 13.165 min). [000180] Synthesis of N-(6-nitropyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M11): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-0.2% MeOH in CH2Cl2, 30 min) to give the title compound as a white solid (31.8 mg, 19.3%).1H NMR (400 MHz, CDCl3) ) 11.48 (s, 1H), 9.03 (s, 1H), 8.76 (dd, J = 8.1, 0.9 Hz, 1H), 8.07 (t, J = 8.0 Hz, 1H), 8.01 (dd, J = 7.9, 0.9 Hz, 1H), 7.75 (t, J = 7.9 Hz, 2H), 7.53 – 7.41 (m, 2H).13C NMR (101 MHz, CDCl3) ) 161.02, 160.54, 154.83, 150.39, 150.05, 141.78, 135.12, 130.16, 125.63, 120.25, 118.42, 117.59, 116.97, 113.61, 77.20. HR-ESIMS: Exact m / z 310.0472 [M-H] calc-d. for C15H9N3O5, found 310.0478. HPLC Purity: 98.6% (Retention Time = 13.4 min). [000181] Synthesis of N-(6-cyanopyridin-2-yl)-8-methoxy-2-oxo-2H-chromene- 3-carboxamide (M27): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-0.6% MeOH in CH2Cl2, 30 min) to give the title compound as a yellow solid (144.9 mg, 52.8%).1H NMR (400 MHz, CDCl3) ) 11.43 (s, 1H), 8.99 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.25 (s, 1H), 4.02 (s, 3H). HR-ESIMS: Exact m / z 320.0676 [M-H]- calcd. for C17H11N3O4,found 320.068.[000182] Synthesis of N-(4-bromopyrimidin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M21): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-0.6% MeOH in CH2Cl2, 30 min) to give the title compound as a yellow solid (170.2 mg, 56.5%).1H NMR (400 MHz, CDCl3) ) 8.92 (d, J = 0.7 Hz, 1H), 8.23 (dd, J = 8.2, 0.7 Hz, 1H), 7.74 – 7.62 (m, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.21 (dd, J = 7.7, 0.7 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 161.03, 159.95, 154.73, 151.14, 149.63, 140.37, 139.73, 134.83, 130.06, 125.52, 124.23, 118.49, 117.94, 116.87, 113.32, 77.21. HR-ESIMS: Exact m / z 345.9819 [M+H]+calcd for C14H8BrN3O3, found 345.9821. [000183] Synthesis of N-(5-cyanothiophen-2-yl)-2-oxo-2H-chromene-3- carboxamide (M22): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification on pre-packed silica gel column using Teledyne Isco system (0-40% EtOAc in Hexanes, 30 min) to give the title compound as a yellow solid (26.7 mg, 10.8%).1H NMR (400 MHz, DMSO-d6) ) 8.95 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.82 – 7.74 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 4.3 Hz, 1H). HR-ESIMS: Exact m / z 295.0182 [M-H]- calcd. for C15H8N2O3S, found 295.0183. HPLC Purity = 99.9% (Retention Time = 13.36 min). [000184] Synthesis of N-(6-cyanopyridin-2-yl)-5-methoxy-2-oxo-2H-chromene- 3-carboxamide (M31): This compound was synthesized by using the method described in Step 1 and Step 2 of Example 6 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-40% EtOAc in Hexanes, 30 min) to give the title compound as an off-white solid (78.3 mg, 8.7%).1H NMR (400 MHz, CDCl3) ) 11.41 (s, 1H), 9.37 (p, J = 1.1 Hz, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.64 (td, J = 8.3, 1.2 Hz, 1H), 7.47 (dd, J = 7.4, 0.9 Hz, 1H), 7.01 (dt, J = 8.4, 0.8 Hz, 1H), 6.82 – 6.78 (m, 1H), 4.00 (d, J = 1.3 Hz, 3H).13C NMR (101 MHz, CDCl3) ) 161.27, 160.66, 157.88, 155.71, 152.36, 145.49, 139.16, 136.05, 131.96, 124.59, 118.54, 116.83, 115.41, 109.78, 108.83, 105.93, 56.32. HR- ESIMS: Exact m / z 322.0822 [M+H]+calcd. for C17H11N3O4. found 322.08223. Scheme 13[000185] Synthesis of N-(6-(1H-tetrazol-5-yl)pyridin-2-yl)-2-oxo-2H-chromene- 3-carboxamide (M10): N-(6-cyanopyridin-2-yl)-2-oxo-2H-chromene-3-carboxamide 150 mg, 0.515mmol) was taken in a 20 mL microwave vial with a small magnetic stir bar, to this 2 mL of anhydrous DMF was added followed by the addition of ammonium chloride (55 mg,1.03mmol), Sodium Azide (67 mg, 1.03mmol). The reaction was sealed and stirred at 130 °C in an oil bath for four days. After completion of reaction monitored by TLC, reaction was cooled down to room temperature, diluted with 50 mL of ice cold water and then extracted with EtOAc (3 X 50 mL), combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure followed by purification on ACCQ-PrepHP-150 reverse- phase column (0-67% ACN in water, 40 min) to give the title compound as an off-white solid (27 mg, 13.17%).1H NMR (400 MHz, DMSO-d6) ) 11.30 (s, 1H), 9.13 (s, 1H), 8.51 – 8.45 (m, 1H), 8.15 (t, J = 8.0 Hz, 1H), 8.08 (dd, J = 7.7, 1.6 Hz, 1H), 8.00 (dd, J = 7.6, 0.9 Hz, 1H), 7.82 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.49 (td, J = 7.5, 1.1 Hz, 1H).13C NMR (101 MHz, DMSO-d6) ) 161.50, 160.72, 154.59, 151.69, 149.74, 141.15, 135.40, 131.19, 125.92, 119.45, 119.03, 116.78. HR-ESIMS: Exact m / z 333.0731 [M-H] calcd. for C16H10N6O3, found 333.0736. HPLC Purity = 99.9% (Retention Time = 1.66 min).[000186] Synthesis of N-(6-cyanopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide hydrochloride (M12): N-(6-cyanopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (0.27 mmol) was taken in an oven dried 50 mL round bottom flask equipped with a magnetic stir bar, to this 8 mL of anhydrous Chloroform:Methanol (4:1) was added. Reaction was sealed with rubber septum to this solution 1.25M HCl (0.539mmol) was added dropwise at 0 °C and the reaction stirred at the same temperature for about 3 hours, after the formation of precipitate reaction mass was concentrated under reduced pressure, this solid material was titrated with diethyl ether. The precipitate was dried on high vacuum to give the title compound as a white solid (73.8 mg, 94%).1H NMR (400 MHz, DMSO-d6) ) 11.33 (s, 1H), 9.03 (s, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.88 – 7.74 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H).13C NMR (101 MHz, DMSO-d6) )161.25, 161.02, 154.54, 152.27, 149.29, 141.20, 135.38, 131.29, 131.12, 125.92, 125.79, 118.99, 118.90, 118.66, 117.40, 116.80. HR-ESIMS: Exact m / z 328.0483 [M+H]+calcd. for C16H10ClN3O3, HPLC Purity = 99.9% (Retention Time = 13.35 min). Example 7 - BBr3-mediated demethylation Scheme 15[000187] General Synthetic Procedure: Methoxy substituted starting material (1 mmol) was taken in an oven dried 50 mL round bottom flask with a small magnetic stir bar, to this 10 mL of anhydrous CH2Cl2 was added using glass syringe under nitrogen atmosphere, and the reaction was stirred on ice bath, followed by the addition of neat BBr3(3 mmol). The reaction stirred on ice for 20 minutes, then room temperature overnight. The following morning, (3 mmol) more BBr3was added as reaction stirred on ice for 20 minutes, then ran at room temperature overnight. This process was repeated one more time. After the completion of reaction monitored by TLC. The flask was placed in an ice bath and quenched with 5mL Methanol (dropwise addition). After 30 minutes, crude reaction mixture was concentrated, diluted with DI-water (100 mL) followed the extraction with EtOAc (2 X 100 mL). Combined organic layer was washed with brine (100 mL), organic layer was separated and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure followed by purification. [000188] Synthesis of N-(6-cyanopyridin-2-yl)-8-hydroxy-2-oxo-2H-chromene-3- carboxamide (M26): This compound was synthesized by using the method described in the General Synthetic Procedure of Example 7 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-43% EtOAc in Hexanes, 38 min) to give the title compound as an off-white solid (14.3 mg, 15.8%).1H NMR (400 MHz, CDCl3) ) 8.98 –8.90 (m, 1H), 8.63 – 8.45 (m, 1H), 7.85 (qd, J = 4.0, 1.7 Hz, 2H), 7.24 – 7.17 (m, 3H). HR- ESIMS: Exact m / z 306.05202 [M-H]- calcd. for C16H10N3O4, found 306.052. [000189] Synthesis of N-(6-cyanopyridin-2-yl)-7-hydroxy-2-oxo-2H-chromene-3- carboxamide (M30): This compound was synthesized by using the method described in the General Synthetic Procedure of Example 7 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-46% EtOAc in Hexanes, 41 min) to give the title compound as an off-white solid (10.3 mg, 10 %).1H NMR (400 MHz, DMSO-d6) ) 11.33 (s, 1H), 9.02 (s, 1H), 8.54 (d, J = 8.6 Hz, 1H), 8.16 – 8.08 (m, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.86 – 7.78 (m, 1H), 7.19 (d, J = 2.4 Hz, 2H), 7.09 (dd, J = 8.8, 2.4 Hz, 1H). HR-ESIMS: Exact m / z 308.0666 [M+H]+calcd. for C16H10N3O4. Found 306.0742. HPLC Purity = 96.5% (Retention Time = 11.463 min). [000190] Synthesis of N-(6-cyanopyridin-2-yl)-5-hydroxy-2-oxo-2H-chromene-3- carboxamide (M32): This compound was synthesized by using the method described in the General Synthetic Procedure of Example 7 above. Purification was carried out with reverse phase HPLC with 43% ACN in Water (22 minutes) to give the title compound as a yellow- green solid (19.3mg, 20.2%).1H NMR (400 MHz, DMSO-d6) ) 11.41 (s, OH), 11.16 (s, 1H), 9.07 (s, 1H), 8.43 (dd, J = 8.3, 0.9 Hz, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.79 (dd, J = 7.6, 1.0 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.60 (t, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 8.2, 0.9 Hz, 1H).13C NMR (101 MHz, DMSO-d6) ) 165.92, 161.47, 160.80, 157.28, 155.58, 150.27, 149.77, 144.41, 140.55, 136.66, 118.67, 116.92, 115.70, 111.17, 108.95, 106.93. HR- ESIMS: Exact m / z 308.0663 [M+H]+calcd. for C16H10N3O4,found 308.0663. HPLC Purity = 99% (Retention Time = 8.58 min). Example 8 – Pd / C mediated reduction Scheme 16[000191] General Synthetic Procedure: Nitro substituted starting material (1 mmol) was taken in an oven dried 50 mL round bottom flask with a magnetic stir bar. To this 5 mL of Ethanol was added, followed by 10% Palladium on Carbon (0.188 mmol), The reaction was sealed with a rubber septum and allowed to stir at room temperature under a H2-balloon for 3 hours. After completion of the reaction monitored by TLC, excess of catalyst was quenched by adding 2 mL of CH2Cl2, then filtered through a short pad of celite, and the filtrate was concentrated under reduced pressure, followed by purification. [000192] Synthesis of N-(6-cyanopyridin-2-yl)-6-nitro-2-oxo-2H-chromene-3- carboxamide (M28): This compound was synthesized according to the General Synthetic Procedure provided for Example 8 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-68% EtOAc in Hexanes, 40 min) to give the title compound as a red-brown solid (23.2 mg, 24.4 %).1H NMR (400 MHz, CDCl3) ) 8.98 (s, 1H), 8.69 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 5.22 (s, 2H). HR-ESIMS: Exact m / z 305.06801 [M-H]- calc-d. for C16H10N4O3, found 305.068. HPLC Purity = 99.9% (Retention Time = 10.99 min). [000193] Synthesis of N-(6-aminopyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M44) This compound was synthesized according to the General Synthetic Procedure provided for Example 8 above. Purification was carried out on pre-packed silica gel column using Teledyne Isco system (0-86% EtOAc in Hexanes with 0.1% Triethylamine, 36 min) to give the title compound as a yellow solid (12.3 mg, 9.1%).1H NMR (400 MHz, DMSO- d6) ) 10.80 (s, 1H), 9.01 (s, 1H), 7.77 (ddd, J = 8.8, 7.3, 1.6 Hz, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.45 (td, J = 7.8, 3.7 Hz, 3H), 7.35 (d, J = 7.8 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H). HR-ESIMS: Exact m / z 282.0870 [M+H]+calcd. for C15H11N3O3, found 281.0861. HPLC Purity = 99.9% (Retention Time = 10.23 min). Example 9 – Additional Synthetic Procedures Scheme 17[000194] Synthesis of N-(6-hydrazineylpyridin-2-yl)-2-oxo-2H-chromene-3- carboxamide (M45): N-(6-bromopyridin-2-yl)-2-oxo-2H-chromene-3-carboxamide (100mg,(0.279 mmol), was taken in an oven dried 50 mL round bottom flask with a magnetic stir bar to this 5 mL of 1,4 Dioxane and 70.5 µL of Hydrazine Hydrate (1.45 mmol). The flask was sealed with a water condenser, rubber septum, and nitrogen balloon and stirred in an oil bath at reflux overnight. After completion of reaction monitored by TLC, reaction mixture was diluted with 50 mL of ice-cold water followed by extraction with EtOAc (3 X 50 mL) combined organic layer was washed with brine (100 mL), organic layer was separated and dried over anhydrous Na2SO4,concentrated under reduced pressure followed by purification on pre- packed silica gel column using Teledyne Isco system (0-54% EtOAc in Hexanes, 24 min) to give the title compound as a yellow solid (10.4 mg, 12.6 %).1H NMR (400 MHz, CDCl3) ) 10.77 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.17 (dd, J = 7.8, 1.6 Hz, 1H), 6.99 (dd, J = 8.3, 1.1 Hz, 1H), 6.90 (td, J = 7.5, 1.1 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 6.06 (d, J = 7.9 Hz, 1H), 4.30 (s, 2H).13C NMR (101 MHz, CDCl3) ) 157.32, 157.19, 154.30, 142.22, 140.25, 130.32, 129.67, 119.48, 118.28, 116.64, 100.60, 95.78, 77.21. Exact m / z 297.0979 [M+H]+calcd. for C15H13N4O3, found 297.0936. HPLC Purity = 99.9% Retention Time = 6.35 min. Scheme 18[000195] Synthesis of 6-((2-oxo-2H-chromen-3-yl)amino)picolinonitrile (M41): 6-bromopicolinonitrile (200 mg, 1.09 mmol) was taken in an oven dried 50 mL round bottom flask with a magnetic stir bar to this 10 mL Toluene was added, followed by the addition of 3- amino-2H-chromen-2-one (211 mg, 1.31 mmol), Cesium Carbonate (497.2 mg, 1.53 mmol), BINAP (54.3 mg, 0.087 mmol), and Palladium Acetate (12.23 mg, 0.05 mmol). Reaction was sealed with a rubber septum and allowed to stir at reflux temperature under a H2-balloon for 20 hours. After completion of reaction monitored by TLC, the crude material was filtered through a short pad of celite, and the filtrate was concentrated under reduced pressure followed by purification on pre-packed neutral aluminum column using Teledyne Isco system (0-31% EtOAc in Hexanes, 12 min) to give the title compound as a white solid (23 mg, 8%).1H NMR (400 MHz, CDCl3) ) 8.85 (s, 1H), 7.77 (s, 1H), 7.68 (dd, J = 8.5, 7.3 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.42 (ddd, J = 8.3, 6.9, 1.6 Hz, 1H), 7.33 (ddd, J = 8.3, 7.5, 1.2 Hz, 2H), 7.29 (dd, J = 7.3, 0.8 Hz, 1H), 7.01 (dd, J = 8.5, 0.8 Hz, 1H).13C NMR (101 MHz, CDCl3) ) 159.62, 154.75, 149.08, 137.97, 131.09, 128.64, 127.57, 125.19, 124.99, 121.33, 120.47, 119.37, 117.46,116.36, 116.20. Exact m / z 264.0765 [M+H]+calcd. for C15H10N3O2, found 264.0767. HPLC Purity = 99.9% (Retention Time 17.54 min).Example 10 – Biological Activity Table 2: Biological Activity Data for Exemplary Compounds M1-M45Table 3: Permeability Results of Test Compounds in MDCK- MDR1 CellsTable 3 shows the results of analyzing the permeability of a compound of the present disclosure (M4). Human Liver Microsomes and Mouse Liver Microsomes were used to acquire the efflux ratio of M4. An efflux ratio of 1 indicates sufficient permeability, which is necessary for a compound that must bypass the blood brain barrier, a characteristic which is in turn essential for drug delivery to the central nervous system.References Anderson, Practical Process Research & Development – A Guide for Organic Chemists, 2nded., Academic Press, New York, (2012). Ahmed et al., Acta Neuropathologica 126(4):537-544 (2013). Casals et al., J Neural Transm (Vienna) 105(6-7):645-76 (1998). Chang et al., Journal of Biomedical Science 25:54 (2018). 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Irwin, Parkinsonism Relat Disord.22(1):29-33 (2016). Kovacs et al., Acta Neuropathologica 131(1):87-102 (2016). Lannuzel et al., Brain 130(3):816-827 (2007). Las Heras et al., npj Genomic Medicine 8:21 (2023). Lefebvre et al., Rev Neurol (Paris) 175(10):641-643 (2019). Liu et al., RSC Adv., 7:6046–6058 (2017). Luo et al., Clinical case reports, 12(1):e8310 (2024). Marrakchi et al., Radiology Case Reports 19(6):2264-2267 (2024). Morris et al., Arch Neurol.58(11):1813-1816 (2001). Noda et al., Neuropathology 26(6):508-518 (2006). Pradeep et al., Neurology 94(13):1445-1447 (2020).Reagan-Shaw et al., FASEB J., 22(3):659-661 (2008). Reitz et al., Nat. Rev. Neurol., 7:137–152 (2011). Rodriguez and Grinberg, Dement Neuropsychol 9(1):2-8 (2015). Roos et al., Ornaphet Journal of Rare Diseases 5:40 (2010). Sanders et al., Neuron 82(6): 1271-1288 (2014). Seidler et al., Nat. Commun.13:5451 (2022). Smith et al., Nature Reviews Neurology, 15:179-183 (2019). 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Claims

What Is Claimed Is:

1. A compound of the formula:wherein: R1, R2, R3, R4 and R12 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X1 and X2 are each independently −NH−, −NCH3− or −C(O)−, provided X1 and X2 are not both-C(O)-;Y is O or NH; Z is a group of the formula:, wherein: R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or−C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2is not −NH− when R5is alkyl(C≤8); and R6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3 is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; oralkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is further defined as:wherein: R1, R2, R3and R4are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; X1 and X2 are each independently−NH−, −NCH3− or −C(O)−, provided X1 and X2are not both-C(O)-;Y is O or NH;Z is a group of the formula:, wherein: R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8),heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11 and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

3. The compound of either claim 1 or claim 2, wherein the compound is further defined as:wherein: R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12),heteroaralkyl(C≤12), or a substituted version of any of these groups; X1and X2are each independently −NH−, −NCH3− or −C(O)−, provided X1and X2 are not both-C(O)-;Z is a group of the formula:, wherein: R5is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups, provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12),heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11 and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein the compound is further defined as:wherein: R1, R2, R3and R4are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; Z is a group of the formula:, wherein: R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; and provided X2is not −NH− when R5is alkyl(C≤8); andR6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-3, wherein the compound is further defined as:wherein: R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; Z is a group of the formula:, wherein: R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9is hydrogen, hydroxy, halo, amino, or mercapto; oralkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), hetero- cycloalkyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; provided X2is not −NH− when R5is alkyl(C≤8); and R6, R7, and R8are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10 and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a group of the formula:, wherein: X3 is absent, −N− or −S−; and X4 and X5 are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−,wherein R11 and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12),aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-3 and 5, wherein the compound is further defined as:wherein: R1, R2, R3and R4are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; R5 is cyano, hydroxy, amino, mercapto, hydrazinyl, nitro; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), arylamino(C≤12), diarylamino(C≤12), or a substituted version of any of these groups; or −C(O)R9, wherein R9 is hydrogen, hydroxy, halo, amino, or mercapto; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), aryl(C≤8), aralkyl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8),alkoxy(C≤8), alkylamino(C≤8), cycloalkylamino(C≤8), dialkylamino(C≤8), arylamino(C≤8), or a substituted version of any of these groups; provided X2 is not −NH− when R5 is alkyl(C≤8); and R6, R7, and R8 are each independently hydrogen, halo, cyano, hydroxy, amino, nitro or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or −NR10R10', wherein R10and R10' are each independently: hydrogen; or alkyl(C≤8), cycloalkyl(C≤8), alkenyl(C≤8), alkynyl(C≤8), acyl(C≤12), aryl(C≤8), heteroaryl(C≤8), heterocycloalkyl(C≤8), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1-3 and 5, wherein the compound is further defined as:wherein: R1, R2, R3 and R4 are each independently hydrogen, halo, cyano, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12),heteroaralkyl(C≤12), or a substituted version of any of these groups; X3is absent, −N− or −S−; and X4and X5are each independently absent, −N−, −NH−, −O− or −S−; or −CR11R11'−, wherein R11 and R11' are each independently: absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-7, wherein R1is hydrogen, hydroxy or alkoxy(C≤12).

9. The compound of claim 8, wherein R1 is hydrogen.

10. The compound according to any one of claims 1-9, wherein R2 is hydrogen, hydroxy, nitro or amino.

11. The compound of claim 10, wherein R2is hydrogen.

12. The compound of claim 10, wherein R2 is nitro.

13. The compound of claim 10, wherein R2is hydroxy.

14. The compound according to any one of claims 1-13, wherein R3 is hydrogen, halo, hydroxy or amino.

15. The compound of claim 14, wherein R3 is halo.

16. The compound of claim 15, wherein R3is chloro.

17. The compound of claim 14, wherein R3 is hydrogen.

18. The compound of claim 14, wherein R3is hydroxy.

19. The compound of claim 14, wherein R3is amino.

20. The compound according to any one of claims 1-19, wherein R4 is hydrogen, hydroxy or alkoxy(C≤12).

21. The compound of claim 20, wherein R4 is hydrogen.

22. The compound of claim 20, wherein R4is alkoxy(C≤12).

23. The compound of claim 22, wherein R4 is methoxy.

24. The compound of claim 1, wherein R12 is hydrogen or hydroxy.

25. The compound according to any one of claims 1-3, wherein X1is −NH− and X2is −C(O)−.

26. The compound according to any one of claims 1-3, wherein X1 is −C(O)− and X2 is −NH−.

27. The compound according to any one of claims 1-3, wherein X1 is −C(O)− and X2 is −NCH3−.

28. The compound according to either claim 1 or claim 2, wherein Y is O.

29. The compound according to any one of claims 1-5 and 8-28, wherein Z is a group of the formula:.

30. The compound according to any one of claims 1-5 and 8-28, wherein Z is a group of the formula:.

31. The compound according to any one of claims 1-6 and 8-29, wherein R5is cyano, nitro, alkyl(C≤12), substituted alkyl(C≤12), alkoxy(C≤12), substituted alkoxy(C≤12)or heteroaryl(C≤12).

32. The compound of claim 31, wherein R5 is cyano.

33. The compound of claim 31, wherein R5is alkyl(C≤12)or substituted alkyl(C≤12).

34. The compound of claim 33, wherein R5is substituted alkyl(C≤12).

35. The compound of claim 34, wherein R5 is −CF3.

36. The compound of claim 31, wherein R5 is heteroaryl(C≤12).

37. The compound of claim 36, wherein R5is 1H-tetrazol-5-yl.

38. The compound according to any one of claims 1-6 and 8-29, wherein R5 is −C(O)R9, wherein R9is hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8).

39. The compound of claim 38, wherein R5is hydroxy, hydrazinyl, or amino.

40. The compound according to any one of claims 1-6 and 8-39, wherein R6 is hydrogen or halo.

41. The compound of claim 40, wherein R6 is hydrogen.

42. The compound of claim 40, wherein R6is fluoro.

43. The compound according to any one of claims 1-6 and 8-42, wherein R7 is hydrogen.

44. The compound according to any one of claims 1-6 and 8-43, wherein R8is hydrogen.

45. The compound according to any one of claims 1-5, 7-28 and 30, wherein X3 is −N−.

46. The compound according to any one of claims 1-5, 7-28 and 30, wherein X3 is −S−.

47. The compound according to any one of claims 1-5, 7-28 and 30, wherein X3is absent.

48. The compound according to any one of claims 1-5, 7-28, 30 and 45-47, wherein X4 is −N−.

49. The compound according to any one of claims 1-5, 7-28, 30 and 45-47, wherein X4 is −CR11R11'−, wherein R11 and R11' are each independently absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups.

50. The compound of claim 49, wherein R11is absent.

51. The compound of either claim 49 or claim 50, wherein R11' is hydrogen.

52. The compound of either claim 49 or claim 50, wherein R11' is −CN.

53. The compound according to any one of claims 1-5, 7-28, 30 and 45-47, wherein X4 is absent.

54. The compound according to any one of claims 1-5, 7-28, 30 and 45-53, wherein X5 is −N−.

55. The compound according to any one of claims 1-5, 7-28, 30 and 45-53, wherein X5is −CR11R11'−, wherein R11 and R11' are each independently absent, hydrogen, halo, nitro, hydroxy, amino or mercapto; or alkyl(C≤12), alkoxy(C≤12), cycloalkyl(C≤12), acyl(C≤12), amido(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups.

56. The compound of claim 55, wherein R11 is absent.

57. The compound of either claim 55 or claim 56, wherein R11' is hydrogen.

58. The compound of either claim 55 or claim 56, wherein R11' is −CN.

59. The compound of claim 1, wherein the compound is further defined as:, ,, , or ; or a pharmaceutically acceptable salt thereof.

60. A compound of the formula:or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising: (A) a compound according to any one of claims 1-60; and (B) an excipient.

62. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is formulated for administration orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

63. The pharmaceutical composition of claim 62, wherein the pharmaceutical composition is formulated for oral administration.

64. The pharmaceutical composition of claim 62, wherein the pharmaceutical composition is formulated for administration via injection.

65. The pharmaceutical composition of claim 62, wherein the pharmaceutical composition is formulated for intraarterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration.

66. The pharmaceutical composition according to any one of claims 62-65, wherein the pharmaceutical composition is formulated as a unit dose.

67. A method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition according to any one of claims 1-66.

68. The method of claim 67, wherein the patient is a mammal.

69. The method of claim 68, wherein the patient is a human.

70. The method according to any one of claims 67-69, wherein the disease or disorder is a disease or disorder associated with tau aggregation.

71. The method according to any one of claims 67-70, wherein the disease or disorder is a neurodegenerative disease.

72. The method of claim 71, wherein the neurodegenerative disease is a tauopathy.

73. The method of claim 71, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, corticobasal degeneration, or Huntington’s disease.

74. The method of claim 73, wherein the neurodegenerative disease is Alzheimer’s disease 75. The method according to any one of claims 67-74, wherein the patient has been diagnosed with Alzheimer's disease by behavioral testing or by a brain scan.

76. The method according to any one of claims 67-75, wherein the patient is over 40 years of age.

77. The method according to any one of claims 67-76, further comprising administering the compound of composition to the patient more than once.

78. The method according to any one of claims 67-77, wherein the patient is treated with at least a second anti-Alzheimer’s disease therapy that reduces risk of developing Alzheimer’s disease and / or reduces symptoms of Alzheimer’s disease.

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