WO2012078909A1 - Thiazolpyrimidine proteostasis regulators - Google Patents

Abstract

The present invention is directed to compounds having the Formula (I), (II), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis comprising an effective amount of these compounds.

Description

THIAZOLPYRIMIDINE PROTEOSTASIS REGULATORS

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/421,050 filed December 8, 2010. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cells normally maintain a balance between protein synthesis, folding, trafficking, aggregation, and degradation, referred to as protein homeostasis, utilizing sensors and networks of pathways [Sitia et al, Nature 426: 891-894, 2003; Ron et al, Nat Rev Mol Cell Biol 8: 519-529, 2007]. The cellular maintenance of protein homeostasis, or proteostasis, refers to controlling the conformation, binding interactions, location and concentration of individual proteins making up the proteome. Protein folding in vivo is accomplished through interactions between the folding polypeptide chain and macromolecular cellular components, including multiple classes of chaperones and folding enzymes, which minimize aggregation [Wiseman et al, Cell 131: 809-821, 2007]. Whether a given protein folds in a certain cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, metabolites and the like [Wiseman et al.]. Human loss of function diseases are often the result of a disruption of normal protein homeostasis, typically caused by a mutation in a given protein that compromises its cellular folding, leading to efficient degradation [Cohen et al, Nature 426: 905-909, 2003]. Human gain of function diseases are similarly frequently the result of a disruption in protein homeostasis leading to protein aggregation [Balch et al. (2008), Science 319: 916-919].

The heat shock response protects cells against a range of acute and chronic stress conditions [Westerheide et al, J Biol. Chem. 280(39): 33097 (2005)]. The human heat shock protein 70 (Hsp70) family is evolutionarily conserved among all organisms from bacteria to humans, suggesting an essential role in cell survival [Gupta et al, Curr. Biol. 4: 1 104-11 14 (1994); Lindquist et al, Ann. Rev. Genet. 22:631-677 (1988)]. Under circumstances of transient cell stress, the heat shock response and activities of molecular chaperones can restore protein homeostasis. In human disease, however, misfolded proteins can accumulate, for example, when polyglutamine-expansion proteins are chronically expressed over the life of the cell. Elevated expression of molecular chaperones suppresses protein misfolding/aggregation and toxicity phenotypes in various model systems including, for example, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Mutations in the respective proteins Huntingtin, tau, alpha- synuclein, and superoxide dismutase (SOD1), associated with these diseases, result in the appearance of misfolded species that adopt alternate conformations. Studies with mammalian tissue culture cells, transgenic mice, Drosophila, and C. elegans have established that the heat shock response can be activated in cells expressing aggregation-prone proteins, suggesting a role for molecular chaperones as an adaptive survival response [Satyal, et al, PNAS USA 97:5750-5755 (2000); Wyttenbach et al, PNAS USA 97:2898-2903 (2000)].

Both dysfunction in proteostasis and the heat shock response have been implicated in a diverse range of diseases including for example, neurodegenerative disease, metabolic diseases, inflammatory diseases, and cancer. There remains a need in the art for compounds and pharmaceutical compositions to treat conditions associated with proteostasis dysfunction and/or to provide therapies that activate the heat shock response.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having the Formula (I), (II), or (III), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis comprising an effective amount of these compounds.

In one embodiment, the invention is directed to a compound having the Formula (I):

(I)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R₂ is CN;

R3a and R3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, N(R₅)C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅ and (C=NR₅)R₅; or yet alternatively, R_3a and R₃b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-10 membered ring selected from the group consisting of C3-C1₀ cycloalkyl, C3-C1₀ cycloalkenyl, heterocyclic, aryl and heteroaryl;

R4 is optionally substituted pyridyl;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and

n is 0, 1 or 2.

In an additional embodiment, the invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

In yet an additional embodiment, the invention is a compound having the Formula

(II):

(II)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R3a and R3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅ and (C=NR₅)R₅; or yet alternatively, R_3a and R3b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-10 membered ring selected from the group consisting of C3-C1₀ cycloalkyl, C3-C1₀ cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

Re is selected from the group consisting of CN, C(0)OR₈, C(0)R₉ and C(O)NHR₁₀; R7 is optionally substituted 4-pyridyl;

Rs is selected from the group consisting of substituted Ci alkyl, optionally substituted C2-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R9 is selected from the group consisting of substituted C1-C3 alkyl, optionally substituted C4-C1₀ alkyl, optionally substituted C4-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

Rio is selected from the group consisting of optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃-C12 cycloalkenyl, optionally substituted heterocyclic, and optionally substituted heteroaryl; and

n is 0, 1 or 2.

In a further embodiment, the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof. The invention is additionally directed to a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

The invention additionally encompasses a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

The invention is further directed to a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering an effective amount of a compound having the Formula (III):

(III)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C₂-C₁₀ alkenyl, optionally substituted C₂-C₁₀ alkynyl, optionally substituted C3-C₁₂ cycloalkyl, optionally substituted C3-C₁₂ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R_3a and R₃b are each independently selected from the group consisting of hydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substituted C₂-C₁₀ alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-Ci2cycloalkyl, optionally substituted C3- C₁₂ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or yet alternatively, R_3a and R₃b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-10 membered ring selected from the group consisting of C3-C₁₀ cycloalkyl, C3-C10 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted; Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

R11 is selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or alternatively, R_u and Ri are taken together to form an optionally substituted, fused 3- 10 membered ring selected from the group consisting of C3-C1₀ cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

R12 is hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl; and

n is 0, 1 or 2.

In some embodiments, R12 is optionally substituted aryl or optionally substituted heteroaryl.

The invention also encompasses compounds described in Table 1 below, pharmaceutical compositions thereof, and a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering an effective amount of a compound shown in Table 1.

The invention additionally encompasses a method of treating cancer or a tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug of any of thereof.

The invention also encompasses a pharmaceutical composition comprising:

a pharmaceutically acceptable carrier or excipient;

an agent selected from the group consisting of a proteostasis regulator and a pharmacologic chaperone; and

a compound having the Formula (III). DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

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.

As discussed above, the present invention is directed to compounds of Formulae (I), (II), or (III), pharmaceutical compositions thereof and methods of use thereof in the treatment of conditions associated with a dysfunction in proteostasis.

In some aspects, the invention is directed to a compound having the Formula (I); or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

In one embodiment, the compound has the Formula (I), wherein R4 is optionally substituted 4-pyridyl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof. In additional aspects of the invention, the compound has the Formula (I), wherein R4 is optionally substituted 2-pyridyl. In yet additional aspects of the invention, the compound has the Formula (I), wherein R4 is optionally substituted 3-pyridyl.

In additional embodiments, the compound has the Formula (I), wherein R_3a is hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof. In yet additional embodiment, the compound of claim has the Formula (I), wherein R_3a is hydrogen or C1-C4 alkyl and R₃b is selected from the group consisting optionally substituted C1-C1₀ alkyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo. In further aspects, R₃b is selected from the group consisting of optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl. In yet further embodiments, R₃b is optionally substituted aryl or optionally substituted heteroaryl. In additional embodiments, R₃b is optionally substituted phenyl.

In an additional embodiment, the compound has the Formula (I), wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof. In yet an additional embodiment, Ri is optionally substituted C1-C1₀ alkyl or optionally substituted C₃-C12 cycloalkyl. In a further embodiment, Ri is optionally substituted C1-C4 alkyl. In additional aspects, the invention is a compound of Formula (II); or a

pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

In one embodiment, the invention is a compound of Formula (II), wherein Rs is selected from the group consisting of optionally substituted C3-C1₀ cycloalkyl, optionally substituted C3-C1₀ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

In another aspect, the invention is a compound of Formula (II), wherein R9 is selected from the group consisting of optionally substituted C3-C1₀ cycloalkyl, optionally substituted C3-C1₀ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

In yet an additional aspect, the invention is a compound of Formula (II), wherein R_3a is hydrogen or C1-C4 alkyl. In an additional aspect, the invention is a compound of Formula (II), wherein R_3a is hydrogen or C₁-C₄ alkyl and R₃b is selected from the group consisting of are each independently selected from the group consisting of optionally substituted C1-C1₀ alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo. In yet an additional aspect, R_3a and R₃b are each independently selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl. In a further embodiment, R₃b is optionally substituted aryl or optionally substituted heteroaryl and R_3a is hydrogen or C₁-C₄ alkyl. In yet another aspect, R₃b is optionally substituted phenyl. In a further aspect, R₃b is optionally substituted phenyl and R_3a is hydrogen.

In yet an additional aspect, the invention is a compound of Formula (II), wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof. In a further aspect, Ri is optionally substituted C1-C1₀ alkyl or optionally substituted C3-C12 cycloalkyl. In yet another embodiment, Ri is optionally substituted C1-C4 alkyl. It is to be understood that the specific embodiments described herein can be taken in combination with other specific embodiments delineated herein. For example, for compounds of Formula (I), R4 was defined as 4-pyridyl in certain embodiments and R_3a was defined as hydrogen or C1-C4 alkyl in certain embodiments. It is thus to be understood that the invention encompasses compounds of Formula (I), wherein R4 is 4-pyridyl and R_3a is hydrogen or C₁-C₄ alkyl.

Exemplary compounds encompassed by the invention are shown in the Table below:

Table 1

3 -fluorophenyl 4-

Ethyl

(3-F phenyl) pyridyl

3-hydroxyphenyl 4-

Ethyl

(3 -OH phenyl) pyridyl

4-cyanophenyl 4-

Ethyl

(4-CN phenyl) pyridyl

4-

4-

Ethyl dimethylaminophenyl

pyridyl

(4-NMe₂ phenyl)

4-

Ethyl 3-thiophene

pyridyl

[l,l '-biphenyl]-3-yl 4-

Ethyl

3-Ph phenyl pyridyl

The present invention encompasses the specific compounds shown above in Table 1, pharmaceutical compositions comprising said compounds and method for the treatment of a condition associated with a dysfunction in protein homeostasis comprising administering to a patient in need thereof an effective amount of a compound shown above.

The term "alkyl", as used herein, unless otherwise indicated, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-Cio alkyl" denotes 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.

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

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

The term "cycloalkyl," as used herein, refers to cyclic alkyl moieties having 3 or more carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The term "cycloalkenyl," as used herein, refers to cyclic alkenyl moieties having 3 or more carbon atoms. The term "cycloalkynyl," as used herein, refers to cyclic alkynyl moieties having 5 or more carbon atoms.

The term "heterocyclic" encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, heteropolycycloalkenyl and the like. Heterocycloalkyl refers to cycloalkyl groups containing one or more heteroatoms (O, S, or N) within the ring. Heterocycloalkenyl as used herein refers to cycloalkenyl groups containing one or more heteroatoms (O, S or N) within the ring. Heterobicycloalkyl refers to bicycloalkyl groups containing one or more heteroatoms (O, S or N) within a ring.

Heterobicycloalkenyl as used herein refers to bicycloalkenyl groups containing one or more heteroatoms (O, S or N) within a ring.

Cycloalkyl, cycloalkenyl, heterocyclic, 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.

The term "aryl", as used herein, refers to mono- or polycyclic aromatic carbocyclic ring systems. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. The term "aryl" embraces aromatic radicals, such as, phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. An aryl group may be substituted or unsubstituted.

The term "heteroaryl", as used herein, refers to aromatic carbocyclic groups containing one or more heteroatoms (O, S, or N) within a ring. A heteroaryl group can be monocyclic or polycyclic. A heteroaryl group may additionally be substituted or

unsubstituted. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. Examples of heteroaryl groups include, but are not limited to, 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, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl,

tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, thiazolopyridinyl, oxazolopyridinyl and azaindolyl. The foregoing heteroaryl groups may be C-attached or heteroatom-attached (where such is possible). For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C- attached).

The term "substituted" refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -Ci- C alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C3-C12 cycloalkyl, -C3-C12 cycloalkenyl, C3-C12 cycloalkynyl, -heterocyclic, -F, -CI, -Br, -I, -OH, -N0₂, -N₃, -CN, -NH₂, oxo, thioxo, -NHR_X, -NR_XR_X, dialkylamino, -diarylamino, -diheteroarylamino, -OR_x, -C(0)R_y, -C(0)C(0)R_y, - OC0₂R_y , -OC(0)R_y, OC(0)C(0)R_y, -NHC(0)R_y, -NHC0₂R_y, -NHC(0)C(0)R_y,

NHC(S)NH₂, -NHC(S)NHR_X, -NHC( H)NH₂, -NHC(NH)NHR_X, -NHC( H)R_X, - C(NH)NHR_X, -NR_xC(0)R_x, -NR_xC0₂R_y, -NR_xC(0)C(0)R_y, -NR_XC(S)NH₂, -

NR_xC(0)NR_xR_x, -NR_xS(0)₂NR_xR_x, -NR_XC(S)NHR_X, -NR_XC(NH)NH₂, -NR_XC( H)NHR_X, - NRxC( H)R_x, -C( Rx)NHR_x -S(0)_nR_y, -NHS0₂R_x, -CH₂NH₂, -CH₂S0₂CH₃, (C=NR_X)R_X; - aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-Ci2-cycloalkyl, - polyalkoxyalkyl, -polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-R_x, or - methylthiomethyl, wherein R_x is selected from the group consisting of -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C₃-C12 cycloalkyl, -aryl, -heteroaryl and -heterocyclic; -R_y is selected from the group consisting of -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C3-C12 cycloalkyl, -aryl, -heteroaryl, -heterocyclic, -NH₂, -NH-C1-C12 alkyl, -NH-C2-C12 alkenyl, - NH-C₂-Ci2-alkynyl, -NH-C₃-C12 cycloalkyl, -NH-aryl, -NH-heteroaryl and -NH-heterocyclic, and n is 0, 1 or 2. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.

The term "haloalkyl" as used herein refers to an alkyl group having 1 to (2m+l) subsistent(s) independently selected from F, CI, Br or I, where n is the maximum number of carbon atoms in the alkyl group.

The term "pyridyl," as used herein is meant to encompass 2-pyridyl, 3-pyridyl and 4- pyridyl groups.

Non-limiting examples of optionally substituted aryl are phenyl, substituted phenyl, napthyl and substituted naphthyl.

Certain of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers may 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 each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The 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 may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

Where 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 an R-configuration at a specific position when it is present in excess compared to the compound having an S-configuration at that position. A compound has an S-configuration at a specific position when it is present in excess compared to the compound having an R- configuration at that position.

It is to be understood that atoms making up the compounds of the present invention are intended to include isotopic forms of such atoms. Isotopes, as used herein, include those 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, ¹³C and ¹⁴C. The invention therefore encompasses embodiments in which one or more of the hydrogen atoms in Formula (I), (II), or (III) are replaced with deuterium. The invention also encompasses embodiments wherein one or more of the carbon atoms in Formula (I), (II), or (III) is replaced with silicon atoms.

The invention additionally encompasses embodiment wherein one or more of the nitrogen atoms in Formula (I), (II), or (III) are oxidized to N-oxide.

An exemplary synthetic route for the preparation of compounds of the invention is shown in the General Synthetic Scheme below. As will be understood by the skilled artisan, diastereomers can be separated from the reaction mixture using column chromatography. eneral Synthetic Scheme

The invention encompasses pharmaceutically acceptable salts of the compounds described herein. Thus, in certain aspects, the invention is directed to pharmaceutically acceptable salts of compounds of Formula (I), (II) or (III) and pharmaceutical compositions thereof. A "pharmaceutically acceptable salt" includes an ionic bond-containing product of the reaction between the disclosed compound with either an acid or a base, suitable for administering 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, 69(1): 1-19, the contents of which are herein incorporated by reference. A non-limiting example of a pharmaceutically acceptable salt is an acid salt of a compound containing an amine or other basic group which can be obtained by reacting the compound with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable salts also can be metallic salts including, but not limited to, sodium, magnesium, calcium, lithium and aluminum salts. Further examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. Salts can also be formed with suitable organic bases when the compound comprises an acid functional group such as -C(0)OH or -SO₃H. Such bases suitable for the formation of a pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases that are nontoxic and strong enough to react with the acid functional group. Such organic bases are well known in the art and include amino acids such as arginine and lysine, mono-, di-, and triethanolamine, choline, mono-, di-, and

trialkylamine, such as methylamine, dimethylamine, and trimethylamine, guanidine, N- benzylphenethylamine, N-methylglucosamine, N-methylpiperazine, morpholine,

ethylendiamine, tris(hydroxymethyl)aminomethane and the like. 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 use of the solvates. In some embodiments, the invention is a solvate of a compound of Formula (I), (II), or (III) or a pharmaceutical composition thereof.

Also included in the present invention are prodrugs of the compounds described herein, for example, prodrugs of a compound of Formula (I), (II), or (III) or a pharmaceutical composition thereof or method of use of the prodrug.

The invention additionally includes clathrates of the compounds described herein, pharmaceutical compositions comprising the clathrates, and methods of use of the clathrates. In some embodiments, the invention is directed to clathrates of a compound of Formula (I), (II), or (III) or a pharmaceutical composition thereof.

As discussed above, the invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound described herein. The compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, can be administered in pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient. The excipient can be chosen based on the expected route of administration of the composition in therapeutic applications. The route of administration of the composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder. The route of

administration and the dosage of the composition to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Pharmaceutical compositions comprising compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, can be administered by a variety of routes including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal and intraperitoneal.

The compositions can also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human

administration. The diluent is selected so as not to affect the biological activity of the pharmacologic agent or composition. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like. Pharmaceutical compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized SEPHAROSE™, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).

The compositions can be administered parenterally such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating a composition into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Parenteral formulations may also include 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 the adjustment of tonicity such as sodium chloride or dextrose may also be added. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

Additionally, auxiliary substances, such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions. Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, 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.

Injectable formulations can be prepared either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The preparation also can also be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above. Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-119, 1997. The compositions and pharmacologic agents described herein can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.

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 the active ingredient 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 saccharine, cellulose, and magnesium carbonate. Topical application can result in transdermal or intradermal delivery. Transdermal delivery can be achieved using a skin patch or using transferosomes. [Paul et al, Eur. J. Immunol. 25: 3521- 24, 1995; Cevc et al, Biochem. Biophys. Acta 1368: 201-15, 1998].

For the purpose of oral therapeutic administration, the pharmaceutical compositions can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Tablets, pills, capsules, troches and the like may also contain binders, excipients, disintegrating agent, lubricants, glidants, sweetening agents, and flavoring agents. Some examples of binders include microcrystalline cellulose, gum tragacanth or gelatin. Examples of excipients include starch or lactose. Some examples of disintegrating agents include alginic acid, corn starch and the like. Examples of lubricants include magnesium stearate or potassium stearate. An example of a glidant is colloidal silicon dioxide. Some examples of sweetening agents include sucrose, saccharin and the like. Examples of flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. In another embodiment, the composition is administered as a tablet or a capsule.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, 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 a flavoring such as cherry or orange flavor, and the like. For vaginal administration, a pharmaceutical composition may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.

The pharmaceutical composition can also be administered by nasal administration. As used herein, nasally administering or nasal administration includes administering the composition to the mucus membranes of the nasal passage or nasal cavity of the patient. As used herein, pharmaceutical compositions for nasal administration of a composition include therapeutically effective amounts of the compounds prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the composition may also take place using a nasal tampon or nasal sponge.

For topical administration, suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be

administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered drop wise to the subject's eye, or a cream formulation can be administered to the skin.

Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas.

Suppository formulations can easily be made 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 the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.

Transdermal administration includes percutaneous absorption of the composition through the skin. Transdermal formulations include patches, ointments, creams, gels, salves and the like.

In addition to the usual meaning of administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment, for purposes of the present invention, "pulmonary" will also mean to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses. For pulmonary administration, an aerosol formulation containing the active agent, a manual pump spray, nebulizer or pressurized metered-dose inhaler as well as dry powder formulations are contemplated. Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.

A drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister. Often, the compound intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.

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

"Treating" or "treatment" includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder. A "patient" is a human subject in need of treatment.

An "effective amount" refers to that amount of the therapeutic agent that is sufficient to ameliorate of one or more symptoms of a disorder and/or prevent advancement of a disorder, cause regression of the disorder and/or to achieve a desired effect.

As used herein, the term "inhibiting" or "decreasing" encompasses causing a net decrease by either direct or indirect means. The term "increasing" means to cause a net gain by either direct or indirect means.

In certain aspects, the invention is directed to a method of treating a patient suffering from a condition associated with decreased Hsp70. In certain additional aspects, the condition associated with decreased Hsp70 includes, but is not limited to, Alzheimer's disease, Huntington's disease, Cystic Fibrosis, Gaucher's disease, Parkinson's disease, diabetes and complications thereof, chronic obstructive pulmonary disease (COPD), AIDS, Alpha-synuclein, and alpha 1 anti-trypsin deficiency.

The invention encompasses the treatment of a condition associated with a dysfunction in proteostasis. Proteostasis refers to protein homeostasis. Dysfunction in protein homeostasis is a result of protein misfolding, protein aggregation, defective protein trafficking or protein degradation. Exemplary proteins of which there can be a dysfunction in proteostasis, for example that can exist in a misfolded state, include, but are not limited to, glucocerebrosidase, hexosamine A, cystic fibrosis transmembrane conductance regulator, aspartylglucsaminidase, a-galactosidase A, cysteine transporter, acid ceremidase, acid a-L- fucosidase, protective protein, cathepsin A, acid β-glucosidase, acid β-galactosidase, iduronate 2-sulfatase, a-L-iduronidase, galactocerebrosidase, acid a -mannosidase, acid β - mannosidase, arylsulfatase B, arylsulfatase A, N-acetylgalactosamine-6-sulfate sulfatase, acid β -galactosidase, N-acetylglucosamine-1 -phosphotransferase, acid sphingmyelinase, NPC-1, acid a-glucosidase, β-hexosamine B, heparin N-sulfatase, a -N-acetylglucosaminidase, a - glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, a -N- acetylgalactosaminidase, a -neuramidase, β -glucuronidase, β-hexosamine A and acid lipase, polyglutamine, a -synuclein, Αβ peptide, tau protein, transthyretin and insulin.

In certain embodiments, the protein is selected from the group consisting of huntingtin, tau, alpha-synuclein, al anti-trypsin and superoxide dismutase.

Protein conformational diseases encompass gain of function disorders and loss of function disorders. In one embodiment, the protein conformational disease is a gain of function disorder. The terms "gain of function disorder," "gain of function disease," "gain of toxic function disorder" and "gain of toxic function disease" are used interchangeably herein. A gain of function disorder is a disease characterized by increased aggregation-associated proteotoxicity. In these diseases, aggregation exceeds clearance inside and/or outside of the cell. Gain of function diseases include, but are not limited to neurodegenerative diseases associated with aggregation of polyglutamine, Lewy body diseases, amyotrophic lateral sclerosis, transthyretin-associated aggregation diseases, Alzheimer's disease and prion diseases. Neurodegenerative diseases associated with aggregation of polyglutamine include, but are not limited to, Huntington's disease, dentatorubral and pallidoluysian atrophy, several forms of spino-cerebellar ataxia, and spinal and bulbar muscular atrophy. Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of Αβ peptide and intracellular aggregates of the microtubule associated protein tau.

Transthyretin-associated aggregation diseases include, for example, senile systemic amyloidoses and familial amyloidotic neuropathy. Lewy body diseases are characterized by an aggregation of a-synuclein protein and include, for example, Parkinson's disease. Prion diseases (also known as transmissible spongiform encephalopathies or TSEs) are

characterized by aggregation of prion proteins. Exemplary human prion diseases are Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt- Jakob Disease, Gerstmann-Straussler- Scheinker Syndrome, Fatal Familial Insomnia and Kuru.

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 folding of a protein resulting in excessive degradation of the protein. Loss of function diseases include, for example, cystic fibrosis and lysosomal storage diseases. In cystic fibrosis, the mutated or defective enzyme is the cystic fibrosis transmembrane conductance regulator (CFTR). One of the most common mutations of this protein is AF508 which is a deletion (Δ) of three nucleotides resulting in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. Lysosomal storage diseases are a group of diseases characterized by a specific lysosomal enzyme deficiency which may occur in a variety of tissues, resulting in the build-up of molecules normally degraded by the deficient enzyme. The lysosomal enzyme deficiency can be in a lysosomal hydrolase or a protein involved in the lysosomal trafficking. Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry's disease, Batten disease, Cystinosis, Farber, Fucosidosis, Galactasidosialidosis, Gaucher's disease (including Types 1, 2 and 3), Gml gangliosidosis, Hunter's disease, Hurler-Scheie's disease, Krabbe's disease, a-Mannosidosis, β-Mannosidosis, Maroteaux-Lamy's disease, Metachromatic Leukodystrophy, Morquio A syndrome, Morquio B syndrome, Mucolipidosis II, Mucolipidosis III, Neimann-Pick Disease (including Types A, B and C), Pompe's disease, Sandhoff disease, Sanfilippo syndrome (including Types A, B, C and D), Schindler disease, Schindler-Kanzaki disease, Sialidosis, Sly syndrome, Tay-Sach's disease and Wolman disease.

In another embodiment, the disease associated with a dysfunction in proteostasis and/or in the heat shock response is a cardiovascular disease. Cardiovascular diseases include, but are not limited to coronary artery disease, myocardial infarction, stroke, restenosis and arteriosclerosis. Conditions associated with a dysfunction of proteostasis also include ischemic conditions, such as, ischemia/reperfusion injury, myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease and cerebral ischemia.

In yet another embodiment, the disease associated with a dysfunction in proteostasis is diabetes and/or complications of diabetes, including, but not limited to, diabetic retinopathy, cardiomyopathy, neuropathy, nephropathy, and impaired wound healing.

In a further embodiment, the disease associated with a dysfunction in proteostasis 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

In some embodiments, 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, ocular diseases and cancer or tumor.

The invention also encompasses methods for the treatment of hemoglobinopathies (such as sickle cell anemia), an inflammatory disease (such as inflammatory bowel disease, colitis, ankylosing spondylitis), intermediate filament diseases (such as non alcoholic and alcoholic fatty liver disease) and drug induced lung damage (such as methotrexate-induced lung damage).

The invention additionally encompasses methods for treating hearing loss, such as noise-induced hearing loss, aminoglycoside-induced hearing loss, and cisplatin-induced hearing loss.

In certain aspects, the method comprises administering to the patient an effective amount of a compound of Formula (III), wherein R12 is an optionally substituted heteroaryl, such as an optionally substituted 5- or 6-membered heteroaryl. In additional embodiments, R12 is a 6-membered heteroaryl containing at least one nitrogen ring atoms. In yet additional embodiments, wherein Ri₂ is selected from the group consisting of pyridyl, pyridazyl and pyrimidyl, each optionally substituted. In further embodiment, Ri₂ is optionally substituted pyridyl. In yet further embodiments, R12 is 4-pyridyl.

In certain aspects, the method comprises administering to the patient an effective amount of a compound of Formula (III), wherein R_3a is hydrogen or C1-C4 alkyl and/or wherein R₃b is selected from the group consisting of are each independently selected from the group consisting of optionally substituted C1-C1₀ alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo. In yet an additional embodiment, R₃b is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl. In a further embodiment, R₃b is aryl or heteroaryl. In certain embodiments, R₃b is optionally substituted phenyl. In certain additional embodiments, R_3a is hydrogen and R₃b is optionally substituted phenyl.

In additional aspects, the method comprises administering the patient an effective amount of a compound of Formula (III), wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl. In yet additional embodiments, Ri is optionally substituted C1-C1₀ alkyl or optionally substituted C3-C1₀ cycloalkyl.

In yet additional aspects, the method comprises administering an effective amount of a compound of Formula (III), wherein R_n is selected from the group consisting of CN, C(0)OR₅, C(0)R₅, and C(0)NR₅R₅. In yet an additional embodiment, the method comprises administering an effective amount of a compound of Formula (III), wherein Rn and Ri are taken together to form an optionally substituted, fused 3-10 membered ring selected from the group consisting of C₃- Cio cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted. In a further embodiment, Rn and Ri are taken together to form an optionally substituted, fused 3-10 membered ring selected from the group consisting of C3-C10 cycloalkenyl, heterocyclic, aryl and heteroaryl, wherein said ring is oxo-substituted and optionally further substituted.

In certain embodiments, the invention includes methods for the treatment of a condition associated with a dysfunction in proteostasis comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, or the compounds described herein, and a second agent (e.g., a second therapeutic agent). Co-administered agents, compounds, or therapeutics need not be administered at exactly the same time. In certain embodiments, however, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, or a compound described herein, is administered substantially simultaneously as the second agent. By "substantially simultaneously," it is meant that the compound of (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, or a compound described herein, is administered before, at the same time, and/or after the administration of the second agent, and encompasses, for example, administration within the same treatment session or as part of the same treatment regimen. Exemplary second agents include pharmacologic chaperones and proteostasis regulators (such as, those described below).

In an additional embodiment, the invention is directed to a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, and a second agent, wherein the second agent is selected from the group consisting of a pharmacologic chaperone and a proteostasis regulator. The invention also encompasses a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering a therapeutically effective amount of a compound of the invention and a second agent, wherein the second agent is a pharmacologic chaperone. Pharmacologic chaperones or kinetic stabilizers refer to compounds that bind an existing steady state level of the folded mutant protein and chemically enhance the folding equilibrium by stabilizing the fold [Bouvier, Chem Biol 14: 241-242, 2007; Fan et al, Nat Med 5: 1 12-1 15, 1999; Sawkar et al., Proc Natl Acad Sci US A 99: 15428-15433, 2002; Johnson and Kelly, Accounts of Chemical Research 38: 91 1-921, 2005]. The pharmacologic chaperone is administered in amount that in combination with a compound described herein in an amount that is sufficient to treat a patient suffering from a condition associated with a dysfunction in proteostasis. Exemplary pharmacologic 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 by reference herein.

In another embodiment, the invention is a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound described herein and a second agent, wherein the second agent is a proteostasis regulator. The term "proteostasis regulator" refers to small molecules, siR A and biologicals (including, for example, proteins) that enhance cellular protein homeostasis. For example, proteostasis regulators can be agents that influence protein synthesis, folding, trafficking and degradation pathways. Proteostasis regulators encompass pharmacologic agents that stimulate the heat shock response (HSR) signaling activity. Proteostasis regulators function by manipulating signaling pathways, including, but not limited to, the heat shock response or the unfolded protein response, or both, resulting in transcription and translation of proteostasis network components. Proteostasis regulators can enhance the folding, trafficking and function of proteins (for example, mutated proteins). Proteostasis regulators can also regulate protein chaperones by upregulating transcription or translation of the protein chaperone, or inhibiting degradation of the protein chaperone.

Proteostasis regulators can influence the biology of folding, often by the coordinated increase in chaperone and folding enzyme levels and macromolecules that bind to partially folded conformational ensembles, thus enabling their progression to intermediates with more native structure and ultimately increasing the concentration of folded mutant protein for export. In one aspect, the proteostasis regulator is distinct from a chaperone in that the proteostasis regulator can enhance the homeostasis of a mutated protein but does not bind the mutated protein. In addition, proteostasis regulators can upregulate an aggregation pathway or a disaggregase activity. Exemplary proteostasis regulators are the celastrols, MG-132 and L- type Ca²⁺ channel blockers (e.g., dilitiazem and verapamil). The term "celastrols" refers to celastrol and derivatives or analogs thereof, including, but not limited to, those celastrol derivatives described in Westerheide et al, J Biol Chem, 2004. 279(53): p. 56053-60, the contents of which are expressly incorporated by reference herein. Celastrol derivatives include, for example, celastrol methyl ester, dihydrocelastrol diacetate, celastrol butyl ether, dihydrocelastrol, celastrol benzyl ester, primesterol, primesterol diacetate and triacetate of celastrol. In certain aspects, the proteostasis regulator is a heat shock response activator. A heat shock response activator is an agent that indirectly or directly activates 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. 279(53): p. 56053-60, the contents of which are expressly incorporated by reference herein). 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 celastrols, non-steroidal antiinflammatory drugs, ansamycin, geldenamycin, radiciol, glucuronic acid, and tributylin. Heat shock response activators have also been described, for example, in U.S. Patent Application Publication Nos. 20070259820, 20070207992, 20070179087, 20060148767, the contents of each of which are expressly incorporated by reference herein. In some embodiments, the heat shock response activator is a small molecule heat shock response activator.

The invention also encompasses a method of treating cancer or a tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound of Formula (I), (II), or (III). The invention additionally encompasses a method of treating cancer or a tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound described herein. Cancers that can be treated according to methods of the present 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, hematologic cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer.

In another embodiment, the invention is a method of treating cancer or a tumor comprising administering a compound of Formula (I), (II), or (III) or a compound described herein in combination with the administration of a chemotherapeutic agent.

Chemotherapeutic agents that can be utilized include, but are not limited to, alkylating agents such as cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;

ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid;

aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil;

bisantrene; edatraxate; defo famine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;

mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine;

mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.) 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-1 1; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and

pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 1 17018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In a further embodiment, the invention is a method of treating cancer or a tumor comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (II), or (III) or a compound described herein in combination with radiation therapy.

The invention is illustrated by the following examples which are not meant to be limiting in any way.

EXEMPLIFICATION

Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ^lH NMR spectra were recorded on either a: Bruker 300 MHz, Bruker 200 MHz, Bruker DRX500 MHz, or Bruker 600 MHz spectrometer. Significant peaks are tabulated in the order: δ (ppm): chemical shift (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons. Low resolution mass spectra were recorded on either a Waters 2695 Separation Module with associated Micromass ZQ system (Agilent Zorbax line, Eclipse Plus C18 column, 2.1 x 30 mm, 1.8 micron; solvent A: 0.1% formic acid in methanol; solvent B: 0.1% formic acid in Water; gradient elution from 1% to 100% of A in 25 min, flow 0.35 mL/min; UV detection at 200-400 nm) or Waters 2695 Separation Module with associated Waters Micromass ZQ system (Nucleosil-100 C-18, 250 x 4mm; solvent A: 0.02% trifluoroacetic acid in acetonitrile; solvent B: 0.02% trifluoroacetic acid in Water; gradient elution from 10% to 90% of A in 25 min, flow 1 mL/min; UV detection at 200 - 400 nm).

General Biginelli Condensation Procedures

Procedure A: A round-bottom flask, equipped with a stir bar, is charged with solid thiourea (1.5 equivalents) and absolute ethanol (0.7 M to limiting reagents). To the stirred thiourea mixture is added neat aldehyde (1 equivalent), followed by β-keto ester or amide (1 equivalent). The resulting mixture is stirred vigorously. Finally, concentrated hydrochloric acid (10 drops) is added to the mixture and a condenser is attached to the flask. The system is heated at 95°C (oil bath, external temperature), open to air, for 4 h. The system is allowed to cool to room temperature and then the mixture is condensed in vacuo. The crude product is recrystallized or precipitated from an appropriate solvent or solvent mixture. The product is collected via vacuum filtration on a Buchner funnel and washed with 95% ethanol. The filtered solid is allowed to dry under suction to afford the product as a dry powder.

Procedure B: Neat aldehyde (1 equivalent, 5,46 mmol), thiourea (1.5 equivalents), and toluene-4-sulfonic acid monohydrate (0.2 equivalents) are combined in a round-bottom flask and diluted with 1,4-dioxane (0.4 M to limiting reagents). A condenser is attached to the flask and the mixture is heated to reflux for 2 h. After cooling the reaction mixture to 60- 65°C, β-keto ester or amide (1.5 equivalents) is added dropwise/portionwise. The reaction mixture is heated to reflux overnight, allowed to cool to room temperature, and then concentrated to dryness. The crude product is purified by flash chromatography to afford the product as a powder.

Example 1

A round-bottom flask, equipped with a stir bar, was charged with solid thiourea (4.0 g, 52.5 mmol) and absolute ethanol (50 mL). To the stirred thiourea mixture was added neat benzaldehyde (3.6 mL, 35.6 mmol), followed by ethyl acetoacetate (4.5 mL, 35.6 mmol). The resulting mixture was stirred vigorously. Finally, concentrated hydrochloric acid (10 drops) was added to the mixture and a condenser was attached to the flask. The system was heated at 95°C (oil bath, external temperature), open to air, for 4 h. The system was allowed to cool to room temperature then the mixture was condensed in vacuo to afford a white solid. The solid was dissolved in a minimum of hot methanol (approx. 25 mL) then was allowed to cool to room temperature. Ethyl acetate was layered onto the saturated methanol mixture and the resulting biphasic mixture was allowed to sit in a -10°C freezer for 12 h to afford a white precipitate. The precipitate was collected via vacuum filtration on a Buchner funnel and washed with 95% ethanol (3 x 15 mL). The remaining solid was powdered and allowed to dry under suction to afford ethyl 6-methyl-4-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine-5- carboxylate as a white powder (4.91 g, 51%).

'H NMR (300 MHz, i¾-DMSO) δ 9.60 (s, 1 H), 7.34-7.08 (m, 5 H), 5.16 (s, 1 H), 3.97 (q, J= 7.2 Hz, 2 H), 2.26 (s, 3 H), 1.06 (t, J= 7.2 Hz, 3 H); LRMS (ESI⁺) 277 (MH⁺, 8), 218 (MH⁺ - CH S, 13), 172 (MH⁺ - C₇H₆N, 48).

General Procedure for Two-Step Preparation of Thiazolopyrimidinones

Step 1: A round-bottom flask, equipped with a stir bar, is charged with solid

tetrahydropyrimidine (1 equivalent) and anhydrous 1,4-dioxane or dichloromethane (0.25 M to limiting reagents). The resulting mixture is stirred at 23 °C and then treated with neat alpha- halo acid chloride (1.3 equivalents). In the case of less reactive acid chlorides (in dioxane) the reaction mixture is allowed to stir at room temperature for 40 min, and is then heated at 50°C (oil bath, external temperature) overnight before cooling the system back to room

temperature. For more reactive acid chlorides (in dichloromethane) the reaction mixture is allowed to stir at room temperature overnight. The mixture is treated with methanol (1.5 mL), allowed to stir at room temperature for 15 min, and is then condensed in vacuo. The crude product mixture purified via recrystallization or chromatography on silica. Step 2: A reaction vessel, equipped with a stir bar, is charged with thiazolopyrimidinone product from Step 1 (1 equivalent) and methanol or 1,4-dioxane (0.2 M in limiting reagent). Neat triethylamine (2.5 equivalents), if a base is required, is added to the mixture, followed by aldehyde (1.4 equivalents). The vessel is sealed and the mixture is heated at 50°C

(methanol) or 100°C (1,4-dioxane), based upon the solvent used, until reaction is complete. The crude product is purified by recrystallization/precipitation from an appropriate solvent mixture or by chromatography on silica.

Example 2

A round-bottom flask, equipped with a stir bar, was charged with solid ethyl 6- methyl-4-phenyl-2-thioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (1.05 g, 3.80 mmol) and anhydrous 1,4-dioxane (15 mL). The resulting heterogeneous mixture was stirred at 23 °C then was treated with neat chloroacetyl chloride (0.4 mL, 5.02 mmol). The

heterogeneous reaction mixture was allowed to stir at room temperature for 40 min, and then was heated at 50°C (oil bath, external temperature) for 16 h before cooling the system back to room temperature. The heterogeneous mixture was treated with methanol (1.5 mL), allowed to stir at room temperature for 15 min, and then was condensed in vacuo. The solid obtained after condensation was suspended in 95% ethanol (40 mL) then filtered via vacuum filtration. The solid was allowed to dry under suction to afford ethyl 7-methyl-3-oxo-5-phenyl-3,5- dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate as a white powder (899 mg, 86%).

'H NMR (300 MHz, i¾-DMSO) δ 7.42-7.26 (m, 5 H), 6.18 (d, J= 0.9 Hz, 1 H), 4.22- 4.07 (m, 4 H), 2.71 (s, 3 H), 1.19 (t, J= 7.2 Hz, 3 H); LRMS (ESI⁺) 317 (MH⁺, 100), 271 (MH⁺ - C₂H₅0, 13), 245 (MH⁺ - C₃H₄0₂, 33).

Example 3

A screw-cap vial, equipped with a stir bar, was charged with ethyl 7-methyl-3-oxo-5- phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (185 mg, 0.585 mmol) and methanol (3 mL). Neat triethylamine (0.2 mL, 1.46 mmol) was added to the mixture, followed by pyridine-2-carboxaldehyde (0.08 mL, 0.841 mmol). The vial was capped and the resulting orange, heterogeneous mixture was placed in a 50°C oil bath for 2.5 d. The system was allowed to cool to room temperature and was diluted with isopropanol (3 mL). The mixture was placed in a -10°C freezer for 30 min and then filtered. The filtered solids were washed with isopropanol (3 x 1 mL) and ¾0 (3 x 1 mL). The material was allowed to dry under suction then was sonicated with MTBE (5 mL), at room temperature for 1 min. The supernatant was decanted and sonication/decanting cycle was repeated three additional times before the solid was allowed to dry in vacuo. Ethyl 7-methyl-3-oxo-5-phenyl-2- (pyridin-2-ylmethylene)-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate was obtained as a bright yellow powder (168 mg, 71%).

'H NMR (300 MHz, CDCI₃) δ 8.74 (d, J= 5.1 Hz, 1 H), 7.74 (dt, J= 1.8, 7.5 Hz, 1 H), 7.66 (s, 1 H), 7.46-7.38 (m, 3 H), 7.34-7.20 (m, 4 H), 6.21 (s, 1 H), 4.12 (q, J= 7.2 Hz, 2 H), 2.54 (s, 3 H), 1.20 (t, J= 7.2 Hz, 3 H); LRMS (ESI⁺) 406 (MH⁺, 100), 360 (MH⁺ - C₂H₆0, 34). xample 4

A screw-cap vial, equipped with a stir bar, was charged with solid ethyl 7-methyl-3- oxo-5-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (285 mg, 0.901 mmol) and dry 1,4-dioxane (3 mL). Pyridine-4-carboxaldeyde (0.09 mL, 0.947 mmol) was added to the mixture; the vial was capped tightly, and then heated at 100°C (oil bath, external temperature). After 24 h, the system was allowed to cool to room temperature and then was condensed in vacuo to afford a dark residue. The residue was absorbed onto Celite (approx. 2 mL) and the products were separated by column chromatography (12 g Si0₂, 3 cm diameter) using a methanol/dicholomethane gradient (0-10%). Fractions containing the single major product were combined and condensed in vacuo to afford a brown solid, which was then recrystallized three times from hot MTBE to afford ethyl 7-methyl-3-oxo-5-phenyl-2- (pyridin-4-ylmethylene)-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate as a dark orange solid (178 mg, 49%).

XH NMR (300 MHz, CDC1₃) δ 8.73 (d, J= 6 Hz, 1 H), 7.63 (s, 1 H), 7.44-7.20 (m, 9

H), 6.21 (s, 1 H), 4.12 (q, J= 6.9 Hz, 2 H), 2.54 (s, 3 H), 1.20 (t, J= 7.2 Hz, 3 H); LRMS (ESI⁺) 406 (MH⁺, 100).

General One-Pot Procedure for Preparation of Thiazoiopyrimidinones

The solid tetrahydropyrimidine (1 equivalent) is dissolved in mixture of acetic acid

(0.3 M in limiting reagents) and acetic anhydride (0.3 M in limiting reagents). To the reaction mixture are added chloroacetyl chloride (1.2 equivalents), aldehyde (1 equivalent) and sodium acetate (1 equivalent). The reaction mixture is heated to reflux overnight and then cooled to room temperature. The solvent is evaporated in vacuo and the remaining residue is suspended in ethyl acetate, followed by washing with 5% aqueous sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product is purified by chromatography on silica to obtain the product as a solid. Analytical Data

Riii H NMR Data Mass Spec

Data

(500 MHz, DMSO) 8.73 (d, J= 427 (MH⁺, 6.0 Hz, 2 H), 7.74 (s, 1 H), 7.54 45%)

(d, J= 6.0 Hz, 2H), 7.37 (q, J= 7.2

2-fluorophenyl

Hz, 2 H), 7.19 (dd, J= 15.6, 8.1

Et (2-F phenyl) 4-pyridyl

Hz, 2 H), 6.26 (s, 1 H), 4.03 (m,

2H), 2.39 (s, 3 H), 1.11 (t, J= 7.1

Hz, 3 H).

(200 MHz, CDC1₃) 8.72 (d, J= 5.9 475/477 (MH⁺, Hz, 2 H), 7.59 (s, 1 H), 7.42 - 50%)

2,4-dichlorophenyl 7.13 (m, 5 H), 6.48 (s, 1 H), 4.12

Et 4-pyridyl

(2,4-di-Cl phenyl) (q, J= 7.1 Hz, 2 H), 2.46 (s, 3 H),

1.20 (t, J= 7.1 Hz, 3 H).

(500 MHz, DMSO) 8.74 (d, J= 413 (MH⁺, 5.8 Hz, 2 H), 7.82 (s, 1 H), 7.56 37%)

(d, J= 5.8 Hz, 2 H), 7.51 (dd, =

3.0, 4.0 Hz 1 H), 7.47 (m, 1 H),

Et 3-thiophene 4-pyridyl

7.04 - 6.96 (m, 1 H), 6.20 (s, 1

H), 4.05 - 4.15 (m, 2 H), 2.40 (s,

3 H), 1.16 (t, J= 7.1 Hz, 3 H).

(500 MHz, DMSO) 8.74 (d, J= 450 (MH⁺, 6.1 Hz, 2 H), 7.85 (d, J= 8.2 Hz, 2 30%)

4-dimethylamino- H), 7.71 (s, 1 H) 7.58 - 7.49 (m, 4

Et phenyl 4-pyridyl H), 6.12 (s, 1 H), 4.10 - 4.00 (m,

(4-NMe₂ phenyl) 2 H), 3.33 (s, 6 H) 2.42 (s, 3 H),

1.12 (t, J= 7.1 Hz, 3 H).

(200 MHz, DMSO) 8.73 (d, J= 425 (MH⁺, 6.0 Hz, 2 H), 7.77 (s, 1 H), 7.54 53%)

(d, J= 6.0 Hz, 2 H), 7.42 (dd, J=

3 -fluorophenyl 14.0, 7.9 Hz, 1 H), 7.20 - 7.13

Et 4-pyridyl

(3-F phenyl) (m, 3 H), 6.06 (s, 1 H), 3.99 - 4.12 (m, 2 H), 2.41 (s, 3 H), 1.11

(t, J= 7.1 Hz, 3 H).

(200 MHz, DMSO) 8.71 (d, J = 545 (MH⁺)

[l,l'-bipenyl]-4-yl

Bn 4-pyridyl 6.0 Hz, 2H), 7.74 (s, 1H), 7.65- (4-Ph phenyl)

7.27 (m, 15H), 7.19 - 7.14 (m,

Example 3: Biological activity assays

Multigene Assay

This assay used the QuantiGene Plex 2.0 Reagent System from Affymetrix. This assay combines the use of bDNA (branch DNA) and xMAP magnetic capture beads from Luminex Technologies to quantitatively and simultaneously detect multiple mRNA transcripts per well. The overall procedure was performed according to the QuantiGene Plex 2.0 Reagent System instruction manual from Affymetrix.

Cells were seeded at a density of 12,000 cells/well in 96-well plates with an overnight incubation at 37°C, 5% CO₂. Cells were treated with serially diluted compounds in a 7-point dose dependent manner. Cell lysis with 50% [v/v] Panomics Lysis Mixture (Lysis Mixture + 10 μΐ/ml 25 Proteinase K) was performed 6 hours post-compound treatment. Lysed cells were heated at 50°C to ensure appropriate lysing and the plates were then frozen at -80°C. Cell lysates, thawed at room temperature on the day of the assay, were pooled with mouse 8- gene multiplex probe sets and with 8 different sets of magnetic capture beads (Luminex Technology, Austin, TX) in a 100 μΐ/well volume. Biomek FX was used at every liquid transfer step. The eight plates containing lysate-probe-bead mixtures were incubated at 54°C ± 1°C on a shaking platform for an overnight incubation in the dark (18-20 hours). The following day the hybridization plates were compressed by transferring the hybridized lysates into a single magnetic capture plate. The plate was kept on a magnet to hold the beads and then washed with Panomics Wash Buffer 2.0 on a BioTek ELx405 select plate washer to remove any unbound sample. This step was followed by serial hybridizations and washings of the bDNA pre-amplifier (1 hour, 50°C), bDNA amplifier (1 hour, 50°C), label probe (1 hour, 50°C), and streptavidin-phycoerythrin (SAPE, 30 minutes, room temperature). (Zhang, A. et al. Small interfering R A and gene expression analysis using a multiplex branched DNA assay without RNA purification. J Biomol Screen 10, 549-56 (2005)). The plate was then washed with SAPE wash buffer to remove unbound SAPE and each well was analyzed with the Luminex FlexMap3D (Luminex, Austin, TX). SAPE fluorescence measured from each bead was proportional to the number of mRNA transcripts captured by the beads (Zheng, Z., Luo, Y. & McMaster, G.K. Sensitive and quantitative measurement of gene expression directly from a small amount of whole blood. Clin Chem 52, 1294-302 (2006)).

Fold changes in gene expression were obtained for each gene per well by normalizing the raw data first to the DMSO control and then to a housekeeping gene (TBP - TATA binding protein or Tubl - alpha-tubulin). PC 12 mHTT Aggregation Assay

A primary cell-based high content screen (HCS) was used to measure aggregation of Huntington polyglutamine 78 EGFP (HTTpq78-GFP; Enhanced GFP under a doxycycline driven promoter) in a non-differentiated, stable rat pheochromocytoma cell line PC- 12 (obtained from Richard Morimoto, Northwestern University, Chicago, IL). The assay was performed at 37°C in collagen coated Nunc 96 well plates and measurements were made using imaging on a ThermoScientific Arrayscab VTi HCS instrument. Cells were plated at 7,000 cells per well and allowed to settle overnight. Wells were then treated with 0. lug/ml doxycycline (DOX) for 48 hours to induce transgene expression, followed by compound addition for final concentrations of 2uM, 200nM, 20nM compound along with fresh media (DMEM, 10% human serum/5% fetal bovine serum; no antibiotics during compound treatment)and doxycycline for 72 hours. Approximately 2,000 cells were analyzed per well and cell number and percent of cells with aggregates were calculated. Triplicate wells were measured for each of the three concentrations (2uM, 200nM, and 20nM).

Exemplary compounds with activity in the multigene or PC 12 Htt aggregation assays described are shown in the tables below.

Table 2: Representative compounds with activity in gene induction assays in human HeLa cell line.

4-

Bn 4-Ph phenyl + + - - + - pyridyl

2,4-diCl 4-

Et + + + + + + phenyl pyridyl

4-F

Et 2-Cl phenyl + - - - + - phenyl

4-

Et Ph + - - - + - pyridyl

4-

Et 3-F phenyl + + - + + - pyridyl

4-

Et 3 -OH phenyl + + - + + - pyridyl

4-

Et 4-CN phenyl + + - + + - pyridyl

4-NMe₂ 4-

Et + + - - + - phenyl pyridyl

4-

Et 3-thiophene + + - - + - pyridyl

- indicates an induction of greater than 1.5 fold

indicates less than 1.5 fold induction

Table 3 : Representative compounds with activity in the PC12 Htt aggregation assay

indicates active in assay

While this invention has been particularly shown and described with references 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 encompassed by the appended claims.

Claims

What is claimed is:

1. A compound having the Formula (I):

(I)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R₂ is CN;

R_3a and R₃b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C12 cycloalkyl, optionally substituted C₃- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, N(R₅)C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or yet alternatively, R_3a and R₃b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-12 membered ring selected from the group consisting of C3-C12 cycloalkyl, C₃-C12 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

R4 is an optionally substituted pyridyl;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C₃-C1₀ cycloalkyl, optionally substituted C₃-C1₀ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and

n is 0, 1 or 2.

2. The compound of claim 1, wherein R4 is optionally substituted 4-pyridyl.

3. The compound of claim 1, wherein R4 is optionally substituted 2-pyridyl.

4. The compound of claim 1, wherein R4 is optionally substituted 3-pyridyl.

5. The compound of claim 1, wherein R_3a is hydrogen or C1-C4 alkyl.

6. The compound of claim 5, wherein R₃b is selected from the group consisting optionally substituted C1-C1₀ alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo.

7. The compound of claim 6, wherein R₃b is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl.

8. The compound of claim 7, wherein R₃b is optionally substituted aryl or optionally substituted heteroaryl.

9. The compound of claim 8, wherein R₃b is optionally substituted aryl.

10. The compound of claim 9, wherein R₃b is optionally substituted phenyl.

11. The compound of claim 1, wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

12. The compound of claim 11, wherein Ri is optionally substituted C1-C1₀ alkyl or optionally substituted C3-C12 cycloalkyl.

13. The compound of claim 12, wherein Ri is optionally substituted C₁-C₄ alkyl.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

15. A compound having the Formula (II):

(II)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R_3a and R₃b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or yet alternatively, R_3a and R₃b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-12 membered ring selected from the group consisting of C3-C12 cycloalkyl, C3-C12 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; Re is selected from the group consisting of CN, C(0)OR₈, C(0)R₉ and C(O)NHR₁₀; R7 is optionally substituted 4-pyridyl;

Rs is selected from the group consisting of substituted Ci alkyl, optionally substituted C2-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R9 is selected from the group consisting of substituted C1-C3 alkyl, optionally substituted C4-C1₀ alkyl, optionally substituted C4-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

Rio is selected from the group consisting of optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, and optionally substituted heteroaryl; and

n is 0, 1 or 2.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 15.

17. The compound of claim 15, wherein R₈ selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

18. The compound of claim 15, wherein R₉ is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

19. The compound of any one of claims 15, 17 and 18, wherein R_3a is hydrogen or C1-C4 alkyl.

20. The compound of claim 19, wherein R₃b is selected from the group consisting of optionally substituted Ci-Cio alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo.

21. The compound of claim 20, wherein R_3a and I¾b are each independently selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

22. The compound of claim 20, wherein is optionally substituted aryl or optionally substituted heteroaryl.

23. The compound of claim 21, wherein R₃b is optionally substituted aryl.

24. The compound of claim 22, wherein R₃b is optionally substituted phenyl.

25. The compound of claim any one of claims 15 and 17 to 24, wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl. 26. The compound of claim 25, wherein Ri is optionally substituted C1-C1₀ alkyl or optionally substituted C3-C12 cycloalkyl.

27. The compound of claim 25, wherein Ri is optionally substituted C1-C4 alkyl.

The compound of claim 15 selected from the compounds shown in the Table below:

Ri Rii Riii

2-chlorophenyl 4-

Ethyl

pyridyl

4-

Benzyl Phenyl

pyridyl

4-

Ethyl [l,l '-biphenyl]-4-yl

pyridyl

4-fluorophenyl 4-

Ethyl

pyridyl

4-methoxyphenyl 4-

Ethyl

pyridyl

2 -fluorophenyl 4-

Ethyl

pyridyl

4-hydroxyphenyl 4-

Ethyl

pyridyl

3 -methoxyphenyl 4-

Ethyl

pyridyl

2 -methoxyphenyl 4-

Ethyl

pyridyl

4-bromophenyl 4-

Ethyl

pyridyl

3-bromophenyl 4-

Ethyl

pyridyl

4-

Benzyl [l,l '-biphenyl]-4-yl

pyridyl

2,4-dichlorophenyl 4-

Ethyl

(2,4-diCl phenyl) pyridyl

2-chlorophenyl 4-F

Ethyl

phenyl

4-

Ethyl Ph

pyridyl

3 -fluorophenyl 4-

Ethyl

pyridyl

3-hydroxyphenyl 4-

Ethyl

pyridyl

4-cyanophenyl 4-

Ethyl

pyridyl

4-

4-

Ethyl dimethylaminophenyl

pyridyl

4-

Ethyl 3-thiophene

pyridyl

4-

Ethyl [l,l '-biphenyl]-3-yl

pyridyl

29. The pharmaceutical composition of claim 16, comprising a compound selected from the compounds shown in the Table below:

4-

Ethyl 3-thiophene

pyridyl

4-

Ethyl [ l , l '-biphenyl]-3-yl

pyridyl

30. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 1.

31. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 15.

32. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound having the Formula (III):

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R_3a and R₃b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or yet alternatively,R_3a and I¾b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-12 membered ring selected from the group consisting of C3-C12 cycloalkyl, C3-C12 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R11 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_n R5R5 and OC(0)OR5; or alternatively, Rn and Ri are taken together to form an optionally substituted, fused 3-10 membered ring selected from the group consisting of C3- C10 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

R12 is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; and

n is 0, 1 or 2.

33. The method of claim 32, wherein R12 is optionally substituted aryl or optionally substituted heteroaryl.

34. The method of claim 33, wherein R₁₂ is an optionally substituted 5- or 6-membered heteroaryl.

35. The method of claim 34, wherein R12 is an optionally substituted 6-membered heteroaryl.

36. The method of claim 35, wherein R 2 is an optionally substituted 6-membered heteroaryl containing at least one nitrogen ring atoms.

37. The method of claim 36, wherein Ri₂ is selected from the group consisting of pyridyl, pyridazyl and pyrimidyl, each optionally substituted.

38. The method of claim 37, wherein Ri₂ is optionally substituted pyridyl.

39. The method of claim 38, wherein Ri₂ is optionally substituted 4-pyridyl.

40. The method of any one of claims 30 to 37 wherein R_3a is hydrogen or C1-C4 alkyl.

41. The method of claim 40, wherein R₃b is selected from the group consisting of are each independently selected from the group consisting of optionally substituted C1-C1₀ alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and halo.

42. The method of claim 41, wherein R₃b is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

43. The method of claim 41 , wherein R₃b is aryl or heteroaryl.

44. The method of claim 42, wherein R₃b is aryl.

45. The method of claim 43, wherein R₃b is optionally substituted phenyl.

46. The method of any one of claims 30 to 43, wherein Ri is optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

47. The method of claim 46, wherein Ri is optionally substituted Ci-Cio alkyl or optionally substituted C3-C12 cycloalkyl.

48. The method of claim 32, wherein Rn is selected from the group consisting of CN, C(0)OR₅, C(0)R₅, and C(0)NR₅R₅.

49. The method of claim 32, wherein the condition associated with a dysfunction of proteostasis is a gain of function condition. 50. The method of claim 32, wherein the condition associated with a dysfunction of protein homeostasis is a loss of function condition.

51. The method of claim 32, wherein the condition is associated with a dysfunction in the proteostasis of a protein selected from the group consisting of hexosamine A, cystic fibrosis transmembrane conductance regulator, aspartylglucsaminidase, a-galactosidase A, cysteine transporter, acid ceremidase, acid a-L-fucosidase, protective protein, cathepsin A, acid β- glucosidase, acid β-galactosidase, iduronate 2-sulfatase, a-L-iduronidase,

galactocerebrosidase, acid a -mannosidase, acid β -mannosidase, arylsulfatase B, arylsulfatase A, N-acetylgalactosamine-6-sulfate sulfatase, acid β -galactosidase, N- acetylglucosamine-1 -phosphotransferase, acid sphingmyelinase, NPC-1, acid a-glucosidase, β-hexosamine B, heparin N-sulfatase, a -N-acetylglucosaminidase, a -glucosaminide N- acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, al anti-trypsin, a -N- acetylgalactosaminidase, a -neuramidase, β -glucuronidase, β-hexosamine A and acid lipase, polyglutamine, a -synuclein, Ab peptide, tau protein, hERG potassium channel, islet amyloid polypeptide, transthyretin, Huntingtin, and superoxide dismutase.

52. The method of claim 51 , wherein the protein is selected from the group consisting of Huntingtin, tau, alpha-synuclein, al anti-trypsin and superoxide dismutase. 53. The method of claim 32, 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 of diabetes.

54. The method of claim 32, further comprising administering a second agent selected from the group consisting of a proteostasis regulator and a pharmacologic chaperone.

55. The method of claim 32 wherein the compound is selected from the compounds shown in the Table below:

4-

4-

Ethyl dimethylaminophenyl

pyridyl

4-

Ethyl 3-thiophene

pyridyl

4-

Ethyl [ l , l '-biphenyl]-3-yl

pyridyl

56. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier or excipient;

an agent selected from the group consisting of a proteostasis regulator and a pharmacologic chaperone; and

a compound having the Formula (III):

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C₂-C₁₀ alkenyl, optionally substituted C₂-C₁₀ alkynyl, optionally substituted C3-C₁₂ cycloalkyl, optionally substituted C3-C₁₂ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R_3a and R₃b are each independently selected from the group consisting of hydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substituted C₂-C₁₀ alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3 -CI 2 cycloalkyl, optionally substituted C3-C₁₂ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)„R₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅ and (C=NR₅)R₅; or yet alternatively, R_3a and R₃b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-10 membered ring selected from the group consisting of C3-C1₀ cycloalkyl, C3-C1₀ cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C1₀ cycloalkyl, optionally substituted C3-C1₀ cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R11 is selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, , S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅ and (C=NR₅)R₅; or alternatively, R_u and Ri are taken together to form an optionally substituted, fused 3-10 membered ring selected from the group consisting of C3-C1₀ cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

R12 is optionally substituted aryl or optionally substituted heteroaryl; and

n is 0, 1 or 2.

57. A method of treating cancer or a tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (III):

(III)

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:

Ri is hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C1₀ alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R3_a and R3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C1₀ alkyl, optionally substituted C2-C1₀ alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3- C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)_nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅, OC(0)OR₅, and (C=NR₅)R₅; or yet alternatively,R_3a and R3b are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3-12 membered ring selected from the group consisting of C3-C12 cycloalkyl, C3-C12 cycloalkenyl, heterocyclic, aryl and heteroaryl, each optionally substituted;

Each R₅ is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

R11 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR₅, SR₅, NR5R5, C(0)OR₅, N0₂, CN, C(0)R₅, C(0)C(0)R₅, C(0)NR₅R₅, NR₅C(0)R₅, NR₅S(0)nR₅, NR₅C(0)OR₅, NR₅C(0)C(0)R₅, NR₅C(0)NR₅R₅, NR₅S(0)nNR₅R5, S(0)_nR₅, S(0)_nNR₅R₅ and OC(0)OR₅;

R12 is optionally substituted aryl or optionally substituted heteroaryl; and

n is 0, 1 or 2.