Activators of the TMEM175 ion channel

Abstract

The present invention is directed to activators of TMEM175 Ion Channel, which are compounds of Formulae: (AAA), (AA), (A), (I), (II), (III), (IV), (V), (VI), (B), (B-I), and (B-II). The activators described herein can be useful in the treatment of diseases or disorders associated with disfunction of TMEM175 Ion Channel, such as Neurological Disorders, Parkinson's Disease, Alzheimer's disease, dementia with Lewy bodies (DEB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP). In particular, the invention is concerned with compounds and pharmaceutical compositions activating TMEM175 Ion Channel in a cell, methods of treating diseases or disorders associated with disfunction of TMEM175 Ion Channel, and methods of synthesizing these compounds.

Description

ES.24.0001.W Activators of the TMEM175 Ion Channel CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application Serial No.63 / 670,795, filed on July 12, 2024, entitled ‘Activators of the TMEM175 Ion Channel.' The disclosure of this provisional application is incorporated herein by reference in its entirety for all purposes. FIELD OF INVENTION

[0002] The present invention is directed to activators of the transmembrane protein 175 (TMEM175) Ion Channel in the lysosomal membrane. The activators described herein can be useful in the treatment of diseases or disorders associated with TMEM175 Ion Channel, such as Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP). In particular, the invention is concerned with compounds and pharmaceutical compositions activating TMEM175 Ion Channel, methods of treating diseases or disorders associated with disfunctions of TMEM175 Ion Channel, and methods of synthesizing these compounds. BACKGROUND

[0003] As society develops and life expectancy increases, countries worldwide are facing the major challenge of aging-related diseases, particularly neurodegenerative diseases that affect cognition and mobility. These diseases are predicted to become the second most common cause of death in the future. A substantial body of evidence now demonstrates that lysosomes play a significant role in neurological disorders, especially neurodegenerative diseases.

[0004] Lysosomes are acidic intracellular organelles with autophagic functions crucial for protein degradation and maintaining mitochondrial homeostasis. Abnormalities in lysosomal functions are closely associated with neurological disorders. The most widely recognized role of lysosomes is the degradation of unwanted materials using hydrolytic enzymes. This process begins either through endocytosis of extracellular foreign bodies or through autophagy to eliminate intracellular abnormalities.

[0005] Neurological diseases are associated with neuronal damage, and the common feature of most such processes is the aggregation of misfold protein and oxidative stress caused by abnormal mitochondrial function. In response to such disturbances, the mitochondrial-derived vesicles (MDVs) and autophagosomes which respectively contain damaged mitochondrial proteins and 1. ASBES.24.0001.W damaged mitochondria, fuse with lysosomes for degradation, indicating that the degradation capacity of lysosomes is particularly important.

[0006] First discovered in 1955, lysosomes are single-membrane organelles with an acidic luminal interior (pH 4.6–5.0), which is the optimal environment for a variety of hydrolytic enzymes within the lumen to function optimally.

[0007] Although the mechanism of lysosomal acidification is poorly understood, it is known to be strongly correlated with channels and transporters. Recent studies have identified a new ion channel in the lysosomal membrane, TMEM175, which was initially thought to be a specific potassium channel mediating the major potassium ion flow in the lysosome. However, improved experimental methods and further research have revealed that TMEM175 is more likely a proton channel with gating properties that play an essential role in lysosomal acidification.

[0008] TMEM175 is also a high-risk gene locus for various neurological diseases. A genome-wide association study (GWAS) has identified numerous missense variants of TMEM175 associated with Parkinson's disease (PD), with the M393T variant being the most extensively studied. Additionally, the p.Q65P TMEM175 variant is linked to α-synucleinopathies, indicating a close relationship between this protein and the pathogenic mechanisms of neurological diseases.

[0009] Transmembrane protein 175 (TMEM175), an ion channel in the lysosomal membrane, is essential for maintaining lysosomal acidity. It has been shown to work in coordination with V- ATPase to regulate the luminal pH of the lysosome, facilitating the digestion of abnormal proteins and organelles.

[0010] V-type ATPase and TMEM175 work together to maintain the acidic environment in the lysosome. V-type ATPase consumes ATP to pump protons from the cytosol into the lumen of the lysosome, and excess protons flow out of the lysosome down the concentration gradient through the TMEM175 channel, thus maintaining lysosomal pH homeostasis.

[0011] In the absence of TMEM175, the acid-base imbalance in the lysosomal lumen leads to decreased activity of hydrolases such as aspartyl protease, cysteine protease, beta- glucocerebrosidase (GBA), Cathepsin D (CTSD), and Cathepsin B (CTSB), which have very specific optimal pH ranges. This results in impaired lysosomal autophagy. Labeling of autophagosomes and autophagic lysosomes in TMEM175 knockout (KO) cells with GFP and RFP markers showed accelerated fusion of autophagosomes and lysosomes. However, the deficiency of TMEM175 was found to reduce the clearance of autophagic substrates. This indicates that while the absence of TMEM175 increases the rate of autophagosome-lysosome fusion, it compromises the autophagic function of lysosomes. In conclusion, various pieces of evidence suggest that TMEM175 promotes lysosomal function in autophagy and degradation. 2. ASBES.24.0001.W

[0012] TMEM175 presents a new therapeutic target, offering a novel direction for the study of lysosome-related neurological diseases. Drugs that effectively modulate and activate TMEM175 may help prevent neurological diseases in individuals with TMEM175 mutations. For patients with TMEM175 deficiency, personalized treatment with TMEM175-modulating drugs may slow the progression of these diseases. SUMMARY

[0013] A first aspect of the invention relates to compounds of Formula (AAA): A), or a pharmaceutically acceptabl lvate, or tautomer thereof, whereinW is selected from ;Y is selected from H, Haloge ; X is selected from O, S, NH,; ASBES.24.0001.W R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3; x is an integer selected from 0 and 1; y is an integer selected from 0 and 1.

[0014] Another aspect of the invention relates to compounds of Formula (AA): W A),or a pharmaceutically acc, , , , or tautomer thereof, wherein 4. ASBES.24.0001.W W is selected from ; X is selected from;R1is selected from OH, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, -N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; 5. ASBES.24.0001.W or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3; x is an integer selected from 0 and 1; y is an integer selected from 0 and 1.

[0015] Another aspect of the invention relates to compounds of Formula (A): A), or a pharmaceutically acc , or tautomer thereof, whereinW is selected from ; X is selected from,oxy, -N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, 6. ASBES.24.0001.W cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0016] Another aspect of the invention relates to compounds of Formula (I): (I), or a pharmaceutically acr tautomer thereof, wherein X is selected from O, S, NH, CH2; R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, 7. ASBES.24.0001.W cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0017] Another aspect of the invention relates to compounds of Formula (II): I), or a pharmaceutically atautomer thereof, wherein X is selected from O, S, NH, CH2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; 8. ASBES.24.0001.W each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0018] Another aspect of the invention relates to compounds of Formula (III): II), or a pharmaceutic mer thereof, whereinX is selected from O, S, NH, CH2; R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; 9. ASBES.24.0001.W each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; two vicinal R3form a double bond; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0019] Another aspect of the invention relates to compounds of Formula (IV): V), or a pharmaceutically atautomer thereof, wherein X is selected from O, S, NH, CH2; R1is selected from OH, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, -N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; R4is selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; 10. ASBES.24.0001.W each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0020] Another aspect of the invention relates to compounds of Formula (V): V), or a pharmaceutically atautomer thereof, wherein X is selected from O, S, NH, CH2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; R4is selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0021] Another aspect of the invention relates to compounds of Formula (VI): 11. ASBES.24.0001.W N N N HN I), or a pharmaceuti mer thereof, whereinX is selected from O, S, NH, CH2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

[0022] Another aspect of the invention relates to compounds of Formula (B): B), or a pharmaceutically acceptable, , , olvate, or tautomer thereof, wherein W is selected from ; ASBES.24.0001.W YY is selected from Y, C1-C6 alkyl, and aryl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; Y is selected from H, Halogen ; each X is independently select CH2;; oxy,-N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3; 13. ASBES.24.0001.W x is an integer selected from 0 and 1; y is an integer selected from 0 and 1; z is an integer selected from 0 and 1; w is an integer selected from 1, 2, and 3.

[0023] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0024] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (AA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0025] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0026] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0027] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0028] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0029] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0030] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, 14. ASBES.24.0001.W stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0031] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0032] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0033] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0034] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (AA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0035] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0036] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0037] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 15. ASBES.24.0001.W Ion Channel an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0038] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0039] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0040] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0041] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0042] Another aspect of the invention relates to a method of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with disfunctions of TMEM175 Ion Channel an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0043] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0044] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (AA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. 16. ASBES.24.0001.W

[0045] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0046] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0047] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0048] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0049] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0050] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0051] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0052] Another aspect of the invention is directed to a method of activating TMEM175 Ion Channel. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0053] Another aspect of the present invention relates to compounds of Formula (AAA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or 17. ASBES.24.0001.W pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0054] Another aspect of the present invention relates to compounds of Formula (AA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0055] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0056] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0057] Another aspect of the present invention relates to compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0058] Another aspect of the present invention relates to compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0059] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0060] Another aspect of the present invention relates to compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0061] Another aspect of the present invention relates to compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel. 18. ASBES.24.0001.W

[0062] Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for activating TMEM175 Ion Channel.

[0063] Another aspect of the present invention relates to use of compounds of Formula (AAA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0064] Another aspect of the present invention relates to use of compounds of Formula (AA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0065] Another aspect of the present invention relates to use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0066] Another aspect of the present invention relates to use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0067] Another aspect of the present invention relates to use of compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0068] Another aspect of the present invention relates to use of compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0069] Another aspect of the present invention relates to use of compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0070] Another aspect of the present invention relates to use of compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or 19. ASBES.24.0001.W pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0071] Another aspect of the present invention relates to use of compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0072] Another aspect of the present invention relates to use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of TMEM175 Ion Channel.

[0073] Another aspect of the present invention relates to compounds of Formula (AAA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0074] Another aspect of the present invention relates to compounds of Formula (AA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0075] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0076] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0077] Another aspect of the present invention relates to compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0078] Another aspect of the present invention relates to compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 20. ASBES.24.0001.W

[0079] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0080] Another aspect of the present invention relates to compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0081] Another aspect of the present invention relates to compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0082] Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0083] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0084] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (AA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0085] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0086] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a 21. ASBES.24.0001.W pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0087] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0088] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0089] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0090] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0091] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0092] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0093] Another aspect of the present invention relates to the use of compounds of Formula (AAA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. 22. ASBES.24.0001.W

[0094] Another aspect of the present invention relates to the use of compounds of Formula (AA), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0095] Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0096] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0097] Another aspect of the present invention relates to the use of compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0098] Another aspect of the present invention relates to the use of compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0099] Another aspect of the present invention relates to the use of compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0100] Another aspect of the present invention relates to the use of compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0101] Another aspect of the present invention relates to the use of compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0102] Another aspect of the present invention relates to the use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0103] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0104] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (AA), or a pharmaceutically 23. ASBES.24.0001.W acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0105] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0106] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0107] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0108] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0109] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0110] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0111] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically 24. ASBES.24.0001.W acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0112] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0113] The present invention provides activators of the TMEM175 Ion Channel that are therapeutic agents in the treatment of diseases and disorders.

[0114] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known activators of the TMEM175 Ion Channel. The present disclosure also provides agents with novel mechanisms of action toward TMEM175 Ion Channel in the treatment of various types of diseases.

[0115] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (AAA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0116] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (AA), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0117] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0118] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0119] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from 25. ASBES.24.0001.W at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0120] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0121] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0122] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0123] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0124] The present invention further provides methods of treating a disease or disorder associated with disfunctions of TMEM175 Ion Channel, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0125] The present invention provides activators of the TMEM175 Ion Channel that are therapeutic agents in the treatment of diseases and disorders.

[0126] The present invention further provides methods of treating a disease, disorder, or condition selected from Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP). 26. ASBES.24.0001.W

[0127] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).

[0128] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part – P1-P25).

[0129] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0130] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0131] In some specific non-limiting aspects, the present disclosure provides methods of preparing compounds of the present disclosure, described in the examples.

[0132] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0133] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0134] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which associated disfunctions of TMEM175 Ion Channel by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0135] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural 27. ASBES.24.0001.W unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions

[0136] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0137] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0138] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, –OH, –CN, –COOH, –CH2CN, –O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, –O-(C2-C6)alkenyl, –O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, – OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6)alkyl, –OC(O)O(C1-C6)alkyl, –NH2, –NH((C1- C6)alkyl), –N((C1-C6)alkyl)2, –NHC(O)(C1-C6)alkyl, –C(O)NH(C1-C6)alkyl, –S(O)2(C1-C6)alkyl, –S(O)NH(C1-C6)alkyl, and –S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0139] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0140] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0141] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such 28. ASBES.24.0001.W as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, –H, -halogen, – O-(C1-C6)alkyl, (C1-C6)alkyl, –O-(C2-C6)alkenyl, –O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2- C6)alkynyl, –OH, –OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6)alkyl, –OC(O)O(C1- C6)alkyl, –NH2, –NH((C1-C6)alkyl), –N((C1-C6)alkyl)2, –S(O)2-(C1-C6)alkyl, –S(O)NH(C1- C6)alkyl, and –S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0142] “Arenediyl”, “arylene" or "arylenyl" means an organic radical derived from an aromatic divalent radical by removal of at least two hydrogens, from a group such as phenyl, naphthyl, indenyl, indanyl and fluorenyl. An arylene is generally present as a bridging or linking group between two other groups. Non-exclusive examples of such arylene groups include 1,2- disubstituted phenyl, 1,3-disubstituted phenyl, 1,4-disubstituted phenyl, etc.

[0143] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3- 29. ASBES.24.0001.W c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2- a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4- b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5- naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H--isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2-a]indol- 1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3- b]puyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H-spiro[cyclopropane-1,8’- pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9’-onyl.

[0144] As used herein, the term “Heteroarendiyl” refers to divalent functional groups derived from heteroarenes by the removal of two hydrogen atoms from ring atoms.

[0145] “Halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine. 30. ASBES.24.0001.W

[0146] “Alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0147] “Alkanediyl”, “alkylene” or “alkylenyl” refers to a straight or branched chain saturated hydrocarbon biradicals containing 1-12 carbon atoms. Unless specified otherwise, such alkanediyls include substituted alkanediyls. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, and the like.

[0148] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0149] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

[0150] “Alkenediyl” refers to a straight or branched chain alkene biradicals containing 2-12 carbon atoms. Unless specified otherwise, such alkenediyls include substituted alkenediyls. The “alkendiyl” group contains at least one double bond in the chain. The double bond of an alkendiyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethendiyl, propendiyl, n-butendiyl, iso-butendiyl, pentendiyl, or hexendiyl.

[0151] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0152] “Alkynediyl” refers to a straight or branched chain unsaturated hydrocarbon biradicals containing 2-12 carbon atoms. The “alkynediyl” group contains at least one triple bond in the chain. Examples of alkendiyl groups include ethyndiyl, propynediyl, n-butynediyl, iso-butynediyl, pentynediyl, or hexynediyl. An alkynediyl group can be unsubstituted or substituted.

[0153] “Cycloalkyl” means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3- 31. ASBES.24.0001.W dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0154] “Cycloalkanediyl” refers to divalent functional groups derived from cycloalkanes by the removal of two hydrogen atoms from ring atoms. Cycloalkanediyl can be mono or polycyclic saturated carbon ring containing 3-18 carbon atoms. Polycyclic cycloalkanediyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkanediyl. A polycyclic cycloalkanediyl comprises at least one non-aromatic ring.

[0155] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0156] As used herein, the term “Heterocyclediyl” refers to divalent functional groups derived from heterocycle by the removal of two hydrogen atoms from ring atoms.

[0157] The term “aromatic” means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[0158] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0159] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0160] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

[0161] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. 32. ASBES.24.0001.W

[0162] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0163] The term “stereoisomer” refers to compounds that have the same molecular formula and sequence of bonded atoms (constitution) but differ in the three-dimensional orientations of their atoms in space.

[0164] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with2H and14C). Deuterated (i.e.,2H or D) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0165] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0166] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. 33. ASBES.24.0001.W

[0167] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0168] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0169] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0170] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0171] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0172] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0173] The term “salt” refers to pharmaceutically acceptable salts.

[0174] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0175] The symbol “ ”, as used in this disclosure, means a double bond in E- or Z-configuration or mi- and Z- configurations.

[0176] “Activators of the TMEM175 Ion Channel” as used herein refer to compounds of Formula AAA and / or compositions comprising a compound of Formula AAA which activates TMEM175 Ion Channel.

[0177] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula AAA (and / or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the 34. ASBES.24.0001.W disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Present Disclosure

[0178] In one aspect, the present disclosure provides compounds of Formula (AAA) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: A), Wherein W, Y, and Z are as de

[0179] It is understood that, for a compound of Formula (AAA), W, Y, and Z can each be, where applicable, selected from the groups described herein, and any group described herein for any W, Y, and Z can be combined, where applicable, with any group described herein for one or more of the remainders of W, Y, and Z.

[0180] In some embodiments, the compound is of Formula (AA): W A),or a pharmaceutically acc, or tautomer thereof.

[0181] It is understood that, for a compound of Formula (AA), W, Z, X, R3, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any W, Z, X, R3, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of W, Z, X, R3, m and n.

[0182] In some embodiments, the compound is of Formula (A): 35. ASBES.24.0001.W A), or a pharmaceutically acc , or tautomer thereof.

[0183] It is understood that, for a compound of Formula (A), W, Z , X, R3, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any W, Z’, X, R3, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of W, Z’, X, R3, m and n.

[0184] In some embodiments, the compound is of Formula (I): I), or a pharmaceutically ac or tautomer thereof.

[0185] It is understood that, for a compound of Formula (I), X, R1, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R1, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R1, R2, R3, R4, k, m and n.

[0186] In some embodiments, the compound is of Formula (I-A): A), or a pharmaceutically, , , , r tautomer thereof.

[0187] In some embodiments, the compound is of Formula (I-B): 36. ASBES.24.0001.W B), or a pharmaceutically acc , or tautomer thereof.

[0188] In some embodiments, the compound is of Formula (I-B-1): 1), or a pharmaceutically ac or tautomer thereof.

[0189] In some embodiments, the compound is of Formula (I-B-2): 2), or a pharmaceutically ar tautomer thereof.

[0190] In some embodiments, the compound is of Formula (I-B-3): 37. ASBES.24.0001.W 3), or a pharmaceutically a r tautomer thereof.

[0191] In some embodiments, the compound is of Formula (I-B-1): 4), or a pharmaceutically ac or tautomer thereof.

[0192] In some embodiments, the compound is of Formula (I-C): O R1(R3)C), or a pharmaceutically ar tautomer thereof.

[0193] In some embodiments, the compound is of Formula (II): 38. ASBES.24.0001.W I), or a pharmaceutically a r tautomer thereof.

[0194] It is understood that, for a compound of Formula (II), X, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R2, R3, R4, k, m and n.

[0195] In some embodiments, the compound is of Formula (II-A): A), or a pharmaceuticallytautomer thereof.

[0196] In some embodiments, the compound is of Formula (II-B): B), or a pharmaceutically acc, , , , or tautomer thereof.

[0197] In some embodiments, the compound is of Formula (II-B-1): 39. ASBES.24.0001.W 1), or a pharmaceutically ac or tautomer thereof.

[0198] In some embodiments, the compound is of Formula (II-B-2): of.3), or a pharmaceutically ar tautomer thereof.

[0200] In some embodiments, the compound is of Formula (II-B-4): 40. ASBES.24.0001.W 4), or a pharmaceutically a or tautomer thereof.

[0201] In some embodiments, the compound is of Formula (II-C): C), or a pharmaceuticallytautomer thereof.

[0202] In some embodiments, the compound is of Formula (III): II), or a pharmaceuticomer thereof.

[0203] It is understood that, for a compound of Formula (III), X, R1, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R1, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R1, R2, R3, R4, k, m and n.

[0204] In some embodiments, the compound is of Formula (III-A): 41. ASBES.24.0001.W A), or a pharmaceutical utomer thereof.

[0205] In some embodiments, the compound is of Formula (III-B): B), or a pharmaceutically r tautomer thereof.

[0206] In some embodiments, the compound is of Formula (III-B-1): 1), or a pharmaceuticallytautomer thereof.

[0207] In some embodiments, the compound is of Formula (III-B-2): 42. ASBES.24.0001.W 2), or a pharmaceutically tautomer thereof.

[0208] In some embodiments, the compound is of Formula (III-B-3): 3), or a pharmaceuticall automer thereof.

[0209] In some embodiments, the compound is of Formula (III-B-4): 4), or a pharmaceuticallytautomer thereof.

[0210] In some embodiments, the compound is of Formula (III-C): 43. ASBES.24.0001.W O R1C), or a pharmaceutical utomer thereof.

[0211] In some embodiments, the compound is of Formula (IV): V), or a pharmaceutically a r tautomer thereof.

[0212] It is understood that, for a compound of Formula (IV), X, R1, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R1, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R1, R2, R3, R4, k, m and n.

[0213] In some embodiments, the compound is of Formula (IV-A): A), or a pharmaceuticallytautomer thereof.

[0214] In some embodiments, the compound is of Formula (IV-B): 44. ASBES.24.0001.W O R1(R3)mB), or a pharmaceutically ac or tautomer thereof.

[0215] In some embodiments, the compound is of Formula (IV-B-1): 1), or a pharmaceutically a r tautomer thereof.

[0216] In some embodiments, the compound is of Formula (IV-B-2): 2), or a pharmaceutically ar tautomer thereof.

[0217] In some embodiments, the compound is of Formula (IV-B-3): 3), ASBES.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0218] In some embodiments, the compound is of Formula (IV-B-4): 4), or a pharmaceutically a r tautomer thereof.

[0219] In some embodiments, the compound is of Formula (IV-C): C), or a pharmaceuticallautomer thereof.

[0220] In some embodiments, the compound is of Formula (V): V), or a pharmaceutically ar tautomer thereof.

[0221] It is understood that, for a compound of Formula (V), X, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R2, R3, R4, k, m and n.

[0222] In some embodiments, the compound is of Formula (V-A): 46. ASBES.24.0001.W A), or a pharmaceutically tautomer thereof.

[0223] In some embodiments, the compound is of Formula (V-B): B), or a pharmaceutically ac or tautomer thereof.

[0224] In some embodiments, the compound is of Formula (V-B-1): 1), or a pharmaceutically acor tautomer thereof.

[0225] In some embodiments, the compound is of Formula (V-B-2): 47. ASBES.24.0001.W 2), or a pharmaceutically a r tautomer thereof.

[0226] In some embodiments, the compound is of Formula (V-B-3): 3), or a pharmaceutically r tautomer thereof.

[0227] In some embodiments, the compound is of Formula (V-B-4): 4), or a pharmaceutically aor tautomer thereof.

[0228] In some embodiments, the compound is of Formula (V-C): 48. ASBES.24.0001.W C), or a pharmaceuticall automer thereof.

[0229] In some embodiments, the compound is of Formula (VI): N N N I), or a pharmaceuticomer thereof.

[0230] It is understood that, for a compound of Formula (VI), X, R2, R3, R4, k, m and n can each be, where applicable, selected from the groups described herein, and any group described herein for any X, R2, R3, R4, k, m and n can be combined, where applicable, with any group described herein for one or more of the remainders of X, R2, R3, R4, k, m and n.

[0231] In some embodiments, the compound is of Formula (VI-A): N N N A), or a pharmaceutical, , , , utomer thereof.

[0232] In some embodiments, the compound is of Formula (VI-B): 49. ASBES.24.0001.W B), or a pharmaceutically r tautomer thereof.

[0233] In some embodiments, the compound is of Formula (VI-B-1): 1), or a pharmaceuticallytautomer thereof.

[0234] In some embodiments, the compound is of Formula (VI-B-2): 2), or a pharmaceuticallytautomer thereof.

[0235] In some embodiments, the compound is of Formula (VI-B-3): 50. ASBES.24.0001.W 3), or a pharmaceuticall automer thereof.

[0236] In some embodiments, the compound is of Formula (VI-B-4): 4), or a pharmaceuticallytautomer thereof.

[0237] In some embodiments, the compound is of Formula (VI-C): N N N C), or a pharmaceuticatomer thereof.

[0238] In some embodiments, the compound is of Formula (B): 51. ASBES.24.0001.W B), or a pharmaceutically acceptabl solvate, or tautomer thereof.

[0239] It is understood that, fora compound of Formula (B), K, R5, W, YY, Het, and z can each be, where applicable, selected from the groups described herein, and any group described herein for any K, R5, W, YY, Het, and z can be combined, where applicable, with any group described herein for one or more of the remainders of K, R5, W, YY, Het, and z.

[0240] In some embodiments, the compound is of Formula (B-I): I), or a pharmaceutically ac or tautomer thereof.

[0241] In some embodiments, the compound is of Formula (B-II): II), or a pharmaceuticallautomer thereof.

[0242] In some embodiments, W is R1-C(O)-.

[0243] In some embodiments .

[0244] In some embodiments, .

[0245] In some embodiments, R1is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0246] In some embodiments, R1is -OCH3.

[0247] In some embodiments, R1is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2. 52. ASBES.24.0001.W

[0248] In some embodiments, R1is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0249] In some embodiments, R1is C3-C10 cycloalkoxy optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0250] In some embodiments, R1is -N(R5)2.

[0251] In some embodiments YY is Y.

[0252] In some embodiments, YY is C1-C6alkyl.

[0253] In some embodiments, YY is aryl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl.

[0254] In some embodiments, Y is H.

[0255] In some embodiments, Y is halogen.

[0256] In some embodiments, Y is selected from F, Cl, Br, and I.

[0257] In some embodiments, Y is F.

[0258] In some embodiments, Y is Cl.

[0259] In some embodiments, Y is Br.

[0260] In some embodiments .

[0261] In some embodiments

[0262] In some embodiments, X is S.

[0263] In some embodiments, X is NH.

[0264] In some embodiments, X is O.

[0265] In some embodiments .

[0266] In some embodiments .

[0267] In some embodiments .N

[0268] In some embodiments3.53. ASBES.24.0001.W

[0269] In some embodiments .

[0270] In some embodiments .

[0271] In some embodiments .

[0272] In some embodiments .

[0273] In some embodiments .

[0274] In some embodiments .

[0275] In some embodiments .

[0276] In some embodiments .

[0277] In some embodiments, .

[0278] In some embodiments, .54. ASBES.24.0001.W

[0279] In some embodiments .

[0280] In some embodiments .

[0281] In some embodiments .

[0282] In some embodiments .

[0283] In some embodiments .

[0284] In some embodiments .

[0285] In some embodiments .

[0286] In some embodiments .

[0287] In some embodiments .55. ASBES.24.0001.W

[0288] In some embodiments .

[0289] In some embodiments .

[0290] In some embodiments .

[0291] In some embodiments .

[0292] In some embodiments .

[0293] In some embodiments .

[0294] In some embodiments .

[0295] In some embodiments .56. ASBES.24.0001.W

[0296] In some embodiments .

[0297] In some embodiments .

[0298] In some embodiments .

[0299] In some embodiments .

[0300] In some embodiments .

[0301] In some embodiments, .

[0302] In some embodiments, .

[0303] In some embodiments,Z is .

[0304] In some embodiments, Z is .

[0305] In some embodiments, .

[0306] In some embodiments, .

[0307] In some embodiments, .. ASBES.24.0001.W

[0308] In some embodiments, M is O.

[0309] In some embodiments, M is -NH-C(O)-.

[0310] In some embodiments, M is -NH-C(O)-CH2-O-.

[0311] In some embodiments

[0312] In some embodiments .

[0313] In some embodiments .

[0314] In some embodiments .

[0315] In some embodiments .

[0316] In some embodiments .58. ASBES.24.0001.W

[0317] In some embodiments .

[0318] In some embodiments .F

[0319] In some embodiments .F

[0320] In some embodiments .

[0321] In some embodiments .

[0322] In some embodiments .. ASBES.24.0001.W CF3. .ES.24.0001.W

[0329] In some embodiments .

[0330] In some embodiments F3.

[0331] In some embodiments .l

[0332] In some embodimentsF3.

[0333] In some embodiments ..

[0336] In some embodiments .61. ASBES.24.0001.W

[0337] In some embodiments .

[0338] In some embodiments, Z’ is selected from ,.cloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0343] In some embodiments, R2is C1-C6alkyl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0344] In some embodiments, R2is C3-C10cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2..

[0345] In some embodiments, R2is C1-C6alkyl.

[0346] In some embodiments, R2is methyl.

[0347] In some embodiments, R2is ethyl.

[0348] In some embodiments, R2is n-propyl. 62. ASBES.24.0001.W

[0349] In some embodiments, R2is iso-propyl.

[0350] In some embodiments R2is .

[0351] In some embodiments .

[0352] In some embodiments opyl.

[0353] In some embodiments, each R3is independently selected from halogen, OH, CN, NO2, C1- C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy.

[0354] In some embodiments, R3is halogen.

[0355] In some embodiments, R3is F.

[0356] In some embodiments, R3is Cl.

[0357] In some embodiments, R3is Br.

[0358] In some embodiments, R3is OH.

[0359] In some embodiments, R3is CN.

[0360] In some embodiments, R3is NO2.

[0361] In some embodiments, R3is C1-C6 alkyl.

[0362] In some embodiments, R3is methyl.

[0363] In some embodiments, R3is ethyl.

[0364] In some embodiments, R3is n-propyl.

[0365] In some embodiments, R3is iso-propyl.

[0366] In some embodiments, R3is C1-C6alkoxy.

[0367] In some embodiments, R3is -OCH3.

[0368] In some embodiments, R3is -OCH2CH3.

[0369] In some embodiments, R3is -OCH2CH2CH3.

[0370] In some embodiments, R3is -OCF3.

[0371] In some embodiments, R3is C3-C10 cycloalkyl.

[0372] In some embodiments, R3is C3-C10 cycloalkoxy.

[0373] In some embodiments, R3is aryl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy. 63. ASBES.24.0001.W

[0374] In some embodiments .

[0375] In some embodiments orm a double bond.

[0376] In some embodiments, each R4is independently selected from halogen, OH, CN, NO2, C1- C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0377] In some embodiments, R4is halogen.

[0378] In some embodiments, R4is F.

[0379] In some embodiments, R4is Cl.

[0380] In some embodiments, R4is Br.

[0381] In some embodiments, R4is OH.

[0382] In some embodiments, R4is CN.

[0383] In some embodiments, R4is NO2.

[0384] In some embodiments, R4is C1-C6 alkyl.

[0385] In some embodiments, R4is methyl.

[0386] In some embodiments, R4is ethyl.

[0387] In some embodiments, R4is n-propyl.

[0388] In some embodiments, R4is iso-propyl.

[0389] In some embodiments, R4is C1-C6alkyl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2.

[0390] In some embodiments, R4is -CF3.

[0391] In some embodiments, R4is C1-C6alkoxy.

[0392] In some embodiments, R4is -OCH3.

[0393] In some embodiments, R4is -OCH2CH3.

[0394] In some embodiments, R4is -OCH2CH2CH3.

[0395] In some embodiments, R4is -OCF3.

[0396] In some embodiments, R4is C3-C10 cycloalkyl.

[0397] In some embodiments, R4is cyclopropyl.

[0398] In some embodiments, R4is C3-C10 cycloalkoxy.

[0399] In some embodiments, k is an integer selected from 0, 1, 2, and 3.

[0400] In some embodiments, k is 0.

[0401] In some embodiments, k is 1. 64. ASBES.24.0001.W

[0402] In some embodiments, k is 2.

[0403] In some embodiments, k is 3.

[0404] In some embodiments, m is an integer selected from 1, 2, 3, and 4.

[0405] In some embodiments, m is 1.

[0406] In some embodiments, m is 2.

[0407] In some embodiments, m is 3.

[0408] In some embodiments, m is 4.

[0409] In some embodiments, n is an integer selected from 1, 2, and 3.

[0410] In some embodiments, n is 1.

[0411] In some embodiments, n is 2.

[0412] In some embodiments, n is 3.

[0413] In some embodiments, x is an integer selected from 0 and 1.

[0414] In some embodiments, x is 0.

[0415] In some embodiments, x is 1.

[0416] In some embodiments, y is an integer selected from 0 and 1.

[0417] In some embodiments, y is 0.

[0418] In some embodiments, y is 1.

[0419] In some embodiments, z is an integer selected from 0 and 1.

[0420] In some embodiments, z is 0.

[0421] In some embodiments, z is 1.

[0422] In some embodiments, w is an integer selected from 1, 2, and 3.

[0423] In some embodiments, w is 1.

[0424] In some embodiments, w is 2.

[0425] In some embodiments, w is 3.

[0426] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0427] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0428] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0429] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0430] In some embodiments, the compound is selected from the compounds described in Table 1. 65. ASBES.24.0001.W

[0431] Table 1. Certain examples of the compound of Formula (AAA) and the compound of Formula (B). # Structure IUPAC name c 5- ]a b66. ASBES.24.0001.W # Structure IUPAC name 5- - 2- 2- - 1- 2-67. ASBES.24.0001.W # Structure IUPAC name - - 2- - -68. ASBES.24.0001.W # Structure IUPAC name F 6- - -69. ASBES.24.0001.W # Structure IUPAC name - - - -70. ASBES.24.0001.W # Structure IUPAC name - - 6- - 6- te71. ASBES.24.0001.W # Structure IUPAC name F y- - - 2-72. ASBES.24.0001.W # Structure IUPAC name 2- - - te 2- 2- te73. ASBES.24.0001.W # Structure IUPAC name o- 6- o- - te )-74. ASBES.24.0001.W # Structure IUPAC name o- )- - 1-75. ASBES.24.0001.W # Structure IUPAC name - d - 6- ic - -76. ASBES.24.0001.W # Structure IUPAC name - - y- - c77. ASBES.24.0001.W # Structure IUPAC name Cl - ]- ic - 5- - 5-78. ASBES.24.0001.W # Structure IUPAC name - - 5- i i -79. ASBES.24.0001.W # Structure IUPAC name - 5- - i 1- - - d80. ASBES.24.0001.W # Structure IUPAC name - - 6- ic - - - - ic81. ASBES.24.0001.W # Structure IUPAC name F F - - o- 6- ic o- d82. ASBES.24.0001.W # Structure IUPAC name - - - - o- i c83. ASBES.24.0001.W # Structure IUPAC name - o- te - - - 1-84. ASBES.24.0001.W # Structure IUPAC name - - 8- - - - e85. ASBES.24.0001.W # Structure IUPAC name - - o- - - - 3- -86. ASBES.24.0001.W # Structure IUPAC name 1- 2- 3- - - - de de87. ASBES.24.0001.W # Structure IUPAC name - - de - e 1- 2-88. ASBES.24.0001.W # Structure IUPAC name - 3- - - e e89. ASBES.24.0001.W # Structure IUPAC name 3- - - - - e90. ASBES.24.0001.W # Structure IUPAC name - - e - - - e - - - - e91. ASBES.24.0001.W # Structure IUPAC name Cl - e - e - de 1-ASBES.24.0001.W # Structure IUPAC name - de - de - - - e - -93. ASBES.24.0001.W # Structure IUPAC name - e - - - - -94. ASBES.24.0001.W # Structure IUPAC name - e - o- - - dASBES.24.0001.W # Structure IUPAC name - 6- ic - - d o-96. ASBES.24.0001.W # Structure IUPAC name 2- - 6- c 2- - 2- o-97. ASBES.24.0001.W # Structure IUPAC name F - - ic - 6- ic98. ASBES.24.0001.W # Structure IUPAC name - d - 1-99. ASBES.24.0001.W # Structure IUPAC name - - ic - 1-100. ASBES.24.0001.W # Structure IUPAC name 2- 6- te - - - 5- - - 5- - - 5-101. ASBES.24.0001.W # Structure IUPAC name 3- - - - - - - - - - -102. ASBES.24.0001.W # Structure IUPAC name thl 2 (2S)24 hl 5- - - - - - - -103. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-chloro-5-meth l-3- - 5- - - 5- - 5- - 5- - 5- -104. ASBES.24.0001.W # Structure IUPAC name - - - - 5-105. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-hlr-5- - 5- - 5- - - - - - -106. ASBES.24.0001.W # Structure IUPAC name methyl 2-[[(2S)-2-[4-chloro-5- - - - - - 5- - - 5-. ASBES.24.0001.W # Structure IUPAC name - 5- - 5- - - -108. ASBES.24.0001.W # Structure IUPAC name F - - - -109. ASBES.24.0001.W # Structure IUPAC name 2 2S 24 hl 5 - - - - - -110. ASBES.24.0001.W # Structure IUPAC name - - - 5- - - -111. ASBES.24.0001.W # Structure IUPAC name F e - - e e - de - - - de112. ASBES.24.0001.W # Structure IUPAC name - de - - de - - ]- - e113. ASBES.24.0001.W # Structure IUPAC name e - ]- de - ]- - - ]- de114. ASBES.24.0001.W # Structure IUPAC name N- n- l]- - ]- e - ]- - - e - ]- e115. ASBES.24.0001.W # Structure IUPAC name - ]- - - ]- - - ]- e - ]- e116. ASBES.24.0001.W # Structure IUPAC name - ]- - de - ]- - )- - de )- de117. ASBES.24.0001.W # Structure IUPAC name 1- e e - -118. ASBES.24.0001.W # Structure IUPAC name - e - o- - - e119. ASBES.24.0001.W # Structure IUPAC name - - - -

[0432] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0433] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0434] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (AAA).

[0435] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (AA).

[0436] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (A).

[0437] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (I).

[0438] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (II).

[0439] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (III). 120. ASBES.24.0001.W

[0440] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (IV).

[0441] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (V).

[0442] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (VI).

[0443] In some embodiments, the compound is a salt of any acid described in the Table 2 and a Compound of Formula (B).

[0444] In some embodiments, the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.

[0445] Table 2. Pharmaceutical acceptable acid forming salts with a compound of Formula (AAA) and a compound of Formula (B). 1-hydroxy-2-naphthoic acid; ethanesulfonic acid; methanesulfonic acid; 2,2-dichloroacetic acid; formic acid; naphthalene-1,5-disulfonic d;

[0446] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0447] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0448] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1. 121. ASBES.24.0001.W

[0449] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0450] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0451] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0452] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0453] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0454] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0455] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0456] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0457] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0458] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0459] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0460] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0461] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0462] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0463] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0464] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (AAA) is isotopically enriched with regard to, or labelled with, one or 122. ASBES.24.0001.W more isotopes as compared to the corresponding compound of Formula (AAA). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0465] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (AA) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (AA). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0466] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (A) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (A). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0467] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (B) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (A). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0468] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0469] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0470] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. 123. ASBES.24.0001.W

[0471] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0472] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0473] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0474] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0475] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0476] In some embodiments, the compound is a18F labeled compound.

[0477] In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof.

[0478] In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0479] It is understood that the18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0480] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,,18F,123I,124I, 124. ASBES.24.0001.W125I,129I,131I,135I,33S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0481] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0482] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 800 Daltons. More usually, the molecular weight of the compound will be less than 800, for example less than 700, or less than 650, or less than 600 Daltons. More conveniently, the molecular weight is less than 550 and, for example, is 500 Daltons or less.

[0483] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0484] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0485] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0486] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0487] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, 125. ASBES.24.0001.W a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0488] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0489] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0490] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0491] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0492] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting 126. ASBES.24.0001.W with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0493] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0494] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0495] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0496] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0497] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted 127. ASBES.24.0001.W compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0498] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0499] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0500] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0501] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0502] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0503] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. 128. ASBES.24.0001.W

[0504] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0505] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0506] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compound of the disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formulae disclosed herein. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. H O OH H+ O- C CC Ce

[0507] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of any one Formula disclosed herein that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. 129. ASBES.24.0001.W

[0508] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0509] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically- produced compound.

[0510] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0511] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable 130. ASBES.24.0001.W pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0512] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0513] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl.

[0514] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). Method of Synthesizing the Compounds

[0515] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0516] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective 131. ASBES.24.0001.W Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0517] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0518] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in the part “Examples” which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. Biological Assays

[0519] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0520] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel 132. ASBES.24.0001.W Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0521] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions

[0522] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0523] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0524] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0525] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable 133. ASBES.24.0001.W colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0526] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0527] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0528] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0529] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β- cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β- cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β- cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β- cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof. 134. ASBES.24.0001.W

[0530] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0531] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0532] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0533] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0534] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0535] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation 135. ASBES.24.0001.W may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0536] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0537] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0538] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0539] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. 136. ASBES.24.0001.W

[0540] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0541] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0542] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0543] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a TMEM175 Ion Channel related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0544] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a TMEM175 Ion Channel related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0545] The size of the dose for therapeutic or prophylactic purposes of a compound of Formulae disclosed herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine. Methods of Use

[0546] In some aspects, the present disclosure provides a method of activating of TMEM175 Ion Channel (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0547] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0548] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a 137. ASBES.24.0001.W therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0549] In some embodiments, the disease or disorder is associated with disfunction or malfunction of the TMEM175 Ion Channel. In some embodiments, the disease or disorder is a disease or disorder in which the TMEM175 Ion Channel is implicated.

[0550] The compounds of the invention are also useful in treating diseases associated with disfunctions of the TMEM175 Ion Channel. For example, diseases and conditions treatable according to the methods of the invention include Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP).

[0551] In some embodiments, the disease or disorder is a Neurological Disorder.

[0552] In some embodiments, the disease or disorder is Parkinson’s Disease.

[0553] In some embodiments, the disease or disorder is Alzheimer's disease.

[0554] In some embodiments, the disease or disorder is dementia with Lewy bodies (DLB).

[0555] In some embodiments, the disease or disorder is multisystem atrophy (MSA).

[0556] In some embodiments, the disease or disorder is progressive supranuclear palsy (PSP).

[0557] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing a Neurological Disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0558] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing Parkinson’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0559] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing Alzheimer's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0560] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing dementia with Lewy bodies (DLB) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present 138. ASBES.24.0001.W disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0561] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing multisystem atrophy (MSA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0562] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing progressive supranuclear palsy (PSP) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0563] In some aspects, the present disclosure provides a method of treating a Neurological Disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0564] In some aspects, the present disclosure provides a method of treating Parkinson’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0565] In some aspects, the present disclosure provides a method of treating Alzheimer's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0566] In some aspects, the present disclosure provides a method of treating dementia with Lewy bodies (DLB) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0567] In some aspects, the present disclosure provides a method of treating multisystem atrophy (MSA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0568] In some aspects, the present disclosure provides a method of treating progressive supranuclear palsy (PSP) in a subject in need thereof, comprising administering to the subject a 139. ASBES.24.0001.W therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0569] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in activating of TMEM175 Ion Channel (e.g., in vitro or in vivo).

[0570] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0571] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0572] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing a Neurological Disorder in a subject in need thereof.

[0573] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing Parkinson’s Disease in a subject in need thereof.

[0574] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing Alzheimer's disease in a subject in need thereof.

[0575] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing dementia with Lewy bodies (DLB) in a subject in need thereof.

[0576] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing multisystem atrophy (MSA) in a subject in need thereof.

[0577] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing progressive supranuclear palsy (PSP) in a subject in need thereof.

[0578] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a Neurological Disorder in a subject in need thereof.

[0579] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Parkinson’s Disease in a subject in need thereof. 140. ASBES.24.0001.W

[0580] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Alzheimer's disease in a subject in need thereof.

[0581] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating dementia with Lewy bodies (DLB) in a subject in need thereof.

[0582] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating multisystem atrophy (MSA) in a subject in need thereof.

[0583] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating progressive supranuclear palsy (PSP) in a subject in need thereof.

[0584] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for activating of TMEM175 Ion Channel (e.g., in vitro or in vivo).

[0585] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0586] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0587] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a Neurological Disorder in a subject in need thereof.

[0588] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Parkinson’s Disease in a subject in need thereof.

[0589] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease in a subject in need thereof.

[0590] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing dementia with Lewy bodies (DLB) in a subject in need thereof. 141. ASBES.24.0001.W

[0591] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing multisystem atrophy (MSA) in a subject in need thereof.

[0592] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing progressive supranuclear palsy (PSP) in a subject in need thereof.

[0593] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a Neurological Disorder in a subject in need thereof.

[0594] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Parkinson’s Disease in a subject in need thereof.

[0595] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Alzheimer's disease in a subject in need thereof.

[0596] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating dementia with Lewy bodies (DLB) in a subject in need thereof.

[0597] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating multisystem atrophy (MSA) in a subject in need thereof.

[0598] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating progressive supranuclear palsy (PSP) in a subject in need thereof.

[0599] The present disclosure provides compounds that function as activators of TMEM175 Ion Channel (e.g., in vitro or in vivo). The present disclosure therefore provides a method of activating of TMEM175 Ion Channel in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0600] In some embodiments, the activator of TMEM175 Ion Channel is a compound of the present disclosure.

[0601] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. 142. ASBES.24.0001.W

[0602] The present disclosure also provides a method of treating a disease or disorder in which TMEM175 Ion Channel is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0603] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Routes of Administration

[0604] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0605] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES General synthetical procedures and examples of the compound’s preparation.

[0606] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC Aluminum sheets silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75^^m) purchased by Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR operating at 400 MHz for1H. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data is reported as follows: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration. The purities were recorded on Waters e2695 separations Module / 2998 PDA Detector HPLC system (Column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L), Eluent: the mixture of mobile phase A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH4OAc, Flow rate: 0.5 mL / min. detection: UV, 254 nm)

[0607] Abbreviations used in the following examples and elsewhere herein are: 143. ASBES.24.0001.W ACN acetonitrile AcOH acetic acid ATP adenosine triphosphate aq. aqueous atm. atmosphere br. broad d duplet DCM dichloromethane DIC diisopropylmethanediimine DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide EA ethyl acetate eq equivalent g gramm, gas h hour(s) HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HPLC high pressure (or performance) liquid chromatography L liter LCMS liquid chromatography mass spectrometry m multiplet M molar MHz megahertz min minutes ml, mL milliliter NMR nuclear magnetic resonance q quadruplet rt room temperature s singlet s solid sat. saturated t temperature, triplet TEA Triethyl amine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Synthesis of Building Blocks Synthesis of ethyl 5-bromo-2-[(3-methoxybenzoyl)amino]benzoate (P1) 144. ASBES.24.0001.W O OH NH2O O O [060To a mixture of 3-methoxybenzoic acid (1 mmol) and HATU (452 mg, 1.19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and ethyl 2-amino-5- bromo-benzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound P1 (82%). Synthesis of Resin P6 145. ASBES.24.0001.W H OH NO2O NO2N O [06To a suspension of Wang-resin (L=2.0 mmol / g) (1 eq), 5-chloro-2-nitro-benzoic acid (1.5 eq), (0.1%) DMAP in DCM (0.3 M) DIC (1.5 eq) was added with stirring. The reaction mixture was stirred at rt for 48 h. The resin was filtered, washed successively with DCM (x2), DMF (x2), MeOH (x2), DCM (x2), MeOH (x2), DCM (x2) and MeOH (x2), and dried under vacuum. The resulting resin 3 was used in the next step.

[0610] Preparation 3. Resin P3. A suspension of resin 3 (1 eq) and a 5-fold excess of 3-methylpiperidine (5 eq) in DMSO was stirred at 60°C for 20 h. Resin P3 is filtered and washed with DMF (x2), MeOH (x2), DCM (x2), MeOH (x2), DCM (x2), MeOH (x2) and dried under vacuum.

[0611] Preparation 4. Resin P4. 146. ASBES.24.0001.W A suspension of resin P3 (1 eq) in a 1 M solution of SnCl2x2H2O (10 eq) in DMF under nitrogen is stirred at rt for 48 h. Resin P4 was filtered and washed with DMF (x2), MeOH (x2), DCM (x2) and MeOH (x2), and dried in vacuum.

[0612] Preparation 5. Resin P5. To a suspension of resin P4 (1 eq) in 5 ml of DCM was added a 5-fold excess of the acyl chloride and a 5-fold excess of pyridine. The reaction mixture was stirred for 18 h at rt. Resin P5 was filtered and washed with DMF (x2), MeOH (x2), DCM (x2) and MeOH (x2), dried under vacuum.

[0613] Preparation 6. Resin P6. Suspension of resin P5 in 4 ml of DMF / NH3 aq. mixture was stirred at rt for 20 h. Resin P6 was filtered and washed with DMF (x2), MeOH (x2), DCM (x2) and MeOH (x2), dried under vacuum. Synthesis of methyl 2-[[4-[(3-propoxybenzoyl)amino]benzoyl]amino]benzoate (P9) NH2O O O O Op . y p p y y . To a mixture of 3-propoxybenzoic acid (1 mmol) and HATU (452 mg, 1.19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and methyl 4- aminobenzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried with Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound P7 (81%).

[0615] Preparation 8.4-[(3-Propoxybenzoyl)amino]benzoic acid (P8). To a solution of P7 (1 mmol) in THF (20 ml) was added lithium hydroxide (2 mmol) in water (10 ml) and the reaction mixture was stirred at 25°C with LCMS control of the reaction mixture. After the reaction completed the solvent was evaporated in vacuo, residue was diluted with water and 147. ASBES.24.0001.W adjusted to pH 2 by 1 M aq. HCl. The formed solid was collected by filtration, washed with water, dry ether to give pure acid P8 (92%).

[0616] Preparation 9. Methyl 2-[[4-[(3-propoxybenzoyl)amino]benzoyl]amino]benzoate (P9). To a mixture of P8 (1 mmol) and HATU (452 mg, 1.19 mmol) in ACN (10 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and methyl 2-aminobenzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 ml), dried with Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound P9 (78%). Synthesis of methyl 2-[[4-[[2-(2,6-dimethylphenoxy)acetyl]amino]benzoyl]amino]benzoate (P12). , . To a mixture of 2-(2,6-dimethylphenoxy)acetic acid (1 mmol) and HATU (452 mg, 1.19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and methyl 4-aminobenzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound P10 (85%).

[0618] Preparation 11.4-[[2-(2,6-Dimethylphenoxy)acetyl]amino]benzoic acid (P11). To a solution of P10 (1 mmol) in THF (20 ml) was added lithium hydroxide (2 mmol) in water (10 ml) and the reaction mixture was stirred at 25°C with LCMS control. After the reaction completed the solvent was evaporated in vacuo, residue was diluted with water and adjusted to pH 2 by 1 M aq. HCl. The formed solid was collected by filtration, washed with water, dry ether to give pure acid P11 (91%). 148. ASBES.24.0001.W

[0619] Preparation 12. Methyl 2-[[4-[[2-(2,6- dimethylphenoxy)acetyl]amino]benzoyl]amino]benzoate (P12). To a mixture of the acid P11 (1 mmol) and HATU (452 mg, 1.19 mmol) in ACN (10 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and methyl 2-aminobenzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound P12 (77%). Synthesis of Resin P17 O-O +O- O+OOES.24.0001.W

[0620] Preparation 13. Resin P13. Wang-resin (1 eq) was suspended in a solution of 5-chloro-2-nitro-benzoic acid (1.5 eq) and DMAP (0.1 %) in dry DCM (400 ml). Then DIC (31.5 ml, 0.2 mol) was added with care. The reaction mixture was shaken at rt for 48 h. The resin was filtered off, washed successively with 2x DCM, DMF, MeOH, 2x DCM, 2x MeOH, 2x DCM, 2x hexane and dried in vacuum to give resin P13 (70%).

[0621] Preparation 14. Resin P14. Resin P13 (1 eq) was treated with 1-(2-methoxyphenyl)piperazine (5 eq) in DMCO and stirred at 60°C for 20 h. Then the resin P14 was filtered off and washed successively with DMF (x2), MeOH (x2), DCM (x2), MeOH (x2), DCM (x2), MeOH (x2) and dried under vacuo with 70% yield.

[0622] Preparation 15. Resin P15. The resin P14 (1 eq) was suspended in 1 M solution of SnCl2x2H2O (10 eq) in DMF and stirred at rt for 48 h in atm. of nitrogen. The resin P15 was filtered off and washed successively with DMF (x2), MeOH (x2), DCM (x2), MeOH (x2) and dried in vacuo to give resin P15 (85%).

[0623] Preparation 16. Resin P16. To the suspension of resin P15 (1 eq) in DCM (5 ml) a pyridine (5 eq) and 4-methoxybenzoyl chloride (5 eq) were added. The reaction mixture was stirred at rt for 18 h. The resin P16 was filtered off and washed successively with DMF (x2), MeOH (x2), DCM (x2), MeOH (x2) and dried under vacuo to give resin P16 (70%).

[0624] Preparation 17. Resin P17. The resin P16 was suspended in 25% aq. NH3 solution (4 ml) in DMF and stirred at rt for 20 h. The resin P17 was filtered off, washed successively with DMF (x2), MeOH (x2), DCM (x2), MeOH (x2) and dried in vacuo to give resin P17 (90%). Synthesis of Resin P21 150. ASBES.24.0001.W [062p . . To a suspension of Wang-resin (L=2.0 mmol / g, 1 eq), 2-nitrobenzoic acid (1.5 eq), 0.1% DMAP in DCM (0.3 M) was added DIC (1.5 eq) with stirring. The reaction mixture is stirred at rt for 48 h. The resin was filtered, washed successively with DCM (x2), DMF (x2), MeOH (x2), DCM (x2), MeOH (x2), DCM (x2) and MeOH (x2), and dried under vacuum to give P18.

[0626] Preparation 19. Resin P19. A suspension of resin P18 (1 eq) in a 1 M solution of SnCl2x2H2O (10 eq) in DMF under nitrogen was stirred at rt for 48 h. Resin P19 was filtered and washed with DMF (x2), MeOH (x2), DCM (x2) and MeOH (x2), dried under vacuum.

[0627] Preparation 20. Resin P20. To a suspension of resin P19 (1 eq) in 5 ml of DCM was added a 2-fold excess of 2-cyanoacetyl chloride and 5-fold excess of pyridine. The reaction mixture was stirred for 18 h at rt. Resin P20 was filtered and washed with DMF (x2), MeOH (x2), DCM (x2) and MeOH (x2), dried under vacuum.

[0628] Preparation 21. Resin P21. Suspension of resin P20 (1eq), 3-phenoxybenzaldehyde (2eq) in 10 ml toluene was stirred at 90°C for 20 h. Resin P21 was filtered and washed with MeOH (x2), DCM (x2) and MeOH (x2), dried under vacuum. 151. ASBES.24.0001.W Synthesis of 3-Amino-2,7-dimethyl-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one (P23) O OO NH2O O N e-3-carboxylate (P22). To 2-amino thiophene (0.01 mol) was added, drop by drop and with stirring, 3 ml of acetic anhydride. The reaction is strongly exothermic. After 1 h of contact, the mixture was placed in the cold for 24 h. The excess of anhydride was destroyed with water (20 ml) and the precipitate was recrystallized from EtOH.

[0630] Preparation 23. 3-Amino-2,7-dimethyl-5,6,7,8-tetrahydrobenzothiopheno[2,3- d]pyrimidin-4-one (P23). P22 (0.0l mol) was dissolved in 25 ml of EtOH and heated to reflux with 10 ml of hydrazine hydrate sealed. Formed precipitate of P23 was recrystallized from EtOH. Synthesis of 11-amino-10-methyl-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9-trien- 12-one (P25)

[0631] Preparation 24. Ethyl 2-acetamido-5,6-dihydro-4H-cyclopenta[b]thiophene-3- carboxylate (P24). To 2-amino thiophene (0.01 mol) were added drop by drop and with stirring, 3 ml of acetic anhydride. The reaction is strongly exothermic. After 1 h the reaction mixture was placed in the cold for 24 h. The excess of anhydride was destroyed with water (20 ml) and formed precipitate was recrystallized from ethanol.

[0632] Preparation 25. 11-Amino-10-methyl-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca- 1(8),2(6),9-trien-12-one (P25). 152. ASBES.24.0001.W P24 (0.0l mol) was dissolved in 25 ml of ethanol and heated to reflux with 10 ml of hydrazine hydrate. Formed precipitate of P25 was recrystallized from ethanol. Examples of the Final Compound

[0633] In the Table 3 presented certain non-limiting examples of the compound of Formula (I).

[0634] Table 3. Selected examples of the compound of Formula (I) [MH]+[MH]+# Structure calculated found153. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found154. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found155. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found156. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found157. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found158. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found159. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found160. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found161. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found162. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found163. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found164. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found165. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found166. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found167. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found168. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found169. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found170. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found171. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found172. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found173. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found174. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found175. ASBES.24.0001.W [MH]+[MH]+# Structure calculated foundASBES.24.0001.W [MH]+[MH]+# Structure calculated found177. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found178. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found179. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found180. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found181. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found182. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found183. ASBES.24.0001.W [MH]+[MH]+# Structure calculated foundASBES.24.0001.W [MH]+[MH]+# Structure calculated found185. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found186. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found187. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found188. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found189. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found190. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found191. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found192. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found193. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found194. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found195. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found196. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found197. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found198. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found199. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found200. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found201. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found202. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found203. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found204. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found205. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found206. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found207. ASBES.24.0001.W [MH]+[MH]+# Structure calculated found208. ASBES.24.0001.W [MH]+[MH]+# Structure calculated foundSynthesis of the Representative Examples of the compound

[0635] Example 1.5-Bromo-2-[(3-methoxybenzoyl)amino]benzoic acid (Compound 1). 209. ASBES.24.0001.W To a d and thereaction mixture was stirred at 25°C. The reaction mixture was analyzed with LCMS. After reaction completed the solvent was evaporated in vacuo, residue was diluted with water and adjusted to pH 2 by 1 M aq. HCl. The formed solid was collected by filtration, washed with water, dry ether to give pure acid 1 (87%). LCMS: 350.3 [MH]+.1H NMR (300 MHz, DMSO-d6), δ: 12.08 (s, 1H), 8.72 (m, 1H), 8.18 (m, 1H), 7.78 – 7.71 (m, 1H), 7.55 – 7.42 (m, 3H), 7.20 – 7.12 (m, 1H), 3.88 (s, 3H).

[0636] Example 2. 2-[(4-Methoxybenzoyl)amino]-5-(3-methyl-1-piperidyl)benzoic acid (Compound 2). Resin P6was removed in vacuo to give the corresponding compound 2. LCMS: 369.2 [MH]+.

[0637] Example 3.2-[[4-[(3-Propoxybenzoyl)amino]benzoyl]amino]benzoic acid (Compound 3).y (10 ml) and the reaction mixture was stirred at 25°C with LCMS monitoring of reaction mixture. After 210. ASBES.24.0001.W reaction completed the solvent was evaporated in vacuo, residue was diluted with water and adjusted to pH 2 by 1 M aq. HCl. Formed precipitate was collected by filtration, washed with water, dry ether to give pure acid 3 (85%). LCMS: 419.1 [MH]+.1H NMR (500 MHz, DMSO-d6), δ: 13.63 (s, 1H), 12.17 (s, 1H), 10.40 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 8.03 – 7.93 (m, 4H), 7.61 – 7.40 (m, 4H), 7.20 – 7.12 (m, 2H), 4.03 (t, J = 6.7 Hz, 2H), 1.79 (m, 2H), 1.05 (t, J = 6.9 Hz, 3H).

[0638] Example 4. 2-[[4-[[2-(2,6-Dimethylphenoxy)acetyl]amino]benzoyl]amino]benzoic acid (Compound 4).ater (10 ml) and the reaction mixture was stirred at 25°C with LCMS control. After the reaction completed the solvent was evaporated in vacuo, residue was diluted with water and adjusted to pH 2 by 1 M aq. HCl. The formed solid was collected by filtration, washed with water, dry ether to give pure acid 4 (83%). LCMS: 419.2 [MH]+.1H NMR (300 MHz, DMSO-d6), δ: 13.45 (s, 1H), 12.28 (s, 1H), 10.19 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.98 – 7.90 (m, 4H), 7.61 (t, J = 8.2 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.06 – 6.88 (m, 3H), 4.42 (s, 2H), 2.31 (s, 6H).

[0639] Example 5. 2-[(4-Methoxybenzoyl)amino]-5-[4-(2-methoxyphenyl)piperazin-1- yl]benzoic acid (Compound 5). ASBES.24.0001.W Resin P17 was treated with 10% solution of TFA / DCM (3 ml) and stirred at rt for 2 h. The mixture was concentrated to give compound 5 (90%). LCMS: 462.4 [MH]+.

[0640] Example 6. Methyl 2-(2-phenoxybutanoylamino)benzoate (Compound 75). T CN (5ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and methyl 2- aminobenzoate (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound 75. LCMS: 313.8 [MH]+.1H NMR (300 MHz, DMSO-d6), δ: 11.66 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 8.6 Hz, 1H), 4.78 (m, 1H), 3.86 (s, 3H), 2.11-1.92 (m, 2H), 1.04(t, J = 6.9 Hz, 3H).

[0641] Example 7. 2-(1,3-Dioxoisoindolin-2-yl)-N-[4-(p-tolyl)thiazol-2-yl]propanamide (Compound 79). O O O O N H N H, , .19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and 4-(4-methylphenyl)-1,3-thiazol-2-amine (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel to give the title compound 79. LCMS: 392.1 [MH]+.1H NMR (300 MHz, CDCl3), δ: 10.39 (s, 1H), 7.85(m, 2H), 7.75(m, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 5.00 (m, 1H), 2.37 (s, 3H), 1.71 (d, J = 6.7 Hz, 3H).

[0642] Example 8. 2-[[(E)-2-cyano-3-(3-phenoxyphenyl)prop-2-enoyl]amino]benzoic acid (Compound 80). 212. ASBES.24.0001.W wasremoved in vacuo to give the corresponding compound 80. LCMS: 385.3 [MH]+.

[0643] Example 9. 2-[4-Chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-N-(2,7-dimethyl-4- oxo-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-3-yl)acetamide (Compound 81).and HATU (452 mg, 1.19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and P23 (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound 81. LCMS: 473.8 [MH]+.1H NMR (300 MHz, DMSO-d6), δ: 11.25 (s, 1H), 5.22 (s, 2H), 3.23 – 2.76 (m, 4H), 2.42 (s, 3(s, 3H), 2.05 – 1.76 (m, 2H), 1.52 (m, 1H), 1.13 (m, 3H).

[0644] Example 10. 2-[4-Chloro-5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-N-(10-methyl- 12-oxo-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9-trien-11-yl)acetamide (Compound 82). 213. ASBES.24.0001.W T mmol)and HATU (452 mg, 1.19 mmol) in ACN (5 ml) DIPEA (1.3 mmol) was added. The mixture was stirred at rt for 30 min, and P25 (1.08 mmol) was added, and stirred overnight. The reaction mixture was diluted with EA (50 ml) and washed with water (3x50 ml), brine (2x50 mL), dried on Na2SO4, and concentrated under reduced pressure, and the crude was purified by flash chromatography on silica gel to give the title compound 82. LCMS: 472.3 [MH]+. Biological Assays

[0645] Example A. TMEM175 activation assay.

[0646] The ability of compounds to potentiate currents in TMEM175-expressing HEK293 cells was assessed using APC system SyncroPatch™ 384PE (SP384PE; Nanion Technologies, Livingston, NJ) test platform. Cell line: TMEM175-expressing HEK293 cells (Charles River Laboratories Cat# CT6634). TMEM175 expression was induced 24 h before electrophysiological experiments. Before testing, cells in culture dishes were washed twice with Hank’s Balanced Salt Solution (HB-PS) and treated with AccutaseTMfor approximately 20 min. Immediately before use in SP384PE, the cells were washed in HB-PS to remove the Accutase and re-suspended in HEPES- buffered physiological saline (HB-PS, Extracellular solution). All experiments were performed at ambient temperature. Recording procedure: Extracellular buffer was loaded into the wells of Nanion 384-well Patch Clamp 8x Medium Hole (8xM NPC-384) chip (80 ^L per well). Then, cell suspension (~1x106cells / mL) was pipetted into the wells (20 ^L per well) of NPC-384 chip. After establishment of the whole-cell configuration, membrane currents were recorded using patch clamp amplifier in the SP384PE system. Extracellular solution, HB-PS (composition in mM): NaCl, 140; KCl, 4.0; CaCl2, 4.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH; ~290 mOsm / L. Intracellular solution (composition in mM): CsCl, 50; CsF, 90; MgCl2, 5; EGTA, 2.5; HEPES, 10; pH adjusted to 7.2 with CsOH; ~265 mOsm / L. In preparation for a recording session, this intracellular solution was loaded into the intracellular compartment of NPC- 384 chip. Test Compounds and Controls Treatment Groups: Eight test compound concentrations 214. ASBES.24.0001.W were applied to the cells from extracellular side (in duplicate per wells / concentration) via the on- board 384-channel pipettor. Duration of exposure to each test article concentration was five minutes. Vehicle control (0.3% DMSO) was applied for a five-minute exposure interval (n = 32, where n = the number of replicates). Positive control (DCPIB; 30 and 5 ^M) was applied for a five-minute exposure interval (n = 16, where n = the number of replicates). Voltage protocol: Onset of inhibition of TMEM175 channels was measured using a stimulus ramp-step voltage protocol repeated every 10 s from the holding potential -90 mV. The protocol was repeated at frequency 0.1 Hz for 3 min before application of test compounds (baseline) and 5 min after application of test compounds. The current amplitudes were measured at test potentials +100 and 0 mV. Potentiation was calculated as: % Potentiation = (I TA - I Baseline) / (IPC#1 Mean - I Baseline) x 100%, where IBaseline and ITA are the currents measured at the test potential 0 mV before a test article application and in the presence of a test article, respectively; IPC#1 Meanis the averaged current elicited with PC #1 (30 ^M DCPIB). The data was corrected for run-up / run-down: %Potentiation’ = 100%- ((%Potentiation - %PC) * (100% / (%VC - %PC)), where %VC and %PC are the mean values of the current potentiation with the vehicle (0.3% DMSO) and with 30 ^M DCPIB, respectively. The results were plotted as Mean ± SD and fit to a Hill equation to calculate EC50values.

[0647] Table A. TMEM175 activation* # EC50, µM # EC50, µM ug,and maximum after a specified exposure time. EC50: A ≤ 10 µM; 10 µM < B ≤ 15 µM; 15 µM < C ≤ 20 µM; 20 < D ≤ 25 µM; E > 25 µM. Equivalents

[0648] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 215. ASB

Claims

ES.24.0001.W CLAIMS What is claimed is:

1. A pharmaceutical composition comprising a compound of Formula (AAA): A), or a pharmaceutically acceptab solvate, or tautomer thereof and apharmaceutically acceptable carrier, wherein: W is selected from ;Y is selected from H, Haloge ; X is selected from O, S, NH,;, , R1is selected from OH, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, -N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; 216. ASBES.24.0001.W each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3; x is an integer selected from 0 and 1; y is an integer selected from 0 and 1.

2. The pharmaceutical composition of claim 1, wherein the compound is of Formula (AA): W A),or a pharmaceutically acc, or tautomer thereof.

3. The pharmaceutical composition of claim 2, wherein the compound is of Formula (A): A), or a pharmaceutically acce, , , , or tautomer thereof, wherein:

217. ASBES.24.0001.W ,(I), or a pharmaceutically ac or tautomer thereof.

5. The pharmaceutical composition of claim 3, wherein the compound is of Formula (II): I), or a pharmaceutically ar tautomer thereof.

6. The pharmaceutical composition of claim 3, wherein the compound is of Formula (III):

218. ASBES.24.0001.W II), or a pharmaceutic omer thereof.

7. The pharmaceutical composition of claim 3, wherein the compound is of Formula (IV): V), or a pharmaceutically a r thereof.

8. The pharmaceutical composition of claim 3, wherein the compound is of Formula (V): V),or a pharmaceutically ar tautomer thereof.

9. The pharmaceutical composition of claim 3, wherein the compound is of Formula (VI):

219. ASBES.24.0001.W N N N HN I), or a pharmaceutic reof.

10. A pharmaceutical composition comprising a compound of Formula (B): B), or a pharmaceutically acceptabl solvate, or tautomer thereof, and apharmaceutically acceptable carrier, wherein: W is selected from ; YY is selected fraryl optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; Y is selected from H, Haloge ; each X is independently selec, , , CH2; ; ASBES.24.0001.W R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3; x is an integer selected from 0 and 1; y is an integer selected from 0 and 1; z is an integer selected from 0 and 1; w is an integer selected from 1, 2, and 3.

11. The pharmaceutical composition of claim 10, wherein the compound is of Formula (B-I): -I), or a pharmaceutically ac, , , , or tautomer thereof.

12. The pharmaceutical composition of claim 10, wherein the compound is of Formula (B-II):

221. ASBES.24.0001.W II), or a pharmaceuticall thereof.

13. A pharmaceutical composition comprising a compound selected from: # Structure IUPAC name c 5- ]a222. ASBES.24.0001.W # Structure IUPAC name b 5- - 2- 2- - 1-223. ASBES.24.0001.W # Structure IUPAC name 2- - - 2- -224. ASBES.24.0001.W # Structure IUPAC name - 6- - -225. ASBES.24.0001.W # Structure IUPAC name - - -226. ASBES.24.0001.W # Structure IUPAC name - - - 6- - 6-227. ASBES.24.0001.W # Structure IUPAC name te y- - -228. ASBES.24.0001.W # Structure IUPAC name 2- 2- - - te 2- 2- teASBES.24.0001.W # Structure IUPAC name o- 6- o- - te )-230. ASBES.24.0001.W # Structure IUPAC name o- )- - 1-231. ASBES.24.0001.W # Structure IUPAC name - d - 6- ic - -232. ASBES.24.0001.W # Structure IUPAC name - - y- - c233. ASBES.24.0001.W # Structure IUPAC name Cl - ]- ic - 5- - 5-234. ASBES.24.0001.W # Structure IUPAC name - - 5- i i -235. ASBES.24.0001.W # Structure IUPAC name - 5- - i 1- - - d236. ASBES.24.0001.W # Structure IUPAC name - - 6- ic - - - - ic237. ASBES.24.0001.W # Structure IUPAC name F F - - o- 6- ic o- d238. ASBES.24.0001.W # Structure IUPAC name - - - - o- i c239. ASBES.24.0001.W # Structure IUPAC name - o- te - - - 1-240. ASBES.24.0001.W # Structure IUPAC name - - 8- - - - e241. ASBES.24.0001.W # Structure IUPAC name - - o- - - - 3- -242. ASBES.24.0001.W # Structure IUPAC name 1- 2- 3- - - - de de243. ASBES.24.0001.W # Structure IUPAC name - - de - e 1- 2-244. ASBES.24.0001.W # Structure IUPAC name - 3- - - e e245. ASBES.24.0001.W # Structure IUPAC name 3- - - - - e246. ASBES.24.0001.W # Structure IUPAC name - - e - - - e - - - - e247. ASBES.24.0001.W # Structure IUPAC name Cl - e - e - de 1-ASBES.24.0001.W # Structure IUPAC name - de - de - - - e - -249. ASBES.24.0001.W # Structure IUPAC name - e - - - - -250. ASBES.24.0001.W # Structure IUPAC name - e - o- - - dASBES.24.0001.W # Structure IUPAC name - 6- ic - - d o-252. ASBES.24.0001.W # Structure IUPAC name 2- - 6- c 2- - 2- o-253. ASBES.24.0001.W # Structure IUPAC name F - - ic - 6- ic254. ASBES.24.0001.W # Structure IUPAC name - d - 1-255. ASBES.24.0001.W # Structure IUPAC name - - ic - 1-256. ASBES.24.0001.W # Structure IUPAC name 2- 6- te - - - 5- - - 5- - - 5-257. ASBES.24.0001.W # Structure IUPAC name 3- - - - - - - - - - -258. ASBES.24.0001.W # Structure IUPAC name thl 2 (2S)24 hl 5- - - - - - - -259. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-chloro-5-meth l-3- - 5- - - 5- - 5- - 5- - 5- -260. ASBES.24.0001.W # Structure IUPAC name - - - - 5-261. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-hlr-5- - 5- - 5- - - - - - -262. ASBES.24.0001.W # Structure IUPAC name methyl 2-[[(2S)-2-[4-chloro-5- - - - - - 5- - - 5-. ASBES.24.0001.W # Structure IUPAC name - 5- - 5- - - -264. ASBES.24.0001.W # Structure IUPAC name F - - - -265. ASBES.24.0001.W # Structure IUPAC name 2 2S 24 hl 5 - - - - - -266. ASBES.24.0001.W # Structure IUPAC name - - - 5- - - -267. ASBES.24.0001.W # Structure IUPAC name F e - - e e - de - - - de268. ASBES.24.0001.W # Structure IUPAC name - de - - de - - ]- - e269. ASBES.24.0001.W # Structure IUPAC name e - ]- de - ]- - - ]- de270. ASBES.24.0001.W # Structure IUPAC name N- n- l]- - ]- e - ]- - - e - ]- e271. ASBES.24.0001.W # Structure IUPAC name - ]- - - ]- - - ]- e - ]- e272. ASBES.24.0001.W # Structure IUPAC name - ]- - de - ]- - )- - de )- de273. ASBES.24.0001.W # Structure IUPAC name 1- e e - -274. ASBES.24.0001.W # Structure IUPAC name - e - o- - - e275. ASBES.24.0001.W # Structure IUPAC name - - - -or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof and a pharmaceutically acceptable carrier.

14. A compound of Formula (A): A), or a pharmaceutically acceor tautomer thereof, wherein: W is selected from ; X is selected from276. ASBES.24.0001.W , xy,-N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

15. The compound of claim 14, wherein the compound is of Formula (I):

277. ASBES.24.0001.W I),or a pharmaceutically ac r tautomer thereof, wherein: X is selected fromO, S, NH, CH2; R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

16. The compound of claim 14, wherein the compound is of Formula (II):

278. ASBES.24.0001.W I), or a pharmaceutically ac tautomer thereof, wherein:X is selected from O, S, NH, CH2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

17. The compound of claim 14, wherein the compound is of Formula (III): II), or a pharmaceuticay p , p g, , , mer thereof, wherein:

279. ASBES.24.0001.W X is selected from O, S, NH, CH2; R1is selected from OH, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, -N(R5)2 wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; each R4is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; two vicinal R3form a double bond; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

18. The compound of claim 14, wherein the compound is of Formula (IV): V), ASBES.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein X is selected from O, S, NH, CH2; R1is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, -N(R5)2wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; R4is selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R5is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; or two R5together with the atom to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

19. The compound of claim 14, wherein the compound is of Formula (V): V), or a pharmaceutically a, , , , r tautomer thereof, wherein 281. ASBES.24.0001.W X is selected from O, S, NH, CH2; R2is selected from C1-C6alkyl and C3-C10cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy; or two vicinal R3form a double bond; R4is selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

20. The compound of claim 14, wherein the compound is of Formula (VI): N N N I), or a pharmaceuticmer thereof, wherein X is selected from O, S, NH, CH2; R2is selected from C1-C6 alkyl and C3-C10 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; each R3is independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, aryl, O-aryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, or aryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy; or two vicinal R3form a double bond; 282. ASBES.24.0001.W each R4is independently selected from halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl or cycloalkoxy is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 1, 2, and 3.

21. A compound selected from: # Structure IUPAC name 2- 2- - 1- 2-283. ASBES.24.0001.W # Structure IUPAC name - - 2- - -284. ASBES.24.0001.W # Structure IUPAC name F 6- - -285. ASBES.24.0001.W # Structure IUPAC name - - - -286. ASBES.24.0001.W # Structure IUPAC name - - 6- - 6- te287. ASBES.24.0001.W # Structure IUPAC name F y- - - 2-288. ASBES.24.0001.W # Structure IUPAC name 2- - - te 2- 2- te289. ASBES.24.0001.W # Structure IUPAC name o- 6- o- - te )-290. ASBES.24.0001.W # Structure IUPAC name o- )- - 1-291. ASBES.24.0001.W # Structure IUPAC name - d - 6- ic - -292. ASBES.24.0001.W # Structure IUPAC name - - y- - c293. ASBES.24.0001.W # Structure IUPAC name Cl - ]- ic - 5- - 5-294. ASBES.24.0001.W # Structure IUPAC name - - 5- i i -295. ASBES.24.0001.W # Structure IUPAC name - 5- - i 1- - - d296. ASBES.24.0001.W # Structure IUPAC name - - 6- ic - - - - ic297. ASBES.24.0001.W # Structure IUPAC name F F - - o- 6- ic o- d298. ASBES.24.0001.W # Structure IUPAC name - - - - o- i c299. ASBES.24.0001.W # Structure IUPAC name - o- - - - 1- -300. ASBES.24.0001.W # Structure IUPAC name - - o- - - - 3- -301. ASBES.24.0001.W # Structure IUPAC name 1- 2- 3- - - - de de302. ASBES.24.0001.W # Structure IUPAC name - - de - e 1- 2-303. ASBES.24.0001.W # Structure IUPAC name - 3- - - e e304. ASBES.24.0001.W # Structure IUPAC name 3- - - - - e305. ASBES.24.0001.W # Structure IUPAC name - - e - - - e - - - - e306. ASBES.24.0001.W # Structure IUPAC name Cl - e - e - de 1-ASBES.24.0001.W # Structure IUPAC name - de - de - - - e - -308. ASBES.24.0001.W # Structure IUPAC name - e - - - - -309. ASBES.24.0001.W # Structure IUPAC name - e - o- - - dASBES.24.0001.W # Structure IUPAC name - 6- ic - - d o-311. ASBES.24.0001.W # Structure IUPAC name 2- - 6- c 2- - 2- o-312. ASBES.24.0001.W # Structure IUPAC name F - - ic - 6- ic313. ASBES.24.0001.W # Structure IUPAC name - d - 1-314. ASBES.24.0001.W # Structure IUPAC name - - ic - 1-315. ASBES.24.0001.W # Structure IUPAC name 2- 6- te - - - 5- - - 5- - - 5-316. ASBES.24.0001.W # Structure IUPAC name 3- - - - - - - - - - -317. ASBES.24.0001.W # Structure IUPAC name mthl 2-[[(2S)-2-[4-hlr-5- - - 3- - ]- - - - - 3- - ]-318. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-chloro-5-meth l-3- - 5- - - 5- - 5- - 5- - 5- -319. ASBES.24.0001.W # Structure IUPAC name - - - - 5-320. ASBES.24.0001.W # Structure IUPAC name 2-[[(2S)-2-[4-hlr-5- - 5- - 5- - - - - - -321. ASBES.24.0001.W # Structure IUPAC name methyl 2-[[(2S)-2-[4-chloro-5- - - - - - 5- - - 5-. ASBES.24.0001.W # Structure IUPAC name - 5- - 5- - - -323. ASBES.24.0001.W # Structure IUPAC name F - - - -324. ASBES.24.0001.W # Structure IUPAC name 2 2S 24 hl 5 - - - - - -325. ASBES.24.0001.W # Structure IUPAC name - - - 5- - - -326. ASBES.24.0001.W # Structure IUPAC name F e - - e e - de - - - de327. ASBES.24.0001.W # Structure IUPAC name - de - - de - - ]- - e328. ASBES.24.0001.W # Structure IUPAC name e - ]- de - ]- - - ]- de329. ASBES.24.0001.W # Structure IUPAC name N- n- l]- - ]- e - ]- - - e - ]- e330. ASBES.24.0001.W # Structure IUPAC name - ]- - - ]- - - ]- e - ]- e331. ASBES.24.0001.W # Structure IUPAC name - ]- - de - ]- - )- - de )- de332. ASBES.24.0001.W # Structure IUPAC name 1- e e - -333. ASBES.24.0001.W # Structure IUPAC name - e - o- - - e334. ASBES.24.0001.W # Structure IUPAC name - - - -22. A method of activating of TMEM175 Ion Channel in a cell, comprising contacting the cell with a compound of Formula (AAA).

23. The method of claim 22, wherein the contacting is in vitro or in vivo.

24. The method of claim 22, wherein the compound is of Formula (AA).

25. The method of claim 22, wherein the compound is of Formula (A).

26. The method of claim 22, wherein the compound is of Formula (I).

27. The method of claim 22, wherein the compound is of Formula (II).

28. The method of claim 22, wherein the compound is of Formula (III).

29. The method of claim 22, wherein the compound is of Formula (IV).

30. The method of claim 22, wherein the compound is of Formula (V).

31. The method of claim 22, wherein the compound is of Formula (VI).

32. A method of activating of TMEM175 Ion Channel activity in a cell, comprising contacting the cell with a compound of Formula (B).

335. ASBES.24.0001.W 33. The method of claim 32, wherein the contacting is in vitro or in vivo.

34. The method of claim 32, wherein the compound is of Formula (B-I).

35. The method of claim 32, wherein the compound is of Formula (B-II).

36. A method for the treatment, mitigation, or prevention of a disease or disorder associated with disfunctions of TMEM175 Ion Channel comprising administering to a subject in need thereof a compound of Formula (AAA).

37. The method of claim 36, wherein the compound is of Formula (AA).

38. The method of claim 36, wherein the compound is of Formula (A).

39. The method of claim 36, wherein the compound is of Formula (I).

40. The method of claim 36, wherein the compound is of Formula (II).

41. The method of claim 36, wherein the compound is of Formula (III).

42. The method of claim 36, wherein the compound is of Formula (IV).

43. The method of claim 36, wherein the compound is of Formula (V).

44. The method of claim 36, wherein the compound is of Formula (VI).

45. The method of claim 36, wherein the disease or disorder is selected from the group comprising Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP).

46. A method for the treatment, mitigation, or prevention of a disease or disorder associated with disfunctions of TMEM175 Ion Channel comprising administering to a subject in need thereof a compound of Formula (B).

47. The method of claim 46, wherein the compound is of Formula (B-I).

48. The method of claim 46, wherein the compound is of Formula (B-II).

49. The method of claim 46, wherein the disease or disorder is selected from the group comprising Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP).

50. The method of any one of claims 22-49, wherein the subject is a mammal.

51. The method of claim 50, wherein the subject is a human.

52. A use of a compound of Formula (AAA) for activating of TMEM175 Ion Channel in a cell.

336. ASBES.24.0001.W 53. The use of claim 52, wherein the compound is of Formula (AA).

54. The use of claim 52, wherein the compound is of Formula (A).

55. The use of claim 52, wherein the compound is of Formula (I).

56. The use of claim 52, wherein the compound is of Formula (II).

57. The use of claim 52, wherein the compound is of Formula (III).

58. The use of claim 52, wherein the compound is of Formula (IV).

59. The use of claim 52, wherein the compound is of Formula (V).

60. The use of claim 52, wherein the compound is of Formula (VI).

61. A use of a compound of Formula (B) for activating of TMEM175 Ion Channel in a cell.

62. The use of claim 61, wherein the compound is of Formula (B-I).

63. The use of claim 61, wherein the compound is of Formula (B-II).

64. A use a compound of Formula (AAA) for the treatment, mitigation, or prevention of a disease or disorder associated with disfunctions of TMEM175 Ion Channel.

65. The use of claim 64, wherein the compound is of Formula (AA).

66. The use of claim 64, wherein the compound is of Formula (A).

67. The use of claim 64, wherein the compound is of Formula (I).

68. The use of claim 64, wherein the compound is of Formula (II).

69. The use of claim 64, wherein the compound is of Formula (III).

70. The use of claim 64, wherein the compound is of Formula (IV).

71. The use of claim 64, wherein the compound is of Formula (V).

72. The use of claim 64, wherein the compound is of Formula (VI).

73. The use of claim 64, wherein the disease or disorder is selected from the group comprising Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP).

74. A use a compound of Formula (B) for the treatment, mitigation, or prevention of a disease or disorder associated with disfunctions of TMEM175 Ion Channel.

75. The use of claim 74, wherein the compound is of Formula (B-I).

76. The use of claim 74, wherein the compound is of Formula (B-II).

337. ASBES.24.0001.W 77. The use of claim 74, wherein the disease or disorder is selected from the group comprising Neurological Disorders, Parkinson’s Disease, Alzheimer's disease, dementia with Lewy bodies (DLB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP).

78. The use of any one of claims 52-77, wherein the subject is a mammal.

79. The use of claim 78, wherein the subject is a human.

338. ASB

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