Proteasome activity enhancing compounds

Abstract

To provide compounds to treat conditions associated with proteostasis dysfunction and / or to provide therapies based on enhancing proteasome activity.SOLUTION: The present invention provides a compound having a structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 690,554, filed June 27, 2018, the disclosure of which is incorporated herein by reference as if set forth in its entirety. [Background technology]

[0002] Cells normally utilize a network of sensors and pathways to maintain a balance between protein synthesis, folding, trafficking, aggregation, and degradation, a process called protein homeostasis [Sitia et al., Nature 426:891-894, 2003; Ron et al., Nat Rev Mol Cell Biol 8:519-529, 2007]. Cellular maintenance of protein homeostasis, or protein homeostasis, refers to the control of the conformation, binding interactions, location, and concentration of individual proteins that make up the proteome. Protein folding in vivo is achieved by interactions between the folding polypeptide chain and macromolecular cellular components, including multiple classes of chaperones and folding enzymes that minimize aggregation (Wiseman et al., Cell 131:809-821 (2007)). Whether a particular protein folds in a particular cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, and metabolites (Wiseman et al.). Loss-of-function diseases in humans are the result of a breakdown in normal protein homeostasis and are typically caused by mutations in a given protein that impair cellular folding and cause it to be efficiently degraded (Cohen et al., Nature 426:905-909, 2003). Similarly, gain-of-function diseases in humans are the result of a breakdown in protein homeostasis, such as the accumulation of misfolded proteins, which often lead to protein aggregation (Balch et al., Science 319:916-919 (2008)).

[0003] The proteasome is a large protein complex consisting of multiple subunits that functions as a protease to degrade misfolded proteins. Most proteasome substrates are targeted for degradation by covalent attachment of a ubiquitin moiety that is recognized by the proteasome (Lee et al., 2010, Nature 467:7312, 179-184). Proteins with long ubiquitin chains tend to associate more strongly with the proteasome than proteins with smaller chains (Lee et al., 2010; Proctor et al., 2007, BMC Systems Biology 1:17). The length of the ubiquitin chains is regulated in part by proteasome-associated deubiquitinases. One such mammalian deubiquitinase is Usp14, which has been shown to act as an inhibitor of the proteasome (Lee et al., 2010).

[0004] Both proteasome dysfunction and dysfunction of protein homeostasis have been implicated in a diverse range of diseases, including, for example, neurodegenerative diseases, metabolic diseases, inflammatory diseases, and cancer. In many such diseases and conditions, the proteasome is impaired in its ability to degrade misfolded or abnormal proteins, leading to the generation of toxic protein aggregates. Moreover, enhancing proteasome activity may be able to treat any disease characterized by a deficiency in proteasome activity or activity of other components of the ubiquitin-proteasome pathway, including, but not limited to, von Hippel-Lindau disease, spinocerebellar degeneration type 1, Angelman syndrome, giant axonal neuropathy, inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), and others (Lehman, NL (2009) Acta Neuropathologica 118(3):329-347; Weihl et al. (2007) Neuromuscular Disorders 17(87-87). Enhancement of proteasome activity may also treat diseases in which proteasome substrates contribute to pathology but do not meet the strict definition of a proteinopathy. For example, numerous oncoproteins are proteasome substrates and their ability to promote cancer could potentially be attenuated by enhancing proteasome activity.

[0005] Thus, there is a need for compounds and pharmaceutical compositions for treating conditions associated with proteostasis dysfunction and / or for providing therapies based on enhancing proteasome activity. Summary of the Invention

[0006] The present invention is based, in part, on the discovery that the compounds of the invention inhibit Usp14. The present invention relates to compounds encompassed by formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, compositions thereof, methods of treating a condition associated with dysfunction of protein homeostasis, methods of enhancing proteasome activity, and methods of treating cancer or tumors.

[0007] In one embodiment, the present invention provides a compound having formula (I): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D1 is any of C1 to C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, and optionally substituted naphthyl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. dS(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)O.R. c , O.C.(O)R c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R6 and R7 is independently selected from the group consisting of optionally substituted C1-C4 alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; Each n is independently 0, 1, or 2.

[0008] In additional embodiments, the present invention provides a compound having formula (IIa) or formula (IIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, N3, halo, OR c, N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R3, R4, and R5 is selected from hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0009] In still further embodiments, the invention relates to compounds as shown in Table 1 below.

[0010] In some embodiments, the present invention provides a compound having formula (IIIa) or (IIIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Z is NR b R b , optionally substituted 6-membered N-heteroaryl, and optionally substituted N-heterocycle; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0011] In some embodiments, the compound has the formula (IV): TIFF2024112835000004.tif91170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)Rc , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Each R b is hydrogen, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, cyclopropyl, cycloheptyl, TIFF2024112835000005.tif127170; Each R cis hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0012] In some embodiments, the compound has the formula (V): TIFF2024112835000006.tif75170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or optionally substituted C1-C4 alkyl; R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, and cyclopropyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c, C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; and Each R 10 is hydrogen and optionally substituted C1-C 10 alkyl.

[0013] In some embodiments, the present invention provides a compound having formula (VI): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X1 and X2 are independently carbon or nitrogen, where one of X1 or X2 is nitrogen; X4 is N or C(R7); R1 is hydrogen or C 1~4 is alkyl; R2 is hydrogen, optionally substituted C 1~4 Alkyl and optionally substituted C 3~8 cycloalkyl; Each R3 and R4 is hydrogen, C 1~4 Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; Each R5 and R6 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; or R5 and R6, taken together with X4, form an optionally substituted 5-membered heterocycle, an optionally substituted 6-membered heterocycle, an optionally substituted 5-membered heteroaryl, or an optionally substituted 6-membered heteroaryl; and R7 is hydrogen or C 1~4 is alkyl; wherein the optionally substituted R2, R5, and R6 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0014] In some embodiments, the present invention provides a compound having formula (VII): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1, R3, and R4 is hydrogen, C 1~4 Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; R 2a Each of these is hydrogen, C 1~4 Alkyl, C 1~4 selected from the group consisting of haloalkyl, halo, CN, CONH2, COOH, and COO-benzyl; R 5a each is selected from the group consisting of hydrogen and OH; each n is independently 0, 1, or 2; q is 0, 1, or 2; r is 1 or 2; and s is 1, 2, or 3.

[0015] In some embodiments, the present invention provides a compound having formula (VIII): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X1 and X2 are independently carbon or nitrogen, where one of X1 or X2 is nitrogen; X4 is N or C(R7); R1 is an optionally substituted C 1~4 Alkyl, optionally substituted C 3~8 Cycloalkyl and optionally substituted C 5~6 aryl; R2 is hydrogen or C 1~4 is alkyl; Each R3 and R4 is hydrogen, C 1~4Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; Each R5 and R6 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; or R5 and R6, taken together with X4, form an optionally substituted 5- to 6-membered heterocycle, or an optionally substituted 5- to 6-membered heteroaryl; and R7 is hydrogen or C 1~4 is alkyl; wherein the optionally substituted R1, R5, and R6 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0016] In some embodiments, the present invention provides a compound having formula (IX): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: R8 is C 1~4 Alkyl or NR 8a R 8b where R 8a -OC 1~4 Hydrogen, C, optionally substituted with alkyl 5~6 aryl, and 5-6 membered heteroaryl; R 5a Each of c or NR d R d C optionally substituted with 1~4 Alkyl, halo, C 1~4 Haloalkyl, OR c , COOR c , N.R. d R d ,CONR d R d ,OCONR d R d , and S(O) n R c selected from the group consisting of; Each R cis hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl, C 1~4 independently selected from the group consisting of haloalkyl, phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 independently selected from the group consisting of cycloalkyl, and heteroaryl optionally substituted with -OCH3; Or two R's d together form a heterocyclyl; each n is independently 0, 1, or 2; q is 0, 1, or 2; and r is 1 or 2.

[0017] In some embodiments, the present invention provides a compound having the formula (X): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: R 5a Each of c or NR d R d C optionally substituted with 1~4 Alkyl, halo, C 1~4 Haloalkyl, OR c , COOR c , N.R. d R d ,CONR d R d ,OCONR d R d , and S(O) n R c selected from the group consisting of; Each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl, C 1~4independently selected from the group consisting of haloalkyl, phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 independently selected from the group consisting of cycloalkyl, and heteroaryl optionally substituted with -OCH3; Or two R's d together form a heterocyclyl; each n is independently 0, 1, or 2; q is 0, 1, or 2; and r is 1 or 2.

[0018] In additional embodiments, the present invention relates to a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas.

[0019] In an additional aspect, the invention relates to a method of inhibiting the deubiquitinating activity of Usp14 protein comprising contacting the Usp14 protein with an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas, in an amount sufficient to inhibit the deubiquitinating activity of the Usp14 protein.

[0020] In yet another embodiment, the present invention relates to a method of enhancing proteasomal protein degradation in a cell comprising contacting the cell with an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of those formulas, in an amount sufficient to enhance proteasomal protein degradation.

[0021] In additional embodiments, the invention encompasses a method of treating a patient suffering from a condition related to dysfunction of protein homeostasis comprising administering to said patient an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas.

[0022] In another aspect, the present invention relates to a method of enhancing proteasome function in a subject in need thereof comprising administering to said subject an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, solvate, clathrate, or prodrug of any compound of any of those formulas.

[0023] In a further embodiment, the present invention relates to a method for treating a condition characterized by defective proteasome activity or other components of the ubiquitin-proteasome pathway in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas.

[0024] In yet another embodiment, the present invention encompasses a method of treating cancer or tumor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas.

[0025] In a further aspect, the present invention provides a method for the preparation of a method for treating a pulmonary artery disease comprising: a pharma- ceutically acceptable carrier or excipient; and an agent selected from the group consisting of a proteostasis regulator and a pharmacological chaperone; and and a compound X) of formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any compound of any of those formulas. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] A description of a preferred embodiment of the present invention follows.

[0027] As used herein, the words "a" and "an" are meant to include one or more, unless otherwise specified. For example, the term "a cell" encompasses both a single cell and a combination of two or more cells.

[0028] Compounds of formula (I) In some embodiments, the present invention relates to compounds of formula (I), or pharma- ceutically acceptable salts, solvates, clathrates, or prodrugs thereof, pharmaceutical compositions thereof, methods of their use in the treatment of conditions associated with dysfunction of protein homeostasis, methods of enhancing proteasome activity, and methods for treating cancer or tumors.

[0029] In one embodiment, the present invention provides a compound having formula (I): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D1 is any of C1 to C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, and optionally substituted naphthyl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, N3, halo, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n Rc , S(O) n NR d R d , O.C.(O)O.R. c , O.C.(O)R c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0030] In some embodiments, in the compound of formula (I), the optionally substituted Z, D1, R1, R2, R6, and R7 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0031] In some embodiments, the present invention relates to a compound in which D1 is an optionally substituted C1-C 10 In some embodiments, D1 is -CH2CF3. In some embodiments, D1 is -CH2CF3.

[0032] In yet an additional embodiment, the present invention relates to an optionally substituted C3-C 12 In some embodiments, D1 is an optionally substituted C3-C6 cycloalkyl. In additional embodiments, D1 is an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl. In certain embodiments, D1 is an optionally substituted cyclohexyl. In some embodiments, the present invention relates to compounds of formula (I) where D1 is an optionally substituted naphthyl.

[0033] In some embodiments, the present invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is: TIFF2024112835000013.tif165170.

[0034] In certain aspects, the present invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is an optionally substituted naphthyl.

[0035] In some embodiments, the present invention provides a compound of formula (Ia) or formula (Ib): TIFF2024112835000014.tif88170 or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, N3, halo, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d Rd , O.C.(O)O.R. c , O.C.(O)R c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; D2 and D3 are hydrogen, CN, fluoro, chloro, -COOH, -CONH2, and TIFF2024112835000015.tif26170; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; dthe groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0036] In some embodiments, in the compound of Formula (Ia) or Formula (Ib), the optionally substituted Z, D2, D3, R1, R2, R6, and R7 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's dtogether with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0037] In yet further embodiments, the invention relates to a compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each independently selected from methyl and ethyl. In further aspects, R6 and R7 are each methyl.

[0038] In some embodiments, the present invention is directed to a compound of formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each of R1 and R2 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O)n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl. In yet further embodiments, R1 and R2 are independently selected from the group consisting of hydrogen and optionally substituted C1-C 10 In some embodiments, R and R are each independently selected from alkyl, aryl ... and alkyl. In some embodiments, R and R are each independently selected from alkyl, aryl, aryl, aryl and alkyl.

[0039] In yet further embodiments, the compound has formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is NR b R b In certain embodiments, each R b is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C3-C 12 cycloalkyl.

[0040] In some embodiments, the compound has formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is an optionally substituted N-heterocycle. In some aspects, Z is 1-pyrrolidinyl or 1-piperidinyl, each of which is optionally substituted.

[0041] In some embodiments, the compound has Formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 5-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0042] In some embodiments, the compound has Formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0043] In additional embodiments, the compound has formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 1-pyrrolidinyl or an optionally substituted 1-piperidinyl, R6 and R7 are each methyl, and R1 and R2 are each hydrogen.

[0044] In some embodiments, the compound has formula (I), (Ia), or (Ib), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is TIFF2024112835000016.tif50170.

[0045] In some embodiments, the compound is selected from the compounds set forth in Table 1 below. [Table 1] TIFF2024112835000018.tif232170TIFF2024112835000019.tif198170TIFF2024112835000020.tif224170

[0046] Compounds of formula (IIa) or (IIb) In some embodiments, the present invention relates to compounds of formula (IIa) or (IIb), or pharma- ceutically acceptable salts, solvates, clathrates, or prodrugs thereof, pharmaceutical compositions thereof, methods of their use in the treatment of conditions associated with dysfunction of protein homeostasis, methods of enhancing proteasome activity, and methods for treating cancer or tumors.

[0047] The present invention further relates to a compound having the formula (IIa) or (IIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, N3, halo, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c, (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R3, R4, and R5 is selected from hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0048] In some embodiments, in the compound of formula (IIa) or (IIb), the optionally substituted Z, D2, R1, R2, R3, R4, and R5 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0049] In some embodiments, the present invention relates to a compound having the formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, provided that the compound is: Not TIFF2024112835000022.tif98170.

[0050] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D2 is an optionally substituted phenyl.

[0051] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D2 is The file is TIFF2024112835000023.tif26170.

[0052] In some embodiments, the present invention is directed to a compound of formula (IIa) or formula (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each of R1 and R2 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, OR c , N.R. d R d , C(O)ORc , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl. In yet further embodiments, R1 and R2 are independently selected from the group consisting of hydrogen and optionally substituted C1-C 10 In some embodiments, R and R are each independently selected from alkyl, aryl, aryl, aryl and alkyl. In some embodiments, R and R are each independently selected from alkyl ...

[0053] In some embodiments, the present invention relates to compounds of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R5 is hydrogen.

[0054] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R3 and R4 are each independently selected from optionally substituted C1-C4 alkyl. In still further embodiments, R3 and R4 are each methyl.

[0055] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is NR b R b In some embodiments, each R b is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C3-C 12 cycloalkyl.

[0056] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted N-heterocycle. In certain aspects, Z is an optionally substituted 1-pyrrolidinyl or an optionally substituted 1-piperidinyl.

[0057] In some embodiments, the present invention relates to a compound of Formula (IIa) or (IIb), or a pharma-ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 5-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0058] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0059] In some embodiments, the present invention relates to a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is TIFF2024112835000024.tif44170.

[0060] The present invention further includes the compounds shown in Table 2 below. [Table 2]

[0061] Compounds of formula (IIIa) or (IIIb) In some embodiments, the present invention relates to compounds of formula (IIIa) or (IIIb), or pharma- ceutically acceptable salts, solvates, clathrates, or prodrugs thereof, pharmaceutical compositions thereof, methods of their use in the treatment of conditions associated with dysfunction of protein homeostasis, methods of enhancing proteasome activity, and methods for treating cancer or tumors.

[0062] The present invention further relates to a compound having formula (IIIa) or (IIIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c, C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Z is NR b R b , optionally substituted 6-membered N-heteroaryl, and optionally substituted N-heterocycle; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0063] In some embodiments, in the compound of formula (IIIa) or (IIIb), optionally substituted Z, R, R, R, R, R, R, R, R, R, R, and R 10 The substituents of are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0064] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 and R2 are selected from hydrogen and optionally substituted C1-C 10 alkyl.

[0065] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 and R2 are each hydrogen.

[0066] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or C1-C4 alkyl.

[0067] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or methyl.

[0068] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, and cyclopropyl.

[0069] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each methyl.

[0070] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4, R6, and R7 are each hydrogen.

[0071] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4, R6, and R7 are each methyl.

[0072] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is an optionally substituted N-heterocycle.

[0073] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is an optionally substituted 5-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0074] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is an optionally substituted 6-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0075] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is 1-pyrrolidinyl or 1-piperidinyl, each optionally substituted.

[0076] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Z is TIFF2024112835000027.tif108170.

[0077] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Z is TIFF2024112835000028.tif63170TIFF2024112835000029.tif231170TIFF2024112835000030.tif68170.

[0078] In some embodiments, the compound has Formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is an optionally substituted N-heteroaryl.

[0079] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Z is The file is TIFF2024112835000031.tif25170.

[0080] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where Z is NR b R b It is.

[0081] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R b is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C3-C 12 cycloalkyl.

[0082] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R b is hydrogen, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, cyclopropyl, cycloheptyl, TIFF2024112835000032.tif165170.

[0083] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R and R 10 is hydrogen.

[0084] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R is hydrogen and each R 10 is independently hydrogen, chloro, or fluoro.

[0085] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R is methyl and each R 10 is hydrogen.

[0086] In some embodiments, the compound has formula (IIIa) or (IIIb), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R is hydrogen, hydroxyl, fluoro, chloro, bromo, -CN, -OCH, -CF, -OCF, -COOH, -SOCH, TIFF2024112835000033.tif57170. In some embodiments, the compound has formula (IIIc), formula (IIId), formula (IIIe), or formula (IIIf): TIFF2024112835000034.tif179170TIFF2024112835000035.tif177170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NRd R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Each Z2 is hydrogen, hydroxy, -F, -CH3, -CF3, -CH2NH2, -N(CH3)2, -CH2N(CH3)2, -CH2CH2OH, -COOH, -CONH2, -SO2CH3, -OCH2CONHCH2CH3, -OCH2CONHC(CH3)2, -OCH2CONHCH2CH2CH3, -CH2NHCOOC(CH3)2, -N(CH3)2, Independently selected from the group consisting of: TIFF2024112835000036.tif94170; Each R bis hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0087] In some embodiments, in the compound of Formula (IIIc), Formula (IIId), Formula (IIIe), or Formula (IIIf), optionally substituted Z, R, R, R, R, R, R, R, R, R, and R 10 The substituents of are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0088] In some embodiments, the compound has Formula (IIIc), Formula (IIId), Formula (IIIe), or Formula (IIIf), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each Z2 is independently hydrogen or hydroxyl; each of R1, R2, R4, R6, R7, and R9 is hydrogen; and each R 10 is methyl; R8 is --COOH, chloro, or CN.

[0089] In some embodiments, the compound has Formula (IIIc), Formula (IIId), Formula (IIIe), or Formula (IIIf), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each Z2 is independently hydrogen or hydroxyl; R1, R2, R4, R7, R9, and R 10 is hydrogen; R6 is methyl or ethyl; and R8 is -COOH, chloro, or CN.

[0090] In some embodiments, the compound has Formula (IIIc), Formula (IIId), Formula (IIIe), or Formula (IIIf), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each Z2 is independently hydrogen or hydroxyl; R4 is hydrogen; R9 and R 10 is hydrogen or halo, each of R6 and R7 is methyl, and R8 is hydrogen, hydroxyl, fluoro, chloro, bromo, -CN, -OCH3, -CF3, -OCF3, -COOH, -SO2CH3, TIFF2024112835000037.tif57170.

[0091] In some embodiments, the compound has formula (IIIg) or formula (IIIh): TIFF2024112835000038.tif88170 or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: R8 is hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Here, Z is Selected from the group consisting of TIFF2024112835000039.tif54170; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and each n is independently 0, 1, or 2; However, the compound is as follows: Not TIFF2024112835000040.tif30170.

[0092] In some embodiments of the compounds having Formula (IIIg) or (IIIh), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, R8 is chloro.

[0093] Compound of formula (IV) In some embodiments, the compound has the formula (IV): TIFF2024112835000041.tif92170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) nNR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Each R b is hydrogen, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, cyclopropyl, cycloheptyl, Independently selected from the group consisting of: TIFF2024112835000042.tif128170; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0094] In some embodiments, in the compound of formula (IV), optionally substituted R b , R1, R2, R4, R5, R6, R7, R8, R9, and R 10 The substituents of are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONRd R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0095] In some embodiments, the compound has formula (IV) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where R4 is hydrogen; each R6 and R7 is methyl; and each R9 and R 10 are each hydrogen; R8 is CN.

[0096] Compound of formula (V) In some embodiments, the compound has the formula (V): TIFF2024112835000043.tif74170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or optionally substituted C1-C4 alkyl; R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, and cyclopropyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) nNR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; and Each R 10 is hydrogen and optionally substituted C1-C 10 alkyl.

[0097] In some embodiments, in the compound of formula (V), optionally substituted R, R, R, R, R, and R 10 The substituents of are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0098] In some embodiments, the compound has formula (V) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R, R, and R 10 each is hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano.

[0099] In some embodiments, the compound has formula (V) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where R4 is an optionally substituted methyl; R9 and R 10 are each independently hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano.

[0100] In some embodiments, the compound has formula (V) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is: TIFF2024112835000044.tif28170; R9 and R 10 each is hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano.

[0101] Compounds of formula (VI) and formula (VII) In some embodiments, the compound has the structure of Formula (VI): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X1 and X2 are independently carbon or nitrogen, where one of X1 or X2 is nitrogen; X4 is N or C(R7); R1 is hydrogen or C 1~4 is alkyl; R2 is hydrogen, optionally substituted C 1~4 Alkyl and optionally substituted C 3~8 cycloalkyl; Each R3 and R4 is hydrogen, C 1~4 Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; Each R5 and R6 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; or R5 and R6, taken together with X4, form an optionally substituted 5-membered heterocycle, an optionally substituted 6-membered heterocycle, an optionally substituted 5-membered heteroaryl, or an optionally substituted 6-membered heteroaryl; and R7 is hydrogen or C 1~4 is alkyl; wherein the optionally substituted R2, R5, and R6 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O)n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl; and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0102] In some embodiments, the compound has formula (VI) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X1 is carbon and X2 and X4 are each nitrogen.

[0103] In some embodiments, the compound has formula (VI) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 is methyl.

[0104] In some embodiments, the compound has formula (VI) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R2 is an optionally substituted cyclobutyl.

[0105] In some embodiments, the compound has formula (VI) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: is an optionally substituted cyclohexyl.

[0106] In some embodiments, the compound has formula (VI) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R5 and R6 are joined with X4 to form an optionally substituted 5-membered heterocycle or an optionally substituted 6-membered heterocycle.

[0107] In some embodiments, the compound has the structure of formula (VII): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1, R3, and R4 is hydrogen, C 1~4 Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; R 2a Each of these is hydrogen, C 1~4 Alkyl, C 1~4 selected from the group consisting of haloalkyl, halo, CN, CONH2, COOH, and COO-benzyl; R 5a each is selected from the group consisting of hydrogen and OH; each n is independently 0, 1, or 2; q is 0, 1, or 2; r is 1 or 2; and s is 1, 2, or 3.

[0108] In some embodiments, the compound has formula (VI) or (VII), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the compound is selected from the group consisting of: TIFF2024112835000047.tif127170TIFF2024112835000048.tif226170TIFF2024112835000049.tif188170TIFF2024112835000050.tif135170

[0109] In some embodiments, the compound has the structure of Formula (VIII): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X1 and X2 are independently carbon or nitrogen, where one of X1 or X2 is nitrogen; X4 is N or C(R7); R1 is an optionally substituted C 1~4 Alkyl, optionally substituted C 3~8 Cycloalkyl and optionally substituted C 5~6 aryl; R2 is hydrogen or C 1~4 is alkyl; Each R3 and R4 is hydrogen, C 1~4 Alkyl, and C 3~8 independently selected from the group consisting of cycloalkyl; Each R5 and R6 is hydrogen, an optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; or R5 and R6, taken together with X4, form an optionally substituted 5- to 6-membered heterocycle, or an optionally substituted 5- to 6-membered heteroaryl; and R7 is hydrogen or C 1~4 is alkyl; wherein the optionally substituted R1, R5, and R6 substituents are OR c or NR d R d C optionally substituted with 1~4 Alkyl;CN;Halo;C 1~4 Haloalkyl;C 2~4 Alkynyl; C 4~6 Cycloalkyl;C 1~4 5-membered heterocyclyl optionally substituted with alkyl; OR c ;COR c ;COOR c ;NR d R d ;CONR d R d ;OCONR d R d ;S(O) n R c ; and S(O) n NR d R d each independently selected from the group consisting of: Here, each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl;C 1~4 independently selected from the group consisting of haloalkyl; phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; and Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 Cycloalkyl and -OC 1~4 independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or two R's d together with the nitrogen form a 3- to 6-membered heterocyclyl; Each n is independently 0, 1, or 2.

[0110] In some embodiments, the compound has the structure of formula (VIII), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X1 and X4 are each nitrogen and X2 is carbon.

[0111] In some embodiments, the compound has formula (VIII) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 is an optionally substituted phenyl.

[0112] In some embodiments, the compound has the formula (VIII) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the phenyl has at least one C 1~4 It is substituted with alkyl and at least one halogen.

[0113] In some embodiments, the compound has formula (VIII) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R2, R3, and R4 are each hydrogen.

[0114] In some embodiments, the compound has formula (VIII) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R5 and R6 are joined with X4 to form an optionally substituted 5-6 membered heterocycle or an optionally substituted 5-6 membered heteroaryl.

[0115] In some embodiments, the compound has the formula (VIII) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the compound is: TIFF2024112835000052.tif84170.

[0116] Compound of formula (IX) In some embodiments, the compound has the structure of formula (IX): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: R8 is C 1~4 Alkyl or NR 8a R 8b where R 8a -OC 1~4 Hydrogen, C, optionally substituted with alkyl 5~6 aryl, and 5-6 membered heteroaryl; R 5a Each of c or NR d R d C optionally substituted with 1~4 Alkyl, halo, C 1~4 Haloalkyl, OR c , COOR c , N.R. d R d ,CONR d R d ,OCONR d R d , and S(O) n R c selected from the group consisting of; Each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl, C 1~4 independently selected from the group consisting of haloalkyl, phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 independently selected from the group consisting of cycloalkyl, and heteroaryl optionally substituted with -OCH3; Or two R's d together form a heterocyclyl; each n is independently 0, 1, or 2; q is 0, 1, or 2; and r is 1 or 2.

[0117] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R is C 1~4 It is an alkyl.

[0118] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R8 is methyl.

[0119] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R8 is NR 8a R 8b It is.

[0120] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 8a is pyrimidinyl.

[0121] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 8a is substituted with methoxy.

[0122] In some embodiments, the compound has the structure of formula (IX), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, where r is 2:

[0123] In some embodiments, the compound has formula (IX) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the compound is selected from the group consisting of: TIFF2024112835000054.tif253170

[0124] Compound of formula (X) In some embodiments, the compound has the structure of formula (X): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: R 5a Each of c or NR d R d C optionally substituted with 1~4 Alkyl, halo, C 1~4 Haloalkyl, OR c , COOR c , N.R. d R d ,CONR d R d ,OCONR d R d , and S(O) n R c selected from the group consisting of; Each R c is hydrogen, phenyl or CONR d R d C optionally substituted with 1~4 Alkyl, C 1~4 independently selected from the group consisting of haloalkyl, phenyl, and heteroaryl optionally substituted with -CH3 or phenyl; Each R d is hydrogen, C 1~4 Alkyl, COOC 1~4 Alkyl, C3-C 12 independently selected from the group consisting of cycloalkyl, and heteroaryl optionally substituted with -OCH3; Or two R's d together form a heterocyclyl; each n is independently 0, 1, or 2; q is 0, 1, or 2; and r is 1 or 2.

[0125] In some embodiments, the compound has the formula (X) or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the compound is selected from the group consisting of: TIFF2024112835000056.tif147170

[0126] The present invention further includes the compounds shown in Table 3 below. [Table 3] TIFF2024112835000058.tif192170TIFF2024112835000059.tif208170TIFF2024112835000060.tif210170TIFF202 4112835000061.tif200170TIFF2024112835000062.tif200170TIFF2024112835000063.tif195170TIFF20241128350 00064.tif199170TIFF2024112835000065.tif198170TIFF2024112835000066.tif215170TIFF2024112835000067.t if191170TIFF2024112835000068.tif216170TIFF2024112835000069.tif199170TIFF2024112835000070.tif207170 TIFF2024112835000071.tif194170TIFF2024112835000072.tif196170TIFF2024112835000073.tif197170TIFF202 4112835000074.tif231170TIFF2024112835000075.tif206170TIFF2024112835000076.tif195170TIFF20241128350 00077.tif195170TIFF2024112835000078.tif221170TIFF2024112835000079.tif185170TIFF2024112835000080.t if207170TIFF2024112835000081.tif225170TIFF2024112835000082.tif190170TIFF2024112835000083.tif218170

[0127] In some embodiments, the invention relates to a compound shown in Table 1 above, wherein the compound is not Compound 93 or Compound 96. In some embodiments, the invention relates to a compound shown in Table 1 above, wherein the compound is not Compound 71.

[0128] definition The term "alkyl," as used herein, unless otherwise specified, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 10 "Alkyl" means an alkyl having 1 to 10 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

[0129] The term "alkenyl," as used herein, refers to both straight-chain and branched-chain moieties having the specified number of carbon atoms and containing at least one carbon-carbon double bond.

[0130] The term "alkynyl," as used herein, refers to both straight-chain and branched-chain moieties having the specified number or number of carbon atoms and containing at least one carbon-carbon triple bond.

[0131] The term "cycloalkyl" as used herein refers to a cyclic alkyl moiety having three or more carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0132] The term "cycloalkenyl," as used herein, refers to a cyclic alkenyl moiety having three or more carbon atoms.

[0133] The term "cycloalkynyl," as used herein, refers to a cyclic alkynyl moiety having five or more carbon atoms.

[0134] The term "heterocycle" encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, and heteropolycycloalkenyl, and the like. Heterocycloalkyl refers to a cycloalkyl group containing one or more heteroatoms (O, S, or N) in the ring. Heterocycloalkenyl, as used herein, refers to a cycloalkenyl group containing one or more heteroatoms (O, S, or N) in the ring. Heterobicycloalkyl refers to a bicycloalkyl group containing one or more heteroatoms (O, S, or N) in the ring. Heterobicycloalkenyl, as used herein, refers to a bicycloalkenyl group containing one or more heteroatoms (O, S, or N) in the ring. The aforementioned heterocycle groups may be C-bonded or heteroatom-bonded (where possible). As used herein, the term N-heterocycle means that the heterocycle group is N-bonded. For example, if Z is an N-heterocycle, it is N-bonded to the carbon to which R1 and R2 are attached. In some embodiments, the heterocycle includes an optionally substituted 5-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N. In some embodiments, the heterocycle includes an optionally substituted 6-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N. In some embodiments, the maximum number of heteroatoms is 3 or 2. In some embodiments, the heterocycle includes a single heteroatom. Representative examples of N-heterocycles include, but are not limited to, pyrrolind-1-yl (1-pyrrolidinyl), piperidin-1-yl (1-piperidinyl), piperazin-1-yl (1-piperazinyl), and morpholin-1-yl (1-morpholinyl).

[0135] The cycloalkyl, cycloalkenyl, heterocycle groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.

[0136] The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic carbocyclic ring system. A polycyclic aryl is a macrocyclic system that includes at least one aromatic ring. A polycyclic aryl can include fused rings, covalently linked rings, or combinations thereof. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Aryl groups can be substituted or unsubstituted. In some embodiments, an aryl is a C4-C6 10 It is aryl.

[0137] The term "heteroaryl" as used herein refers to an aromatic carbocyclic group containing one or more heteroatoms (O, S, or N) in the ring. Heteroaryl groups can be monocyclic or polycyclic. Heteroaryl groups can be further substituted or unsubstituted. The heteroaryl groups of the present invention can also include ring systems substituted with one or more oxo moieties. Polycyclic heteroaryls can include fused rings, covalently bonded rings, or combinations thereof. Polycyclic heteroaryls are macrocyclic systems that include at least one aromatic ring containing one or more heteroatoms in the ring. Polycyclic aryls can include fused rings, covalently bonded rings, or combinations thereof. Examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, o-, aryl, aryl- ... Examples of heteroaryl groups include, but are not limited to, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl, thiazolopyridinyl, oxazolopyridinyl, and azaindolyl. The aforementioned heteroaryl groups can be C-linked or heteroatom-linked (where possible). As an example, a group derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). In some embodiments, the heteroaryl is a 4-10 membered heteroaryl.

[0138] The term "substituted" refers to any group selected from the group consisting of -C1 to -C 12 Alkyl, -C2~C 12 Alkenyl, -C 12 Alkynyl, -C3~C 12 Cycloalkyl, -C3~C 12Cycloalkenyl, C3-C 12 Cycloalkynyl, -heterocycle, -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, oxo, thioxo, -NHR x , -NR x R x , dialkylamino, -diarylamino, -diheteroarylamino, -OR x , -C(O)R y , -C(O)C(O)R y , -OCO2R y , -OC(O)R y , O.C.(O)C(O)R y , -NHC(O)R y , -NHCO2R y , -NHC(O)C(O)R y , NHC(S)NH2, -NHC(S)NHR x , -NHC(NH)NH2, -NHC(NH)NHR x , -NHC(NH)R x , -C(NH)NHR x , and (C=NR x )R x ;-NRxC(O)R x , -NR x C(O)N(R x )2, -NRxCO2R y , -NRxC(O)C(O)R y , -NR x C(S)NH2, -NR x C(S)NHR x , -NR x C(NH)NH2, -NR x C(NH)NHR x , -NRxC(NH)R x , -C(NRx)NHR x -S(O)R y , -NHSO2R x , -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -Cycloalkyl, -polyalkoxyalkyl, -polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -SR xor -methylthiomethyl, where R x is hydrogen, -C1 to -C 12 Alkyl, -C2~C 12 Alkenyl, -C 12 Alkynyl, -C3~C 12 -R is selected from the group consisting of cycloalkyl, -aryl, -heteroaryl, and -heterocycle; y is hydrogen, -C1 to -C 12 Alkyl, -C2~C 12 Alkenyl, -C 12 Alkynyl, -C3~C 12 Cycloalkyl, -aryl, -heteroaryl, -heterocycle, -NH2, -NH-C1~C 12 Alkyl, -NH-C2~C 12 Alkenyl, -NH-C 12 -Alkynyl, -NH-C 12 It is selected from the group consisting of cycloalkyl, -NH-aryl, -NH-heteroaryl, and -NH-heterocycle. It is understood that the aryl, heteroaryl, alkyl, and the like can be further substituted.

[0139] The term "haloalkyl," as used herein, refers to an alkyl group having 1 to (2n+1) substituents independently selected from F, Cl, Br, or I, where n is the maximum number of carbon atoms in the alkyl group.

[0140] As will be understood by those of ordinary skill in the art, "H" is the symbol for hydrogen, "N" is the symbol for nitrogen, "S" is the symbol for sulfur, and "O" is the symbol for oxygen. "Me" is an abbreviation for methyl.

[0141] Non-limiting examples of optionally substituted aryls are phenyl, substituted phenyl, napthyl, and substituted naphthyl.

[0142] Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereoisomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R--S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to contain both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0143] The term "enantiomerically pure" refers to a stereoisomerically pure composition of a compound. For example, a stereochemically pure composition is a composition that is free or substantially free of other stereoisomers of the compound. In another example, for a compound with one chiral center, an enantiomerically pure composition of the compound is free or substantially free of other enantiomers. In yet another example, for a compound with two chiral centers, an enantiomerically pure composition is free or substantially free of other diastereoisomers.

[0144] When a particular stereochemistry is described or depicted, it is intended to mean that a particular enantiomer is present in excess relative to the other enantiomer. A compound has the R configuration at a particular position if it is present in excess relative to a compound having the S configuration at that particular position. A compound has the S configuration at a particular position if it is present in excess relative to a compound having the R configuration at that particular position.

[0145] Likewise, all tautomeric forms are also intended to be included. When a particular compound is described or depicted, it is intended to encompass that chemical structure and any tautomeric forms of that structure.

[0146] It should be understood that the atoms constituting the compounds of the present invention are intended to include isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. Isotopes of hydrogen include, for example, tritium and deuterium, and isotopes of carbon include, for example, tritium and deuterium. 13 C and 14The present invention therefore includes embodiments in which one or more hydrogen atoms in a compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or any compound described herein, are replaced with deuterium. The present invention also includes embodiments in which one or more carbon atoms in the compounds of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or the compounds described herein, are replaced with a silicon atom.

[0147] The present invention additionally includes embodiments in which one or more nitrogen atoms in a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound described herein, are oxidized to an N-oxide.

[0148] Synthesis method Methods for synthesizing a compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound described herein, are described, for example, in the following references: (1) Banik, B. et al., "Simple Synthesis of Substituted Pyrroles," J. Org. Chem (2004) 69, 213; (2) Sawada, Y. et al., "Eight-Membered Oxygen Hetercycles by Brook Rearrangement-mediated [3+4] Annulation," Org. Lett. (2004) 6, 2277; (3) Aube, J. et al., "Synthetic Aspects of an Asymmetric Nitrogen-Insertion Process: Preparation of Chiral, Non-Racemic Caprolactams and Valerolactams. Total Synthesis of (-)-Alloyohimbane," J. Am. Chem. Soc. (1990) Vol. 112, p. 4879; (4) Ookawa, A. et al., "Asymmetric Synthesis of Optically Active threo- and erythro-Pyrrolidinylbenzyl Alcohol by the Highly Stereospecific Arylation of (S)-Proline and the Subsequent Highly Diastereoselective Reduction of the α-Amineo Ketone," J. Chem. Soc. Perkin Trans. I (1987) Vol. 7, p. 1465.

[0149] Exemplary synthetic routes for preparing compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are shown in Schemes I-II below. As one of skill in the art will appreciate, diastereoisomers can be separated from reaction mixtures using column chromatography.

[0150] TIFF2024112835000084.tif37170

[0151] The Pahl-Knorr pyrrole synthesis using aniline and the appropriate diketone provides Pyrrole A 1 Friedel-Crafts acylation with chloroacetyl chloride and AlCl3 gives intermediate B. The chloride can be reacted with various O 2 , N 3 , S, and C based nucleophiles to provide the desired compounds.

[0152] TIFF2024112835000085.tif47170

[0153] Friedel-Crafts acylation with an appropriately substituted acetyl chloride and pyrrole A gives the desired acylpyrrole E, where X is N, S, C, O, or 4 may be optionally substituted with

[0154] formulation The present invention encompasses pharma- ceutically acceptable salts of the compounds described herein. Thus, in certain aspects, the present invention relates to pharma- ceutically acceptable salts of the compounds of the present invention and pharmaceutical compositions thereof. "Pharmaceutically acceptable salts" include ionic bond-containing products of the reaction between the disclosed compounds and either an acid or a base, suitable for administration to a subject. Pharmaceutically acceptable salts are well known in the art and are described, for example, in Berge et al. (1977) "Pharmaceutical Salts. Journal of Pharmaceutical Sciences" Vol. 69, No. 1, pp. 1-19, the contents of which are incorporated herein by reference. Non-limiting examples of pharma- ceutically acceptable salts are acid salts of compounds containing amines or other basic groups, which can be obtained by reacting the compounds with suitable organic or inorganic acids. Examples of pharma- ceutically acceptable salts can also be metal salts, including, but not limited to, sodium, magnesium, calcium, lithium, and aluminum salts. Further examples of pharma- ceutically acceptable salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, trifluoroacetates, benzoates, and salts with amino acids such as glutamic acid. When the compound contains an acidic functional group, such as -C(O)OH or -SO3H, salts can also be formed with suitable organic bases. Such bases suitable for forming pharma- ceutically acceptable base addition salts with the compounds of the present invention include organic bases that are non-toxic and strong enough to react with the acidic functional group. Such organic bases are known in the art and include amino acids such as arginine and lysine, mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines such as methylamine, dimethylamine, and trimethylamine, guanidine, N-benzylphenethylamine, N-methylglucosamine, N-methylpiperazine, morpholine, ethylenediamine, and tris(hydroxymethyl)aminomethane.

[0155] The activity of the compounds described herein to inhibit USP14 can be measured using previously described methodology (BH Lee et al., Nature (2010) 467(9) 179, the contents of which are expressly incorporated herein by reference).

[0156] The invention also includes hydrates of the compounds described herein, including, for example, solvates of the compounds described herein, pharmaceutical compositions comprising the solvates, and methods of using the solvates. In some embodiments, the invention is a solvate of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or any compound described herein, or a pharmaceutical composition thereof.

[0157] The present invention also includes prodrugs of the compounds described herein, e.g., a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or any compound described herein, or a pharmaceutical composition of any of these, or methods of using the prodrugs.

[0158] The invention further includes clathrates of the compounds described herein, pharmaceutical compositions comprising the clathrates, and methods of using the clathrates. In some embodiments, the invention relates to a clathrate of a compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or any compound described herein, or a pharmaceutical composition thereof.

[0159] Treatment method The invention encompasses methods of inhibiting the deubiquitination activity of Usp14 protein, comprising contacting Usp14 protein with a compound described herein, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, in an amount sufficient to inhibit the deubiquitination activity of Usp14 protein. In certain embodiments, a cell is contacted with a compound described herein, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, in an amount sufficient to inhibit the deubiquitination activity of Usp14 protein.

[0160] The invention also includes a method of enhancing proteasomal protein degradation in a cell, comprising contacting the cell with a compound of the present invention, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, in an amount sufficient to enhance proteasomal protein degradation.

[0161] In some embodiments, the present invention includes a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and a compound described herein. The compounds described herein, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, can be administered in a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient. The excipient can be selected based on the expected route of administration of the composition in therapeutic use. The route of administration of the composition depends on the condition being treated. For example, intravenous injection may be preferred for the treatment of systemic disorders, while oral administration may be preferred for the treatment of gastrointestinal disorders. The route of administration and the dosage of the composition to be administered can be determined by one of skill in the art without undue experimentation with standard dose-response studies. Relevant circumstances to consider when making these decisions include the condition or conditions being treated, the choice of the composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0162] Pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug, or a compound described herein, can be administered by a variety of routes, including, but not limited to, parenteral, oral, pulmonary, ocular, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal, and intraperitoneal.

[0163] The composition may also include pharmaceutically acceptable non-toxic carriers or diluents, defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration, depending on the desired formulation. The diluent is selected so as not to affect the biological activity of the drug (pharmacologic agent) or composition. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, and non-immunogenic stabilizers, and the like. The pharmaceutical composition may also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acid, polyglycolic acid and copolymers (such as latex-functionalized SEPHAROSE™, agarose, and cellulose), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).

[0164] The composition can be administered parenterally, for example, by intravenous, intramuscular, intrathecal, or subcutaneous injection. Parenteral administration can be accomplished by incorporating the composition into a solution or suspension. Such solutions or suspensions can also contain sterile diluents, such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents. Parenteral formulations can also contain antibacterial agents, such as, for example, benzyl alcohol or methyl parabens, antioxidants, such as, for example, ascorbic acid or sodium bisulfite, and chelating agents, such as EDTA. Buffers, such as acetates, citrates, or phosphates, and agents for adjusting osmotic pressure, such as sodium chloride or dextrose, can also be added. Parenteral formulations can be placed into ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0165] In addition, auxiliary substances such as wetting or emulsifying agents, surfactants, and pH buffering substances may be present in the composition. Other components of pharmaceutical compositions are oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. In general, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

[0166] Injectable preparations can be prepared either as liquid solutions or suspensions. Solid forms suitable for dissolution or suspension in liquid vehicles prior to injection can also be prepared. Preparations can also be emulsified or encapsulated in liposomes or microparticles, such as polylactides, polyglycolides, or copolymers, to enhance adjuvant effect (Langer, Science, vol. 249, p. 1527 (1990); and Hanes, Advanced Drug Delivery Reviews, vol. 28, p. 97-119 (1997)). The compositions and drugs described herein can be administered in the form of depot injections or implant preparations, which can be formulated in such a way as to allow sustained or pulsatile release of the active ingredient.

[0167] Additional formulations suitable for other modes of administration include oral, intranasal, and pulmonary formulations, suppositories, transdermal applications, and ocular delivery. For suppositories, binders and carriers include, for example, polyalkylene glycols or triglycerides. Such suppositories can be formed from mixtures containing active ingredients in the range of about 0.5% to about 10%, preferably about 1% to about 2%. Oral formulations include excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Topical application can be transdermal or intradermal delivery. Transdermal delivery can be achieved using skin patches or transferosomes. (Paul et al., Eur. J. Immunol. 25:3521-24 (1995); Cevc et al., Biochem. Biophys. Acta 1368:201-15 (1998)).

[0168] For the purpose of oral therapeutic administration, the pharmaceutical composition may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. The tablets, pills, capsules, troches, and the like may also contain binders, excipients, disintegrants, lubricants, glidants, sweeteners, and flavoring agents. Some examples of binders include crystalline cellulose, tragacanth, or gelatin. Examples of excipients include starch or lactose. Some examples of disintegrants include alginic acid and corn starch, and the like. Examples of lubricants include magnesium stearate and potassium stearate. An example of a lubricant is colloidal silicon dioxide. Some examples of sweeteners include sucrose and saccharin, and the like. Examples of flavoring agents include peppermint, methyl salicylate, and orange flavor, and the like. Materials used in preparing these various compositions should be pharma- ceutically pure and non-toxic in the amounts used, hi another embodiment, the composition is administered as a tablet or capsule.

[0169] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and sweeteners such as cherry or orange flavoring. For vaginal administration, the pharmaceutical composition may be provided as a pessary, tampon, cream, gel, paste, foam, or spray.

[0170] The pharmaceutical composition can also be administered by nasal administration. As used herein, nasal administration or nasal administration includes administering the composition to the mucous membrane of the patient's nostril or nasal cavity. As used herein, the pharmaceutical composition for nasal administration of the composition comprises a therapeutically effective amount of the compound, which is prepared by known methods, for example, administered as a nasal spray, nasal drops, suspension, gel, ointment, cream, or powder. The administration of the composition can also be performed using a nasal tampon or nasal sponge.

[0171] For topical administration, suitable formulations may include biocompatible oils, waxes, gels, powders, polymers, or other liquid or solid carriers. Such formulations may be administered by direct application to the affected tissue, for example, a liquid formulation may be administered by drops to the subject's eye to treat an infection of the conjunctival tissue, or a cream formulation may be administered to the skin.

[0172] Rectal administration includes administering a pharmaceutical composition to the rectum or large intestine. This can be achieved using a suppository or enema. Suppository formulations can be easily prepared by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120°C, dissolving the pharmaceutical composition in glycerin, mixing the heated glycerin, adding purified water, and pouring the hot mixture into a suppository mold.

[0173] Transdermal administration involves absorption of a composition through the skin. Transdermal formulations include patches, ointments, creams, gels, oils, and the like.

[0174] For purposes of the present invention, in addition to its usual meaning of administering the formulations described herein to any part, tissue, or organ whose primary function is gas exchange with the external environment, "pulmonary" is also meant to include tissues or cavities associated with the airways, particularly the sinuses. For pulmonary administration, aerosol formulations, including those administered with the active agent, manual pump sprays, nebulizers, or pressurized metered dose inhalers, and dry powder formulations are contemplated. Suitable formulations of this type may also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.

[0175] A drug delivery device for delivering an aerosol includes a suitable aerosol canister with a metering valve containing the described pharmaceutical aerosol formulation, and an actuator housing adapted to hold the canister and enable drug delivery. The canister in the drug delivery device has a headspace of greater than about 15% of the total volume of the canister. Often, compounds intended for pulmonary administration are dissolved, suspended, or emulsified in a mixture of a solvent, a surfactant, and a propellant. The mixture is maintained under pressure in the canister, which is sealed with a metering valve.

[0176] The invention also includes a method of treating a patient suffering from a condition associated with dysfunction in protein homeostasis, comprising administering to said patient a therapeutically effective amount of a compound described herein.

[0177] "Treating" or "treatment" includes preventing or delaying the onset of symptoms, complications, or biochemical manifestations of a disease, alleviating or ameliorating symptoms, or arresting or inhibiting further development of a disease, condition, or disorder. A "subject" is an animal being treated or in need of treatment. A "patient" is a human subject in need of treatment.

[0178] "Effective amount" refers to an amount of an agent sufficient to achieve a desired and / or described effect. In the context of a therapeutic agent, an "effective amount" of a therapeutic agent sufficient to ameliorate one or more symptoms of a disorder and / or prevent progression of a disorder, cause regression of the disorder and / or achieve the desired effect.

[0179] As used herein, the terms "inhibiting" or "reducing" encompass causing a net reduction, either by direct or indirect means. The terms "enhancing" or "enhancing" mean causing a net gain, either by direct or indirect means.

[0180] The present invention encompasses the treatment of conditions associated with dysfunction of proteostasis. Proteostasis refers to protein homeostasis. Dysfunction of protein homeostasis is the result of protein misfolding, protein aggregation, defective protein trafficking, or protein degradation. Exemplary proteins that may be dysfunctional in protein homeostasis, e.g., may exist in a misfolded state, include glucocerebrosidase, hexosamine A, cystic fibrosis transmembrane conductance regulator, aspartylglucsaminidase, α-galactosidase A, cysteine ​​transporter, acid ceremidase, acid α-L-fucosidase, protective protein, cathepsin A, acid β-glucosidase, acid β-galactosidase, idronate-2-sulfatase, α-L-idronidase, galactocerebrosidase, acid α-mannosidase, acid β-mannosidase, arylsulfatase B, arylsulfatase A, N-acetylgalactosamine-6-sulfate sulfatase, acid β-galactosidase, N-acetylglucosamine-1-phosphotransferase, acid sphingomyelinase, and acid β-galactosidase. sphingmyelinase, NPC-1, acid α-glucosidase, β-hexosamine B, heparin N-sulfatase, α-N-acetylglucosaminidase, islet amyloid polypeptide (IAPP or amylin), α-glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, α-N-acetylgalactosaminidase, α-neuramidase, β-glucuronidase, β-hexosamine A and acid lipase, polyglutamine, α-synuclein, Aβ peptide, Tau protein, transthyretin, insulin, TAR DNA binding protein 43 (TDP-43), ataxin-3, superoxide dismutase (SOD), and rhodopsin.

[0181] In certain embodiments, the protein is selected from the group consisting of huntingtin, Tau, alpha-synuclein, alpha 1 antitrypsin, and superoxide dismutase.

[0182] Protein conformational diseases include gain-of-function and loss-of-function disorders. In one embodiment, a protein conformational disease is a gain-of-function disorder. The terms "gain-of-function disorder", "gain-of-function disease", "toxic gain-of-function disorder", and "toxic gain-of-function disease" are used interchangeably herein. Gain-of-function disorders are diseases characterized by increased aggregation-associated proteotoxicity. In these diseases, aggregation exceeds clearance inside and / or outside the cell. Gain-of-function diseases include neurodegenerative diseases associated with polyglutamine aggregation, Lewy body disease, amyotrophic lateral sclerosis, transthyretin-associated aggregation disease, Alzheimer's disease, Machado-Joseph disease, cerebral B amyloid angiopathy, retinal ganglion cell degeneration, tautopathies (progressive supranuclear palsy, corticobasal degeration, frontotemporal lobar degeneration), cerebral hemorrhage with amyloidosis, Alexander disease, serpinopathies, familial amyloid polyneuropathy, senile systemic amyloidosis, ApoA I amyloidosis, ApoA II amyloidosis, ApoA IV amyloidosis, familial amyloidosis of the Finnish type, lysozyme amyloidosis, and tautopathies (progressive supranuclear palsy, corticobasal degeration, frontotemporal lobar degeneration). amyloidosis, fibrinogen amyloidosis, dialysis amyloidosis, inclusion body myositis / myopathy, cataracts, medullary thyroid cancer, cardiac atrial amyloidosis, pituitary prolactinoma, hereditary lattice corneal dystrophy, cutaneous lichen amyloidosis, corneal lactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic tumor amyloid, testicular amyloid, sickle cell disease, severe myopathy, von Hippel-Lindau disease, spinocerebellar degeneration type 1, Angelman syndrome, giant axonal neuropathy, Paget's disease of bone and inclusion body myopathy with Paget disease of bone, frontotemporal dementia (IBMPFD), and prion diseases.Neurodegenerative diseases associated with polyglutamine aggregation include, but are not limited to, Huntington's disease, dentatorubral-pallidoluysian atrophy, some forms of spinocerebellar ataxia, and spinal-bulbar muscular atrophy. Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of A peptide and intracellular aggregates of the microtubule-associated protein Tau. Transthyretin-related aggregation diseases include, for example, senile systemic amyloidosis and familial amyloid polyneuropathy. Lewy body diseases are characterized by the aggregation of -synuclein protein, including, for example, Parkinson's disease. Prion diseases (also known as transmissible spongiform encephalopathies or TSEs) are characterized by the aggregation of prion proteins. Exemplary human prion diseases are Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia, and kuru. Additional neurodegenerative diseases include tauopathies, Frontal Lobe Dementia (FLD), dementia (Dementia with Lewy bodies (DLB)), familial dementia, serpinopathies, Down's syndrome dementia, multiple sclerosis, and neuropathic pain.

[0183] In a further embodiment, the protein conformation disease is a loss-of-function disorder. The terms "loss-of-function disease" and "loss-of-function disorder" are used interchangeably herein. Loss-of-function diseases are a group of diseases characterized by inefficient protein folding, which leads to excessive protein degradation. Loss-of-function diseases include, for example, lysosomal storage diseases. Lysosomal storage diseases are a group of diseases characterized by specific lysosomal enzyme deficiencies, which can occur in a variety of tissues causing the accumulation of molecules that are normally degraded by the defective enzyme. The lysosomal enzyme deficiency can occur in lysosomal hydrolases or proteins involved in lysosomal trafficking. Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry disease, Batten disease, cystinosis, Farber disease, fucosidosis, galactasidosialidosis, Gaucher disease (including types 1, 2, and 3), Gm1 gangliosidosis, Hunter disease, Hurler-Scheie disease, Krabbe disease, α-mannosidosis, β-mannosidosis, Maroteaux-Lamy disease, metachromatic leukodystrophy, Morquio A syndrome, Morquio B syndrome, mucolipidosis II, mucolipidosis III, Niemann-Pick disease (including types A, B, and C), Pompe disease, Sandhoff disease, Sanfilippo syndrome (including types A, B, C, and D), Schindler disease, Schindler-Kanzaki disease, sialidosis, Sly syndrome, Tay-Sachs disease, and Wolman disease.

[0184] In yet further embodiments, the disease associated with dysfunction of protein homeostasis is a myopathy. In some embodiments, the myopathy is selected from the group consisting of Duchenne muscular dystrophy (DMD), Becker's muscular dystrophy (BMD), Spinal muscular atrophy (SMA), Spinal-bulbar muscular atrophy (SBMA), Inclusion body myositis, Freidreich's ataxia, Multiple System Atrophy, Spinocerebellar ataxia, and Seipinopathy.

[0185] In another embodiment, the disease associated with dysfunction of protein homeostasis is cardiovascular disease.Cardiovascular disease includes, but is not limited to, coronary artery disease, myocardial infarction, stroke, restenosis and arteriosclerosis.The condition associated with dysfunction of protein homeostasis also includes ischemic conditions such as ischemia / reperfusion injury, myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease and cerebral ischemia.

[0186] In yet another embodiment, the disease associated with dysfunction of protein homeostasis is diabetes and / or a diabetic complication, including but not limited to diabetic retinopathy, cardiomyopathy, neuropathy, nephropathy, and wound healing disorders.

[0187] In further embodiments, the disease associated with a dysfunction in protein homeostasis is an ocular disease, including, but not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP), and dry macular degeneration.

[0188] In some embodiments, the condition associated with dysfunction of protein homeostasis is selected from the group consisting of Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes and its complications, eye diseases, and cancer or tumors.

[0189] Additional conditions associated with dysfunction of protein homeostasis include hemoglobinopathies, inflammatory diseases, intermediate filament diseases, drug-induced lung injury, and hearing loss. The present invention also includes methods for treating hemoglobinopathies (such as sickle cell anemia), inflammatory diseases (such as inflammatory bowel disease, colitis, ankylosing spondylitis), intermediate filament diseases (such as non-alcoholic and alcoholic fatty liver disease), and drug-induced lung injury (such as methotrexate-induced lung injury). The present invention also includes methods for treating hearing loss, such as noise-induced hearing loss, aminoglycoside-induced hearing loss, and cisplatin-induced hearing loss.

[0190] In addition to conditions associated with dysfunction of protein homeostasis, the compounds of the invention can be used to treat diseases or conditions characterized by defective proteasome activity or defective activity of other components of the ubiquitin-proteasome pathway, including, for example, Hippel-Lindau disease, spinocerebellar degeneration type 1, Angelman syndrome, giant axonal neuropathy, Paget's disease, and inclusion body myopathy with frontotemporal dementia.

[0191] In certain embodiments, the invention encompasses a method of treating a condition selected from the group consisting of Parkinson's disease, Alzheimer's disease, frontotemporal lobar dementia (FTLD), Progressive Supranuclear Palsy (PSP), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), retinitis pigmentosa, prion diseases, and autism.

[0192] In certain embodiments, the present invention includes a method of treating a condition associated with a dysfunction in protein homeostasis comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, and a second agent (e.g., a second therapeutic agent). Co-administered agents, compounds, or therapeutic agents need not be administered at exactly the same time. However, in certain embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug, or a compound described herein, is administered substantially simultaneously as a second agent. By "substantially simultaneously" it is meant that a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any thereof, is administered prior to, simultaneously with, and / or after administration of a second agent, including, for example, administration within the same treatment session or as part of the same treatment regimen. Exemplary second agents include pharmacological chaperones and proteostasis regulators (such as, for example, those described below).

[0193] In yet a further aspect, the invention includes a method for treating a condition characterized by a deficiency in proteasome activity or other components of the ubiquitin-proteasome pathway in a subject, comprising administering to the subject an effective amount of a compound of the invention, or a pharma-ceutically acceptable salt, solvate, clathrate, or prodrug of such a compound.

[0194] In additional embodiments, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, and a second agent, wherein the second agent is selected from the group consisting of pharmacological chaperones and proteostasis regulators. The present invention also encompasses a method of treating a patient suffering from a condition associated with a dysfunction of proteostasis, comprising administering a therapeutically effective amount of a compound of the present invention and a second agent, wherein the second agent is a pharmacological chaperone. Pharmacological chaperones or kinetic stabilizers refer to compounds that chemically enhance the folding equilibrium by binding to the existing steady-state levels of folded mutant proteins and stabilizing the folding (Bouvier, Chem Biol 14:241-242 (2007); Fan et al., Nat Med 5:112-115 (1999); Sawkar et al., Proc Natl Acad Sci USA 99:15428-15433 (2002); Johnson and Kelly, Accounts of Chemical Research 38:911-921 (2005)). Pharmacological chaperones are administered in combination with the compounds described herein in an amount sufficient to treat a patient suffering from a condition associated with a dysfunction of protein homeostasis. Exemplary pharmacological chaperones are described in U.S. Patent Application Publication Nos. 20080056994, 20080009516, 20070281975, 20050130972, 20050137223, 20050203019, 20060264467, and 20060287358, the contents of each of which are incorporated herein by reference.

[0195] In another embodiment, the present invention is a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis, comprising administering to the patient an effective amount of a compound herein, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any thereof, and a second agent, wherein the second agent is a proteostasis regulator. The term "proteostasis regulator" refers to small molecules, siRNAs, and biologics (including, for example, proteins) that enhance cellular protein homeostasis. For example, proteostasis regulators can be drugs that affect protein synthesis, folding, trafficking, and degradation pathways. Proteostasis regulators include drugs that stimulate heat shock response (HSR) signaling activity. Proteostasis regulators function by manipulating signaling pathways, including, but not limited to, heat shock response or unfolded protein response, or both, which trigger the transcription and translation of proteostasis network components. Proteostasis regulators can enhance protein (e.g., mutant protein) folding, trafficking, and function. Proteostasis regulators can also regulate protein chaperones by upregulating transcription or translation of the protein chaperone or by inhibiting degradation of the protein chaperone. Proteostasis regulators can affect folding biology, many of which allow progression to intermediates with more native structures by a coordinated increase in the levels of chaperones and folding enzymes, as well as macromolecules that bind to partially folded conformational ensembles, ultimately increasing the concentration of folded mutant proteins for excretion. In one aspect, proteostasis regulators differ from chaperones in that proteostasis regulators can enhance mutant protein homeostasis but do not bind mutant proteins. Moreover, proteostasis regulators can upregulate aggregation pathways or disaggregase activity. Exemplary proteostasis regulators are celastrol, MG-132, and L-type Ca 2+Channel blockers (e.g., diltiazem and verapamil). The term "celastrol" refers to celastrol and its derivatives or analogs, including, but not limited to, celastrol derivatives described in Westerheide et al., J Biol Chem, vol. 279, vol. 53, pp. 56053-60, 2004, the contents of which are expressly incorporated herein by reference. Celastrol derivatives include, for example, celastrol methyl ester, dihydrocelastrol diacetate, celastrol butyl ether, dihydrocelastrol, celastrol benzyl ester, primesterol, primesterol diacetate, and celastrol triacetate. In certain embodiments, the proteostasis regulator is a heat shock response activator. Heat shock response activators are agents that indirectly or directly activate the heat shock response, for example, by directly or indirectly activating heat shock transcription factor 1 (HSF1), inhibiting Hsp90, and / or activating chaperone expression. (Westerheide et al., J Biol Chem (2004) vol. 279, no. 53, pp. 56053-60, the contents of which are expressly incorporated herein by reference). The terms "heat shock response activator", "heat shock activator", "heat shock response inducer", and "heat shock inducer" are used interchangeably herein. Non-limiting examples of heat shock response activators are celastrol, nonsteroidal anti-inflammatory drugs, ansamycin, geldenamycin, radiciol, glucuronic acid, and tributyrin. Heat shock response activators are also described in, for example, U.S. Patent Application Publication Nos. 20070259820, 20070207992, 20070179087, and 20060148767, the contents of each of which are expressly incorporated herein by reference. In some embodiments, the heat shock response activator is a small molecule heat shock response activator.

[0196] The invention also encompasses a method of treating cancer or tumor in a patient in need thereof comprising administering to the patient an effective amount of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them. The invention further encompasses a method of treating cancer or tumor in a patient in need thereof comprising administering to the patient an effective amount of a compound described herein. Cancers that can be treated according to the methods of the invention include, but are not limited to, breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, multiple myeloma, basal cell carcinoma, neuroblastoma, blood cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer.

[0197] In another embodiment, the invention is a method of treating cancer or tumors comprising administering a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, in combination with the administration of a chemotherapeutic agent. Chemotherapeutic agents that may be utilized include alkylating agents such as cyclosphosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, mesuredopa, and uredopa; ethylenediamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine. methylamelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosurea such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramicin, rodorubicin antibiotics such as streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and floxiridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK (trademark);Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2''-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes (e.g., paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE®; Aventis Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. This definition also includes antiestrogens, including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxyphene, keoxyphene, LY-117018, onapristone, and toremifene (Fareston); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above, which act to regulate or inhibit hormone action on tumors.

[0198] In a further embodiment, the present invention is a method of treating cancer or tumors comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, in combination with radiation therapy.

[0199] In yet further embodiments, the present invention is a method of treating a viral infection comprising administering an effective amount of a compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of any of them, to a subject in need thereof. In certain embodiments, the viral infection is an infection from a virus of the Flavivirus family. Examples of viruses of the Flavivirus family include, for example, Dengue virus, West Nile virus, Japanese encephalitis virus, Yellow fever virus, and Tick-borne encephalitis virus. In further embodiments, the virus is La Crosse virus. In another embodiment, the virus is Dengue virus or West Nile virus.

[0200] EMBODIMENTS OF THE PRESENT DISCLOSURE Further embodiments are provided herein.

[0201] Embodiment 1: A compound having formula (I): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D1 is any of C1 to C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, and optionally substituted naphthyl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, N3, halo, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)O.R. c , O.C.(O)R c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0202] Embodiment 2: D1 is an optionally substituted C1-C 10 The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R is alkyl.

[0203] Embodiment 3: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is optionally substituted methyl or optionally substituted ethyl.

[0204] Embodiment 4: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is -CH2CF3.

[0205] Embodiment 5: D1 is an optionally substituted C3-C 12 The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

[0206] Embodiment 6: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is an optionally substituted C3-C6 cycloalkyl.

[0207] Embodiment 7: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl.

[0208] Embodiment 8: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is optionally substituted naphthyl.

[0209] Embodiment 9: The compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D1 is optionally substituted cyclohexyl.

[0210] Embodiment 10: D1 comprises TIFF2024112835000087.tif148170. Embodiment 11: A compound having formula (Ia) or formula (Ib): TIFF2024112835000088.tif88170In the formula, D2 and D3 are hydrogen, CN, fluoro, chloro, -COOH, -CONH2, and TIFF2024112835000089.tif28170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0211] Embodiment 12: The compound of any one of embodiments 1-11, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each independently selected from methyl and ethyl.

[0212] Embodiment 13: A compound according to any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each methyl.

[0213] Embodiment 14: R1 and R2 are selected from hydrogen and optionally substituted C1-C 10 14. The compound of any one of embodiments 1-13, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, each independently selected from alkyl.

[0214] Embodiment 15: A compound according to any one of embodiments 1 to 13, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 and R2 are each hydrogen.

[0215] Embodiment 16: Z is NR b R b 16. The compound of any one of embodiments 1-15, wherein:

[0216] Embodiment 17: Each R b is hydrogen, optionally substituted C1-C10 Alkyl and optionally substituted C3-C 12 The compound of any one of embodiments 6, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, independently selected from the group consisting of: cycloalkyl.

[0217] Embodiment 18: The compound of any one of embodiments 1-15, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted N-heterocycle.

[0218] Embodiment 19: The compound of embodiment 18, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 5-membered N-heterocycle optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0219] Embodiment 20: The compound of embodiment 18, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0220] Embodiment 21: The compound of embodiment 18, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is 1-pyrrolidinyl or 1-piperidinyl, each of which is optionally substituted.

[0221] Embodiment 22: Z is TIFF2024112835000090.tif52170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0222] Embodiment 23: A compound according to embodiment 21 or 22, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each methyl, and R1 and R2 are hydrogen.

[0223] Embodiment 24: A compound according to embodiment 1, selected from the group consisting of compound numbers 5, 8, 9, 32, 35, 36, 37, 45, 46, 65, 76, 97, 103, 105, 107, 120, 121, 122, and 143, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof. Embodiment 25: Compound having formula (IIa) or (IIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: D2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. dS(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; Each of R3, R4, and R5 is selected from hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Z is NR b R b , optionally substituted N-heterocycle, and optionally substituted N-heteroaryl; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and each n is independently 0, 1, or 2; However, the compound is as follows: Not TIFF2024112835000092.tif97170, compound.

[0224] Embodiment 26: The compound of embodiment 25, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein D2 is optionally substituted phenyl.

[0225] Embodiment 27: D2 comprises TIFF2024112835000093.tif26170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0226] Embodiment 28: R1 and R2 are selected from hydrogen and optionally substituted C1-C 10 28. The compound of any one of embodiments 25-27, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, each independently selected from alkyl.

[0227] Embodiment 29: A compound according to any one of embodiments 25 to 27, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 and R2 are each hydrogen.

[0228] Embodiment 30: A compound according to any one of embodiments 25 to 29, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R5 is hydrogen.

[0229] Embodiment 31: R3 and R4 are each independently an optionally substituted C1-C4 alkyl, a compound according to any one of embodiments 25-30, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0230] Embodiment 32: A compound according to any one of embodiments 25 to 30, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R3 and R4 are each methyl.

[0231] Embodiment 33: Z is NR b R b or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0232] Embodiment 34: Each R b is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C3-C 12 The compound of embodiment 33, wherein said compound is independently selected from the group consisting of: cycloalkyl, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0233] Embodiment 35: The compound of any one of embodiments 25-32, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted N-heterocycle.

[0234] Embodiment 36: The compound of embodiment 35, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 5-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0235] Embodiment 37: The compound of embodiment 35, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0236] Embodiment 38: The compound of embodiment 35, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is 1-pyrrolidinyl or 1-piperidinyl, each of which is optionally substituted.

[0237] Embodiment 39: The compound of embodiment 35, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is optionally substituted 1-pyrrolindinyl.

[0238] Embodiment 40: The compound of embodiment 35, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is optionally substituted 1-piperidinyl.

[0239] Embodiment 41: Z is TIFF2024112835000094.tif25170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0240] Embodiment 42: A compound according to embodiment 25, selected from the group consisting of: compound numbers 92, 94, and 95, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof. Embodiment 43: Compound having formula (IIIa) or (IIIb): or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Each of R1 and R2 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Z is NR b R b , optionally substituted 6-membered N-heteroaryl, and optionally substituted N-heterocycle; Each R b is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0241] Embodiment 44: R1 and R2 are selected from hydrogen and optionally substituted C1-C 10 44. The compound of embodiment 43, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, each independently selected from alkyl.

[0242] Embodiment 45: A compound according to embodiment 43, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R1 and R2 are each hydrogen.

[0243] Embodiment 46: A compound according to any one of embodiments 43 to 45, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or C1-C4 alkyl.

[0244] Embodiment 47: A compound according to any one of embodiments 43 to 45, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4 is hydrogen or methyl.

[0245] Embodiment 48: A compound according to any one of embodiments 43 to 47, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, and cyclopropyl.

[0246] Embodiment 49: A compound according to any one of embodiments 43 to 47, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6 and R7 are each methyl.

[0247] Embodiment 50: A compound according to any one of embodiments 43 to 45, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4, R6, and R7 are each hydrogen.

[0248] Embodiment 51: A compound according to any one of embodiments 43 to 45, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R4, R6, and R7 are each methyl.

[0249] Embodiment 52: The compound of any one of embodiments 43-51, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted N-heterocycle.

[0250] Embodiment 53: The compound of embodiment 52, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 5-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0251] Embodiment 54: The compound of embodiment 52, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heterocycle, optionally having an additional heteroatom selected from the group consisting of O, S, and N.

[0252] Embodiment 55: The compound of embodiment 52, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is 1-pyrrolidinyl or 1-piperidinyl, each of which is optionally substituted.

[0253] Embodiment 56: A compound having the formula (IIIc), (IIId), (IIIe), or (IIIf): TIFF2024112835000096.tif178170TIFF2024112835000097.tif176170In the formula, each Z2 is hydrogen, hydroxy, -F, -CH3, -CF3, -CH2NH2, -N(CH3)2, -CH2N(CH3)2, -CH2CH2OH, -COOH, -CONH2, -SO2CH3, -OCH2CONHCH2CH3, -OCH2CONHC(CH3)2, -OCH2CONHCH2CH2CH3, -CH2NHCOOC(CH3)2, -N(CH3)2, TIFF2024112835000098.tif91170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0254] Embodiment 57: Z is TIFF2024112835000099.tif104170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0255] Embodiment 58: Z is TIFF2024112835000100.tif176170TIFF2024112835000101.tif172170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0256] Embodiment 59: The compound of any one of embodiments 43-51, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is an optionally substituted 6-membered N-heteroaryl.

[0257] Embodiment 60: Z is TIFF2024112835000102.tif28170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0258] Embodiment 61: Z is NR b R b or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0259] Embodiment 62: Each R b is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C3-C 12 The compound of embodiment 61, wherein said compound is independently selected from the group consisting of: cycloalkyl, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0260] Embodiment 63: Each R b is hydrogen, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, cyclopropyl, cycloheptyl, TIFF2024112835000103.tif124170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0261] Embodiment 64: Each R and R 10 and R are each hydrogen; or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0262] Embodiment 65: Each R is hydrogen and each R 10 is independently hydrogen, chloro, or fluoro; or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0263] Embodiment 66: Each R is methyl and each R 10 The compound according to any one of embodiments 43-63, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein is hydrogen.

[0264] Embodiment 67: Each R8 is hydrogen, hydroxyl, fluoro, chloro, bromo, -CN, -OCH3, -CF3, -OCF3, -COOH, -SO2CH3, TIFF2024112835000104.tif50170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0265] Embodiment 68: Compound having formula (IIIg) or (IIIh): TIFF2024112835000105.tif89170 or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Here, Z is Selected from the group consisting of TIFF2024112835000106.tif54170; Each R c is hydrogen, optionally substituted C1-C10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; d the groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and each n is independently 0, 1, or 2; TIFF2024112835000107.tif28170However, the compounds are as follows: Not a compound.

[0266] Embodiment 69: The embodiment of claim 68, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R8 is chloro.

[0267] Embodiment 70: A compound having the formula (IV): TIFF2024112835000108.tif94170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; During the ceremony: Each of R1 and R2 is hydrogen, optionally substituted C1-C10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted aryl, halo, N3, OR c , N.R. d R d , C(O)OR c , NO2, CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , N.R. d C(O)R c , N.R. d S(O) n R c , N(R d )(COOR c ), N.R. d C(O)C(O)R c , N.R. d C(O)NR d R d , N.R. d S(O) n NR d R d , N.R. d S(O) n R c , S(O) n R c , S(O) n NR d R d , O.C.(O)R c , O.C.(O)O.R. c , (C=NR d )R c , optionally substituted heterocycle, and optionally substituted heteroaryl; R4 is hydrogen and optionally substituted C1-C 10 independently selected from the group consisting of alkyl; Each of R6 and R7 is independently selected from optionally substituted C1-C4 alkyl; R8 is hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; Each R 10 is hydrogen and optionally substituted C1-C 10 selected from the group consisting of alkyl; Each R b is hydrogen, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, cyclopropyl, cycloheptyl, Independently selected from the group consisting of: TIFF2024112835000109.tif127170; Each R c is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Each R d is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C1-C 10 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C3-C 12 or two geminal R independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; dthe groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heteroaryl; and Each n is independently 0, 1, or 2.

[0268] Embodiment 71: R4 is hydrogen; each R6 and R7 is methyl; and each R9 and R 10 are each hydrogen; and R8 is CN, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0269] Embodiment 72: A compound having the formula (V): TIFF2024112835000110.tif74170, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof; wherein R4 is hydrogen or optionally substituted C1-C4 alkyl; R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, and cyclopropyl; R8 is hydrogen, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Alkenyl, halo, OR c , C(O)OR c , C.N., S(O) n R c , and S(O) n NR d R d selected from the group consisting of; Each R9 is independently selected from the group consisting of hydrogen and halo; and Each R 10 is hydrogen and optionally substituted C1-C 10 A compound selected from the group consisting of alkyl.

[0270] Embodiment 73: R4, R9, and R 10is hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0271] Embodiment 74: R4 is optionally substituted methyl; R9 and R 10 are each hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0272] Embodiment 75: R4 is TIFF2024112835000111.tif28170; R9 and R 10 is hydrogen; R6 and R7 are methyl; and R8 is chloro or cyano, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0273] Embodiment 76: Compound Nos. 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 , 77, 79, 80, 81, 82, 83, 84, 85, 89A, 89B, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 105, 107, 110, 111, 112, 113, 114, 117, 120, 121, 122, 134, 135, 136, 137, 138, 139, 140, 143, 157, 158, and 159, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0274] Embodiment 77: A pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient, and a compound according to any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0275] Embodiment 78: A method for inhibiting the deubiquitination activity of Usp14 protein, comprising contacting the Usp14 protein with an effective amount of a compound described in any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, in an amount sufficient to inhibit the deubiquitination activity of the Usp14 protein.

[0276] Embodiment 79: A method for enhancing proteasomal protein degradation in a cell, comprising contacting the cell with an effective amount of a compound of any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof, in an amount sufficient to enhance proteasomal protein degradation.

[0277] Embodiment 80: A method for treating a patient suffering from a condition associated with a dysfunction of protein homeostasis, comprising administering to said patient an effective amount of a compound according to any one of embodiments 1 to 76.

[0278] Embodiment 81: The method of embodiment 78, wherein said condition associated with dysfunction of protein homeostasis is a gain-of-function state.

[0279] Embodiment 82: The method of embodiment 78, wherein said condition associated with dysfunction of protein homeostasis is a loss-of-function condition.

[0280] Embodiment 83: The condition is characterized in that the condition is characterized by an increased risk of developing a cystic fibrosis transmembrane conductance regulator, an aspartylglucsaminidase, an alpha-galactosidase A, a cysteine ​​transporter, an acid ceremidase, an acid alpha-L-fucosidase, a protective protein, a cathepsin A, an acid β-glucosidase, an acid β-galactosidase, an idronate-2-sulfatase, an alpha-L-idronidase, a galactocerebrosidase, an acid α-mannosidase, an acid β-mannosidase, an arylsulfatase B, an arylsulfatase A, an N-acetylgalactosamine-6-sulfatase, an acid β-galactosidase, an N-acetylglucosamine-1-phosphotransferase, an acid sphingomyelinase, an acid 79. The method of embodiment 78, wherein the protein is associated with a dysfunction of proteostasis of a protein selected from the group consisting of: sphingmyelinase, NPC-1, acid α-glucosidase, β-hexosamine B, heparin N-sulfatase, α-N-acetylglucosaminidase, islet amyloid polypeptide (IAPP or amylin), α-glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, α1-antitrypsin, α-N-acetylgalactosaminidase, α-neuramidase, β-glucuronidase, β-hexosamine A and acid lipase, polyglutamine, α-synuclein, Aβ peptide, Tau protein, transthyretin, insulin, TAR DNA binding protein 43 (TDP-43), ataxin-3, superoxide dismutase (SOD), and rhodopsin.

[0281] Embodiment 84: The method of embodiment 83, wherein the protein is selected from the group consisting of huntingtin, Tau, alpha-synuclein, alpha 1 antitrypsin, and superoxide dismutase.

[0282] Embodiment 85: The method of embodiment 78, wherein the condition is selected from the group consisting of Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, and complications thereof.

[0283] Embodiment 86: The method of embodiment 78, wherein the condition is selected from the group consisting of Parkinson's disease, Alzheimer's disease, frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), retinitis pigmentosa, prion disease, and autism.

[0284] Embodiment 87: The method of embodiment 78, further comprising administering a second agent selected from the group consisting of proteostasis regulators and pharmacological chaperones.

[0285] Embodiment 88: A method for enhancing proteasome function in a subject, comprising administering to the subject an effective amount of a compound described in any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0286] Embodiment 89: A method for treating a condition characterized by a deficiency in proteasome activity or another component of the ubiquitin-proteasome pathway in a subject, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug of such a compound.

[0287] Embodiment 90: A method of treating cancer or tumor in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0288] Embodiment 91: A pharmaceutical composition comprising: a pharma- ceutically acceptable carrier or excipient; and an agent selected from the group consisting of a proteostasis regulator and a pharmacological chaperone; and A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 76, or a pharma- ceutically acceptable salt, solvate, clathrate, or prodrug thereof.

[0289] Exemplary embodiments The present invention is illustrated by the following examples, which are not intended to be limiting in any way.

[0290] Example Examples 1 to 4 Benzyl trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-1H-pyrrol-1-yl]-cyclohexane carboxylate (compound 120), trans-4-(2,5-dimethyl-3-(2-(piperidin-1-yl)acetyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (compound 121), trans-4-(2,5-dimethyl-3-(2-(piperidin-1-yl)acetyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxamide (compound 122), trans-4-(2,5-dimethyl-3-(2-(piperidin-1-yl)acetyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonitrile (compound 143) TIFF2024112835000112.tif154170

[0291] Synthesis of trans-4-(2,5-dimethyl-1H-pyrrol-1-yl)-cyclohexanecarboxylic acid (II): To a mixture of trans-4-amino-cyclohexanecarboxylic acid (5.00 g, 0.035 mol) in methanol (50 mL) was added 2,5-hexanedione (4.90 mL, 0.042 mol). The reaction mixture was heated under reflux for 3 h and then allowed to cool to room temperature. The reaction mixture was concentrated under vacuum and the remaining residue was diluted with water (50 mL). The mixture was extracted with dichloromethane (2×25 mL) and then the combined organic extracts were washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and then concentrated. The crude product mixture was purified by column chromatography on silica gel (100-200 mesh) using 25% ethyl acetate in hexane as the eluent to give compound II (5.10 g, 65%) as an off-white solid. 1 HNMR (400MHz, CDCl3) δ 11.22 (bs, 1H), 5.73 (s, 2H), 3.97-3.89 (m, 1H), 2.42-2.35 (m, 1H), 2.27 (bs, 6H), 2.23-2.20 (m, 1H), 2.20-2.17 (m, 1H), 2.07-1.90 (m, 4H), 1.66-1.56 (m, 2H); MS (ESI, negative mode) m / z 220 (M - -H).

[0292] Synthesis of benzyl trans-4-(2,5-dimethyl-1H-pyrrol-1-yl)-cyclohexanecarboxylate (III): To a stirred solution of compound II (4.40 g, 0.020 mol) in dry tetrahydrofuran (50 mL) maintained at room temperature under nitrogen atmosphere, cesium carbonate (12.94 g, 0.0398 mol) was added followed by bromomethylbenzene (7.20 mL, 0.060 mol). The resulting mixture was then heated under reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and then extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with water and brine, then the organic layer was dried over sodium sulfate and concentrated. The crude product mixture was purified by column chromatography on silica gel (100-200 mesh) using 3% ethyl acetate in hexane as eluent to give compound III (2.80 g, 46%) as a brown sticky gum. 1 HNMR (400MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.26-7.22 (m, 1H), 7.17-7.13 (m, 1H), 5.13 (s, 2H), 3.95-3.88 (m, 1H), 2.42-2.36 (m, 1H), 2.27 (brs, 6H), 2.19-2.14 (m, 2H), 2.02-1.94 (m, 4H), 1.67-1.53 ​​(m, 2H); MS (ESI, positive mode) m / z 312 (MH + ).

[0293] Synthesis of benzyl trans-4-[3-(2-chloro-acetyl)-2,5-dimethyl-1H-pyrrol-1-yl]-cyclohexanecarboxylate (IV): To a cold (0° C.) solution of aluminum chloride (1.44 g, 0.011 mol) in dichloromethane (20 mL) was added chloroacetyl chloride (0.85 mL, 0.011 mol) dropwise. The resulting mixture was stirred at low temperature for 0.5 h. Then, a solution of compound III (2.80 g, 0.009 mol) in dichloromethane (5 mL) was added in one portion to the reaction mixture. The resulting mixture was stirred at room temperature for 2 h and then poured onto crushed ice (200 mL). The mixture was basified with saturated aqueous sodium bicarbonate (100 mL) and then extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, and then concentrated under vacuum. The crude product mixture was purified by column chromatography on silica gel (100-200 mesh) using 8% ethyl acetate in hexane as eluent to give compound IV (0.950 g, 28%) as a brown oil. 1 H-NMR (400MHz, CDCl3): δ 7.39-7.30 (m, 5H), 6.15 (s, 1H), 5.12 (s, 2H), 4.40 (s, 2H), 4.04-3.99 (m, 1H), 2.62 (s, 3H), 2.38-2.41 (m, 1H), 2.26-2.18 (m, 5H), 2.06-1.99 (q, 2H), 1.62 (dq, J = 12.9, 3.4Hz, 2H), 1.64-1.60 (m, 2H); MS (ESI, positive mode) m / z 388 (MH + ).

[0294] Synthesis of benzyl trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-1H-pyrrol-1-yl]-cyclohexanecarboxylate (compound 120): To a solution of compound IV (0.070 g, 0.180 mmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (0.062 g, 0.452 mmol) and piperdine (0.023 g, 0.452 mmol). The resulting mixture was stirred at room temperature for 3 hours and then poured onto crushed ice. The mixture was extracted with dichloromethane (2×10 mL) and the combined organic extracts were then washed with water (2×10 mL) followed by saturated brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated under vacuum. The crude product mixture was purified by column chromatography on silica gel (100-200 mesh) using 5% methanol in dichloromethane as eluent to give compound 120 (0.030 g, 38%) as a brown sticky mass. 1 H-NMR (400MHz, CDCl3): δ7.38-7.30(m,5H),6.20(s,1H),5.12(s,2H),4.03-3.97( m,1H),3.61(brs,2H),2.64(brs,3H),2.60(brs,3H),2.44-2.36(m,1H),2.25(brs ,2H),2.18(d,J=12.2Hz,2H),2.04-1.99(m,2H),1.92-1.90(m,2H),1.68-1.62(m, 4H),1.60-1.56(m,2H),1.46(brs,2H),1.24(s,2H);MS(ESI, positive mode)m / z437(MH + ).

[0295] Synthesis of trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-pyrrol-1-yl]-cyclohexanecarboxylic acid (compound 121). To a solution of compound 120 (0.900 g, 2.06 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-1H-pyrrol-1-yl]-cyclohexane benzyl carboxylate, 200 mg, 20% by weight). The resulting mixture was placed under 1 atmosphere of hydrogen gas and stirred at room temperature for 16 hours. The reaction mixture was then filtered through a pad of Celite (5.00 g) and the filter pad was washed with methanol (about 50 mL). The filtrate was then concentrated under vacuum and the remaining solid was washed with diethyl ether (about 10 mL) to give compound 121 (0.300 g, 42%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ 12.11 (brs, 1H), 6.26 (s, 1H), 4.04 (brt, J = 12.5Hz, 1H), 3.35 (s, 2H), 2.53 (s, 3H), 2.50-2.48 (m, 2H), 2.39 (bs, 3H), 2.33-2.29 (m, 1H), 2.24 (brs, 3H), 2.03-1.96 (m, 4H), 1.78-1.75 (m, 2H), 1.53-1.46 (m, 5H), 1.37-1.33 (m, 2H); MS (ESI, positive mode) m / z 347 (MH + ).

[0296] Synthesis of trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-pyrrol-1-yl]-cyclohexanecarboxamide (compound 122): To a cold (0° C.) solution of compound 121 (0.100 g, 0.289 mmol) in acetonitrile (2 mL), triethylamine (0.120 mL, 0.867 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.120 g, 0.317 mmol) were added. The resulting mixture was treated with solid ammonium chloride (0.017 g, 0.317 mmol), then warmed to room temperature and stirred for 2 h. The reaction mixture was filtered and the filtered solid was washed with n-pentane (2×10 mL) to give compound 122 (0.015 g, 19%) as an off-white solid. 1 HNMR (400MHz, DMSO-d6) δ 7.71-767 (d, 1H), 7.22 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 4.14-4.12 (m, 1H), 4.03 (bs, 2H), 3.01-2.99 (m, 1H), 2.58-2.51 (m, 3H), 2.25 (brs, 3H), 2.19-2.13 (m, 1H), 2.01-1.77 (m, 6H), 1.63-1.52 (m, 5H), 1.38-1.31 (m, 2H), 1.28-1.23 (m, 2H), 0.89-0.87 (m, 1H); MS (ESI, negative mode) m / z 346 (M - -H).

[0297] Synthesis of trans-4-[2,5-dimethyl-3-(2-piperidin-1-yl-acetyl)-pyrrol-1-yl]-cyclohexanecarbonitrile (compound 143): To a solution of compound 122 (0.200 g, 0.579 mmol) in dry ethylene dichloride (10 mL), 1-propylphosphonic acid cyclic anhydride (0.85 mL, 1.44 mmol) was added. The reaction mixture was then heated under reflux for 4 hours and then allowed to cool to room temperature. The reaction mixture was concentrated under vacuum and the crude product mixture was purified by column chromatography on neutral alumina using 70% ethyl acetate in hexane as eluent to give compound 143 (0.040 g, 21%) as a brown solid.1 H-NMR (400MHz, CDCl3): δ6.24(s,1H),4.00(brt,J=11.8Hz,1H),3.47(s,2H),2.60(s,3H),2.48-2.45(m,4H),2.33(brs,1H)2.30 (brs,1H),2.25(s,3H),2.07-1.93(m,4H),1.80-1.69(m,2H),1.63-1.62(m,6H),1.43-1.42(m,2H);MS(ESI, positive mode)m / z328(MH + ).

[0298] Example 5: 4-(2,5-dimethyl-3-(2-(piperidin-1-yl)acetyl)-1H-pyrrol-1-yl)benzonitrile (Compound 81) TIFF2024112835000113.tif47170

[0299] Synthesis of 4-(2,5-dimethyl-1H-pyrrol-1-yl)benzonitrile (VI): A mixture of p-aminobenzonitrile (V, 2.00 g, 0.010 mol) and hexane-2,5-dione (5.70 g, 0.050 mol) in acetic acid (30 mL) was heated to reflux for 2 h. After cooling to room temperature, excess acetic acid was removed under vacuum and the remaining material was then diluted with water. The mixture was extracted with ethyl acetate (3x100 mL) and the combined organic extracts were washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum to give the crude product mixture. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 2% ethyl acetate in hexane as the eluent to give compound VI (3.00 g, 97%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.76(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),5.93(s,2H),2.03(s,6H).

[0300] Synthesis of 4-(3-(2-chloroacetyl)-2,5-dimethyl-1H-pyrrol-1-yl)benzonitrile (VII): To a cold (0° C.) suspension of anhydrous aluminum chloride (2.60 g, 0.019 mol) in dry dichloromethane (50 mL) was added chloroacetyl chloride (2.20 g, 0.019 mol). The resulting mixture was stirred at low temperature for 0.5 h, then a solution of compound VI (3.30 g, 0.018 mol) in dichloromethane (30 mL) was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, then poured into ice water. The mixture was extracted with dichloromethane (3×100 mL) and the combined organic extracts were dried over sodium sulfate. After the organic layer was concentrated, the remaining crude product mixture was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate in hexane to give compound VII (1.40 g, 31%) as a black solid. 1 H NMR (400MHz, CDCl3): δ7.76(d,J=8.5Hz,1H),7.31(d,J=2.3Hz,1H),6.97(dd,J=8.5,2.4Hz,1H),6.30(s,1H),4.45(s,2H),2.33(s,3H),2.00(s,3H).

[0301] Synthesis of 4-(2,5-dimethyl-3-(2-(piperidin-1-yl)acetyl)-1H-pyrrol-1-yl)benzonitrile (compound 81): To a cold (0° C.) suspension of compound VII (0.300 g, 1.00 mmol) in acetonitrile (25 mL) was added piperidine (0.180 g, 2.00 mmol) and triethylamine (0.330 g, 3.00 mmol). The mixture was allowed to warm to room temperature for 2 h. The reaction mixture was poured onto ice (10 g) and then extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (40 mL) and brine, then dried over anhydrous sodium sulfate. The organic layer was then concentrated under reduced pressure and the crude product mixture was triturated with n-pentane to give compound 81 (0.035 g, 10%) as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 3.55 (s, 2H), 2.52 (brs, 4H), 2.31 (s, 3H), 1.98 (s, 3H), 1.68-1.60 (m, 4H), 1.45 (brs, 2H); MS (ESI, positive mode) m / z 322 (MH + ).

[0302] The compounds shown below in Table 4 were prepared using procedures similar to those described above in Examples 1-5. [Table 4] TIFF2024112835000115.tif196170TIFF2024112835000116.tif197170TIFF2024112835000117.tif199170TIFF2024112 835000118.tif201170TIFF2024112835000119.tif194170TIFF2024112835000120.tif194170TIFF2024112835000121.t if194170TIFF2024112835000122.tif190170TIFF2024112835000123.tif195170TIFF2024112835000124.tif193170TIF F2024112835000125.tif194170TIFF2024112835000126.tif197170TIFF2024112835000127.tif193170TIFF20241128350 00128.tif193170TIFF2024112835000129.tif191170TIFF2024112835000130.tif196170TIFF2024112835000131.tif19 7170TIFF2024112835000132.tif196170TIFF2024112835000133.tif194170TIFF2024112835000134.tif191170TIFF202 4112835000135.tif194170TIFF2024112835000136.tif229170TIFF2024112835000137.tif217170TIFF20241128350001 38.tif212170TIFF2024112835000139.tif217170TIFF2024112835000140.tif225170TIFF2024112835000141.tif178170

[0303] Example 6: USP14 Inhibition Assay Using previously described methodology (BH Lee et al., Nature (2010) 467(9):179, the contents of which are expressly incorporated herein by reference), select compounds described herein were found to inhibit USP14 as shown in Table 5. In the table below, "I" refers to an IC greater than 5 μM. 50 In the table below, "II" indicates an IC of 0.5 to 5 μM. 50 and "III" indicates an IC below 0.5 μM 50 The IC in the table below shows 50 Values ​​represent the mean of determinations from at least two experiments. [Table 5] TIFF2024112835000143.tif207170TIFF2024112835000144.tif226170TIFF2024112835000145.t if198170TIFF2024112835000146.tif212170TIFF2024112835000147.tif202170TIFF2024112835 000148.tif193170TIFF2024112835000149.tif231170TIFF2024112835000150.tif190170TIFF20 24112835000151.tif192170TIFF2024112835000152.tif203170TIFF2024112835000153.tif22817 0TIFF2024112835000154.tif229170TIFF2024112835000155.tif227170TIFF2024112835000156. tif229170TIFF2024112835000157.tif228170TIFF2024112835000158.tif204170TIFF2024112835 000159.tif226170TIFF2024112835000160.tif226170TIFF2024112835000161.tif212170TIFF20 24112835000162.tif233170TIFF2024112835000163.tif218170TIFF2024112835000164.tif82170

[0304] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A compound having the structure of formula (VIII): or a pharma- ceutically acceptable salt thereof, wherein: X １ and X ２ are independently carbon or nitrogen, where X １ and X ２ one of which is nitrogen; X ４ is N or C(R ７ ) and R １ is the substituted C ３～８ selected from the group consisting of cycloalkyl and phenyl substituted with at least one halogen; R ２ is hydrogen or C １～４ is alkyl; Each R ３ and R ４ is hydrogen, C １～４ Alkyl, and C ３～８ cycloalkyl; Each R ５ and R ６ is hydrogen, optionally substituted C １ ~C １０ Alkyl, optionally substituted C ２ ~C １０ Alkenyl, optionally substituted C ２ ~C １０ Alkynyl, optionally substituted C １ ~C １０ Alkoxy, optionally substituted C ３ ~C １２ Cycloalkyl, optionally substituted C ３ ~C １２ independently selected from the group consisting of cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Or, R ５ and R ６ , X ４ joined to form an optionally substituted 5- to 6-membered heterocycle or an optionally substituted 5- to 6-membered heteroaryl; and R ７ is hydrogen or C １～４ is alkyl; where optionally substituted R １ , R ５ , and R ６ The substituent of is OR ｃ Or NR ｄ R ｄ C optionally substituted with １～４ Alkyl; CN; Halo; C １～４ Haloalkyl; C ２～４ Alkynyl; C ４～６ Cycloalkyl; C １～４ 5-membered heterocycle optionally substituted with alkyl; OR ｃ ; COR ｃ ; COOR ｃ ;NR ｄ R ｄ ; CONR ｄ R ｄ ;OCONR ｄ R ｄ ; S (O) ｎ R ｃ and S(O) ｎ N.R. ｄ R ｄ are each independently selected from the group consisting of: Here, each R ｃ is hydrogen, phenyl or CONR ｄ R ｄ C optionally substituted with １～４ Alkyl; C １～４ haloalkyl; phenyl, and -CH ３ or heteroaryl optionally substituted with phenyl; and Each R ｄ is hydrogen, C １～４ Alkyl, COOC １～４ Alkyl, C ３ ~C １２ Cycloalkyl and -OC １～４ independently selected from the group consisting of heteroaryl optionally substituted with alkyl; Or, two R ｄ together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycle; Each n is independently 0, 1, or 2, or a pharma- ceutically acceptable salt thereof.

2. X １ and X ４ are nitrogen, and X ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is carbon.

3. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is phenyl substituted with at least one halogen.

4. The phenyl is at least one C １～４ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, substituted with alkyl and at least one halogen.

5. R ２ , R ３ , and R ４ or a pharma- ceutically acceptable salt thereof. The compound of claim 1, wherein each of

6. R ５ and R ６ But, X ４ or a pharma- ceutically acceptable salt thereof, which is linked to an optionally substituted 5- to 6-membered heterocycle or an optionally substituted 5- to 6-membered heteroaryl.

7. The compound is 2. The compound of claim 1, selected from the group consisting of:

8. A compound having the structure of formula (IX): or a pharma- ceutically acceptable salt thereof, wherein: R ８ is N.R. ８ａ R ８ｂ where R ８ａ is -OC １～４ C optionally substituted with alkyl ５～６ aryl and 5- to 6-membered heteroaryl; R ８ｂ is hydrogen; Each R ５ａ is hydrogen, OR ｃ Or NR ｄ R ｄ C optionally substituted with １～４ Alkyl, halo, C １～４ Haloalkyl, OR ｃ , COOR ｃ , N.R. ｄ R ｄ , C.O.R. ｄ R ｄ , OCONR. ｄ R ｄ , and S(O) ｎ R ｃ are independently selected from the group consisting of: Each R ｃ is hydrogen, phenyl or CONR ｄ R ｄ C optionally substituted with １～４ Alkyl, C １～４ Haloalkyl, phenyl, and -CH ３ or heteroaryl optionally substituted with phenyl; Each R ｄ is hydrogen, C １～４ Alkyl, COOC １～４ Alkyl, C ３ ~C １２ Cycloalkyl, and -OCH ３ independently selected from the group consisting of heteroaryl optionally substituted with Or, two R ｄ together form a heterocycle; each n is independently 0, 1, or 2; q is 0, 1, or 2; and A compound, or a pharma- ceutically acceptable salt thereof, wherein r is 1 or 2.

9. R ８ａ is pyrimidinyl, or a pharma- ceutically acceptable salt thereof.

10. R ８ａ 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein: is substituted with methoxy.

11. 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein r is 2.

12. below: or a pharma- ceutically acceptable salt thereof.

13. A compound having the structure of formula (X): or a pharma- ceutically acceptable salt thereof, wherein: Each R ５ａ is hydrogen, OR ｃ Or NR ｄ R ｄ C optionally substituted with １～４ Alkyl, halo, C １～４ Haloalkyl, OR ｃ , COOR ｃ , N.R. ｄ R ｄ , C.O.R. ｄ R ｄ , OCONR. ｄ R ｄ , and S(O) ｎ R ｃ are independently selected from the group consisting of: Each R ｃ is hydrogen, phenyl or CONR ｄ R ｄ C optionally substituted with １～４ Alkyl, C １～４ Haloalkyl, phenyl, and -CH ３ or heteroaryl optionally substituted with phenyl; Each R ｄ is hydrogen, C １～４ Alkyl, COOC １～４ Alkyl, C ３ ~C １２ Cycloalkyl, and -OCH ３ independently selected from the group consisting of heteroaryl optionally substituted with Or, two R ｄ together form a heterocycle; each n is independently 0, 1, or 2; q is 0, 1, or 2; and r is 1 or 2; or a pharma- ceutically acceptable salt thereof.

14. below:

14. The compound of claim 13, selected from the group consisting of:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

16. A medicament for treating a condition associated with dysfunction of protein homeostasis, comprising an effective amount of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof.

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