Proteasome activators and uses thereof

Abstract

Described herein are compounds, methods for making such compounds, and the use of such compounds in the treatment of, among other conditions, cancer, an inflammatory disease or condition or neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and ALS.

Description

PROTEASOME ACTIVATORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U. S. Appl. No.63 / 753,794, filed February 4, 2025, which is incorporated by reference as if fully set forth herein.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant number R61 NS111347 and R21 AG076994 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] The regulation of protein synthesis, degradation, folding, trafficking and aggregation within a cell are collectively known as proteostasis. Proteostasis is maintained by a wide array of cellular machinery that work to ensure that proteins are present in the proper location, amounts and form to perform their respective functions. When one of the pathways involved with proteostasis becomes dysregulated there can be disastrous effects on the cell and even on neighboring cells. One increasingly prevalent example of this is seen in neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In these neurodegenerative diseases, accumulation of specific aggregation-prone proteins (hereafter referred to as intrinsically disordered proteins (I DPs)) leads to toxic signaling and disruption of proteostasis caused by their uncontrolled aggregation and oligomerization (hereafter, aggregation and oligomerization are used interchangeably). For example, the IDP a-synuclein (a-syn) and its oligomers are associated with the pathogenesis of PD. I DPs are named fortheir lack of tertiary structure allowing them to adopt numerous conformations and interact with multiple binding partners. IDPs are generally short-lived signaling proteins or transcription factors that are highly bound to other cellular components keeping free cytosolic levels low. Additionally, unbound IDPs are readily degraded by the 20S proteasome, the default protease responsible for IDP digestion. The accumulation of IDPs seen in neurodegenerative diseases can begin as a result of one of several disruptions (e.g. mutations, changes in expression, oxidative stress, aging, proteasome impairment, etc.) to their normal regulation. While a-syn may not be the sole cause of PD, there is strong evidence supporting its key role in the disease, including familial forms of PD resulting from mutations in the SNCA gene. Elevated monomeric a-syn levels are also known to cause apoptosis-inducing aggregation in neurons. Additionally, oligomeric forms of a-syn and other IDPs have recently beenTEC2025-0036 3000.222W01shown to directly inhibit the proteasome, further disrupting its ability to regulate I DPs concentrations. These data collectively suggest that the accumulation of a-syn and formation of oligomeric species of the IDP play a critical role in the progression of PD. Due to a lack of defined binding pockets, I DPs such as a-syn, and their aggregation are difficult to target through traditional small molecule drug design. There are currently no effective treatments to hinder the progression of neurodegenerative diseases that are associated with IDP accumulation.BRIEF DESCRIPTION OF THE FIGURES

[0004] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein.

[0005] FIG. 1 is a scheme of the synthesis of compounds of the disclosure.

[0006] FIG. 2A is a plot of 20S proteasome activity as a function of the concentration log [M] of compound 1.

[0007] FIG. 2B is the structure of compound 1.

[0008] FIG. 2C is a Western blot of a-synuclein degradation by compound 1, where “TCH-165” is a compound of the formula:

[0009] FIG. 2D is a quantitation of western blots from FIG. 1 C.

[0010] FIG. 3A is quantitation of western blots (n=3) for E7 and E6 proteins from HeLa cells treated with vehicle (DMSO), bortezomib (negative control), and 5 and 10 pM compound 1.

[0011] FIG. 3B is a plot of the inhibition of HeLa cell growth by compound 1 after 72 hours using cell titer gio reagent.

[0012] FIGS. 4-5 are tables of chemical structures and activity data for compounds of the disclosure. The structure-activity relationship (SAR) biological evaluation and physicochemical properties were generated by SwissADME (logKIAM was generated by HPLC column).

[0013] FIGS. 6A-6C are plots of purified enzyme degradation of recombinant a-synuclein protein for 3 hours and 45 minutes (1:30 ratio of enzyme to protein) (A) Set 1, (B) Set 2, (C) Set 3. Control: SS-4-1540 And a vehicle. The percentage was compared to the negative control. Statistical analysis: one-way ANOVA post-hocTEC2025-0036 3000.222W01multiple comparison Dunnett’s test (****p<0.0001, **p<0.001, **p<0.01, *p<0.05, ns=not significant).

[0014] FIGS. 7A-7B are plots showing HEK293T degradation of transiently transfected A53T a-syn. (A, B) 10 uM screen of selected analogs. Control: TCH-165 and vehicle.45 Percentage was compared to negative control. Statistical analysis: one-way ANOVA post-hoc multiple comparison Dunnett’s test (***p<0.0001, **p<0.001, **p<0.01,*p<0.05, ns=not significant).

[0015] FIGS. 8A-8D are plots showing HEK293T degradation of transiently transfected A53T a-syn - dose response — control: TCH-165 and vehicle.45 The percentage was compared to the negative control. Statistical analysis: non-linear regression curve fit, log (inhibitor) vs response (four parameters).

[0016] FIGS. 9A-9B are plots showing HEK293T degradation of transiently transfected A53T a-syn (A) with or without 300 nM bortezomib (B) with and without 500 nM bafilomycin. The percentage was compared to the negative control. Statistical analysis: one-way ANOVA post-hoc multiple comparison Dunnett’s test (***p<0.0001, **p<0.001, **p<0.01, *p<0.05, ns=not significant).

[0017] FIGS.10A-10B are plots of a recombinant a-syn monomer aggregation study, seeded with a 1:10 ratio of recombinant pre-formed aggregated to monomer for 24 hours. Aggregation was quantified with aggregation ELISA. Control: vehicle and Anel138b.67 The percentage was compared to the negative control. Statistical analysis: one-way ANOVA post-hoc multiple comparison Dunnett’s test (***p<0.0001, **p<0.001, **p<0.01, *p<0.05, ns=not significant).

[0018] FIG. 11 is plots of a synergetic cellular degradation study. HEK293T cells were transiently transfected with 13 pg of pH M6 A53T a-syn plasmid, followed by co-dosing of 13 in dose response and 20S proteasome enhacer. The percentage was compared to the negative control.

[0019] FIGS. 12A-12C are plots showing (A) Fold Increase of proteolytic degradation of a combination of fluorogenic small peptide substrates representing the Chymotrypsin-like, Caspase-like, and Trypsin-like activities of 20S proteasome treated with different concentrations of Compound 1 ranging from 0.62 to 40.00 pM, n = 3; (B) B1: Representative E6 (left) and E7 (right) immunoblot of HeLa cells treated lane 1 vehicle, lane 2 bortezomib (0.3 pM), lane 3 positive control TCH-165 (5 pM), lane 4 positive control TCH-165 (10 pM), lane 5 Compound 1 (5 pM), lane 6 Compound 1 (10 pM),. B2: Quantitation and statistical analysis (One-way ANOVA) of Western blots (n=3) Western blots of E6 and E7; (C) HeLa cells treated with Compound 1 (10 pM) in the presence and absence of E1 -ligase inhibitor (50 uM PYR-41). One-way ANOVA statistical analysis was used to determine statistical significance (ns = not significant,TEC2025-0036 3000.222W01*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). Error bars based on standard deviation.

[0020] FIG. 13 is a plot showing quantification of HPV16-E7 in Ca Ski cells after 24 hours of compound treatments. Control: HPV16-E7 siRNA and vehicle. Percentage was compared to negative control. Statistical analysis: one-way ANOVA post-hoc multiple comparison Dunnett’s test (***p<0.0001, **p<0.001, **p<0.01, *p<0.05, ns=not significant).

[0021] FIG. 14 is plots showing cell viability and toxicity results using cell titer gio (viability) and cell tox green (toxicity) of TCH-165, MM, and Sorafenib dosing HeLa and CaSki cells for 72 hours.SUMMARY

[0022] The disclosure relates to small molecules that enhance proteasome function and restore the activity of impaired proteasomes. Small molecule proteasome enhancers prevent, among other things, the toxic accumulation of aggregation-prone proteins and prevent neuronal cell death caused by aggregation-prone proteins. In one aspect, the disclosure relates to the use of small molecules as therapeutic agents to treat neurodegenerative diseases. Neurodegenerative diseases include, but are not limited to Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Motor neuron diseases (MND), Huntington’s disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA). The disclosure also relates to the use of small molecules as therapeutic agents to reduce, substantially eliminate or eliminate the expression of E5, E6, and / or E7 viral oncoproteins in host cells following infection of host cells by the human papillomavirus (HPV).DESCRIPTION

[0023] The disclosure relates to compounds of the formula (IB):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamide or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, formTEC2025-0036 3000.222W01a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R6is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.

[0024] Compounds of the formula (IB) include compounds of the formula (I) or (IA):R1R3R4R2(IA),or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and Rs, together with the atoms to which they are attached, form a heterocyclyl group;TEC2025-0036 3000.222W01X1is N or OR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or OR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;provided that:X2is not N when R1is NH2and R1is not Cl when X1and X2are both simultaneously N;R2is not H when R5is Cl,R2is not H when R6is methyl;R2is not H when R1is Cl or F;R4is not CH3when R6is optionally substituted phenyl;Rsis not phenoxy or CF3when R1methoxy;Rsis not CF3when R1is aminomethyl or pyrrolidinyl;R6is not optionally substituted phenyl or phenoxy when Y1is S;R6is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl.

[0025] The disclosure also relates to compounds of the formula compound of the formula (IC) and (ID):R18R3R4R2(ID)or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;TEC2025-0036 3000.222W01R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy;R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;provided that:X2is not N when R18is NH2and R18is not Cl when X1and X2are both simultaneously N;R2is not H when R21is Cl,R2is not H when R22is methyl;R2is not H when R18is Cl or F;R4is not CH3when R22is optionally substituted phenyl;R22is not phenoxy or CF3when R18methoxy;R22is not CF3when R18is aminomethyl or pyrrolidinyl;R22is not optionally substituted phenyl or phenoxy when Y1is S;R22is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl.

[0026] In the compounds of the formulae (I), (I A), and (IB), R1can be halo or alkyl. Examples of halo include F, Br, and Cl. Examples of alkyl include C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl. R1can be halo, such as Cl. Alternatively, R1can be alkyl, such as substituted alkyl. For example, the alkyl group of R1can be substituted alkyl, such as halo substituted alkyl. In one example, halo substituted alkyl is fluoro substituted alkyl including CF3, CF2H, CFH2, CH2CF3, CHFCF3, CHFCHCF2, and the like. Fluoro substituted alkyl is perfluoro substituted alkyl, such as CF3, CF2CF3, CF2CF2CF3, and the like.

[0027] Alternatively or in addition to the options for R1, R2can be H or C(O)R7, wherein R7is alkyl or alkoxy, or R1and R2together with the atoms to which they are attached, form a ring. In one example, R2can be C(O)R7, wherein R7is alkyl or alkoxy. In one example, R7can be alkyl such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, such as methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. In another example, R7can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy,TEC2025-0036 3000.222W01C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0028] Alternatively or in addition to the options for R1and R2, R3and R4can each be H. or in addition to the options for R1and R2, R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring. For example, R3and R4, together with the nitrogen atoms to which they are attached can form a five- and the six membered heterocyclyl ring is of the formula:and Y, respectively, each of which is optionally substituted.

[0029] Alternatively or in addition to the options for R1, R2, R3, and R4, R5can be H. Alternatively or in addition to the options for R1, R2, R3, and R4, R5can be halo, such as Cl or F. Alternatively or in addition to the options for R1, R2, R3, and R4, R5can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0030] Alternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be H. Alternatively or in addition to the options for R1, R2, R3, R4, R5, R6can be alkyl, such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, including methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. Alternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be aryloxy, such as C6-C10aryloxy group, including phenoxy, napthyloxy, 1,4-biphenyloxy, and the like. Iternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy. The alkoxy can be substituted alkoxy, such as halo substituted alkoxy. Examples of halo substituted alkoxy include fluoro substituted alkoxy such as OCF3, OCF2H, OCFH2, OCH2CF3, OCHFCF3, OCHFCHCF2, and the like. Fluoro substituted alkoxy can also include perfluoro substituted alkyl, such as OCF3, OCF2CF3, OCF2CF2CF3, and the like. Alternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be heteroaryloxy such as C2-C5heteroaryloxy. Examples of C2-C5heteroaryloxy is pyridyl, pyrollyl, furanyl, imidazolyl, oxazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzoxazolyl and the like. The heteroaryloxy (e.g., C2-C5 heteroaryloxy) can be optionally substituted with any substituent, including with one or more halo and acyl. In one example, the heteroaryloxy (e.g., C2-C5heteroaryloxy) can be mono-, di-or trisubstituted. The acyl group can be, for example, C(O)OR12, wherein R12is C1-C8TEC2025-0036 3000.222W01alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl. One example of heteroaryloxy group is a heteroaryloxy group of the formulawhich is optionally substituted, such as:

[0031] Alternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be halo, such as Cl or F. In one example, R6is Cl. Alternatively or in addition to the options for R1, R2, R3, R4, and R5, R6can be cyano.

[0032] In one example, R5and R6, together with the atoms to which they are attached, form a heterocyclyl group, such as a C3-C5heterocyclyl group. One example of a C3-C5 heterocyclyl group is a C3heterocyclyl group, such as a C3heterocyclyl group of the formula:

[0033] Alternatively or in addition to the options for R1, R2, R3, R4, R5, and R6, Y1can be O. Or Y1can be S.

[0034] Alternatively or in addition to the options for R1, R2, R3, R4, R5, R6, and Y1, X1can be N and X2can be CR9. In one example, R9can be H. Alternatively or in addition to the options for R1, R2, R3, R4, R5, R6, and Y1, X1can be CR8and X2can be N. In one example, R8can be H. Alternatively or in addition to the options for R1, R2, R3, R4, R5, R6, and Y1, X1can be N and X2can be N.

[0035] Alternatively or in addition to the options for R1, R2, R3, R4, R5, R6, Y1, and X2, X3can be S.

[0036] Compounds of the formulae (I), (IA), and (IB) include compounds wherein X3is O; and R1-R5, X1and X2are selected as shown below in Table 1 and FIGS. 4 and 5:Table 1TEC2025-0036 3000.222W01R1R2R5R6X1X2R3R4Cl COOEt Cl H N C H H Cl H Cl H N C H H H H Cl H N C H H Cl H H H N C H H Cl H F H N C H H Cl H OCH3H N C H H Cl H Cl H C C H H Cl H Cl H N C H H Cl H Cl H N C Me H Cl H Cl H N C H Me Cl H Cl H N C Me Me Cl H Cl H C N H H CF3H Cl H C N H H ClCl H H N C H HCl COOEt H / -OX^N N C H HCl H H OPh N C H H Cl H H OCF3N C H H Cl H H OMe N C H H Cl H H AN CH H Cl H H t-Bu N C H H Cl COOEt H t-Bu N C H H Cl H H CN N C H H Cl H H Cl N C H H Cl H Cl t-Bu N C H HTEC2025-0036 3000.222W01

[0037] The disclosure also relates to compounds of the formula compound of the formula (IC) and (ID):R18R3R4R2(ID)or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR,6R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy;R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;provided that:X2is not N when R18is NH2and R18is not Cl when X1and X2are both simultaneously N;R2is not H when R21is Cl,R2is not H when R22is methyl;R2is not H when R18is Cl or F;R4is not CH3when R22is optionally substituted phenyl;R22is not phenoxy or CF3when R18methoxy;TEC2025-0036 3000.222W01R22is not CF3when R18is aminomethyl or pyrrolidinyl;R22is not optionally substituted phenyl or phenoxy when Y1is S;R22is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl.

[0038] In the compounds of the formulae (IC) and (ID), R18can be halo or alkyl. Examples of halo include F, Br, and Cl. Examples of alkyl include C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl. R18can be halo, such as Cl. Alternatively, R18can be alkyl, such as substituted alkyl. For example, the alkyl group of R18can be substituted alkyl, such as halo substituted alkyl. In one example, halo substituted alkyl is fluoro substituted alkyl including CF3, CF2H, CFH2, CH2CF3, CHFCF3, CHFCHCF2, and the like. Fluoro substituted alkyl is perfluoro substituted alkyl, such as CF3, CF2CF3, CF2CF2CF3, and the like.

[0039] Alternatively or in addition to the options for R18, R2can be H or C(O)R7, wherein R7is hydroxy, alkyl or alkoxy, or R18and R2together with the atoms to which they are attached, form a ring. In one example, R2can be C(O)R7, wherein R7is hydroxy, alkyl or alkoxy. In one example, R7can be alkyl such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, such as methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. In another example, R7can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0040] Alternatively or in addition to the options for R18and R2, R3and R4can each be H. or in addition to the options for R18and R2, R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring. For example, R3and R4, together with the nitrogen atoms to which they are attached can form a five- and the six membered heterocyclyl ring is of the formula:vY YY and Y, respectively, each of which is optionally substituted.

[0041] Alternatively or in addition to the options for R18, R2, R3, and R4, R21can be H. Alternatively or in addition to the options for R18, R2, R3, and R4, R21can be halo, such as Cl or F. Alternatively or in addition to the options for R18, R2, R3, and R4, R21can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.TEC2025-0036 3000.222W01

[0042] Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be H. Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be alkyl, such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, including methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be aryloxy, such as C3-Cio aryloxy group, including phenoxy, napthyloxy, 1,4-biphenyloxy, and the like. Iternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy. The alkoxy can be substituted alkoxy, such as halo substituted alkoxy. Examples of halo substituted alkoxy include fluoro substituted alkoxy such as OCF3, OCF2H, OCFH2, OCH2CF3, OCHFCF3, OCHFCHCF2, and the like. Fluoro substituted alkoxy can also include perfluoro substituted alkyl, such as OCF3, OCF2CF3, OCF2CF2CF3, and the like. Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be heteroaryloxy such as C2-C5heteroaryloxy. Examples of C2-C5heteroaryloxy is pyridyl, pyrollyl, furanyl, imidazolyl, oxazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzoxazolyl and the like. The heteroaryloxy (e.g., C2-C5heteroaryloxy) can be optionally substituted with any substituent, including with one or more halo and acyl. In one example, the heteroaryloxy (e.g., C2-C5heteroaryloxy) can be mono-, di-or trisubstituted. The acyl group can be, for example, C(O)OR12, wherein R12is C1-C8alkyl, C2-C5alkyl, C1-C5 alkyl or C3-C8alkyl. One example of heteroaryloxy group is a heteroaryloxy group of the formulawhich is optionally substituted, such as:

[0043] Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be halo, such as Cl or F. In one example, R22is Cl. Alternatively or in addition to the options for R18, R2, R3, R4, and R21, R22can be cyano.

[0044] In one example, R21and R22, together with the atoms to which they are attached, form a heterocyclyl group, such as a C3-C5heterocyclyl group. One exampleTEC2025-0036 3000.222W01of a C3-C5 heterocyclyl group is a C3heterocyclyl group, such as a C3heterocyclyl group of the formula:

[0045] Alternatively or in addition to the options for R18, R2, R3, R4, R21, and R22, Y1can be O. Or Y1can be S.

[0046] Alternatively or in addition to the options for R18, R2, R3, R4, R21, R22, and Y1, X1can be N and X2can be CR9. In one example, R9can be H. Alternatively or in addition to the options for R18, R2, R3, R4, R21, R22, and Y1, X1can be CR8and X2can be N. In one example, R8can be H. Alternatively or in addition to the options for R18, R2, R3, R4, R21, R22, and Y1, X1can be N and X2can be N.

[0047] Alternatively or in addition to the options for R18, R2, R3, R4, R21, R22, Y1, and X2, X3can be S.

[0048] Compounds of the formulae (IC) and (ID) include compounds wherein X3is O; and R18, R2-R4, R21, R22,, X1and X2are selected as shown in FIGS. 4 and 5.

[0049] The disclosure also relates to a compound of the formula (II) or (IIA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;TEC2025-0036 3000.222W01R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.

[0050] In the compounds of the formulae (II) and (HA), R1can be alkoxy, such as Ci-Cs alkoxy, C2-C5 alkoxy, C1-C5 alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0051] Alternatively or in addition to the options for R1, R2can be H.

[0052] Alternatively or in addition to the options for R1and R2, R3and R4can each be H.

[0053] Alternatively or in addition to the options for R1, R2, R3, and R4, X1can be CR8and X2can be N.

[0054] Alternatively or in addition to the options for R1, R2, R3, X1, and X2, X3can be NR9, wherein R9can be H, halo, alkyl, alkoxy, aryloxy or amino.

[0055] Alternatively or in addition to the options for R1, R2, R3, X1, X2, and X3, R5can be H.

[0056] Alternatively or in addition to the options for R1, R2, R3, X1, X2, X3, and R5, R6can be alkyl, such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, such as methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like.

[0057] One example of a compound of the formulae (II) and / or (HA) is a compound of the formula:

[0058] The disclosure also relates to a compound of the formula (III) or (II I A):TEC2025-0036 3000.222W01R1R3R4R1aR2R2a(| 11 A)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1and R1aare each independently halo, alkyl, alkoxy, aryloxy or amino;R2and R2aare each independently H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2or R1aand R2atogether with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X1ais N or CR8a, wherein R8ais H, halo, alkyl, alkoxy, aryloxy or amino;X2ais N or CR9a, wherein R9ais H, halo, alkyl, alkoxy, aryloxy or amino, or R8aand R9a, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;X3ais O or NR9a, wherein R9ais H or alkyl; andY1is 0, S or NR10, wherein R10is H or alkyl.

[0059] In the compounds of the formulae (III) and (111 A), R1and R1acan each independently be halo, such as chloro and fluoro. In one example, R1is chloro. In another example, R1ais chloro. In yet another example, R1and R1aare each chloro.

[0060] Alternatively or in addition to the options for R1and R1a, X1can be N. Or X1acan be N. Or X1and X1acan each be N. Alternatively or in addition to the options for R1, R1a, and X1, X2can be CR9. Or X2acan be CR9. Or In one example, each R9can be H. X2and X2acan each be CR9. In one example, each R9can be H.

[0061] Alternatively or in addition to the options for R1, R1a, X1, and X1a, X3can be O. Or X3acan be O. Or X3and X3acan each be O.

[0062] Alternatively or in addition to the options for R1, R1a, X1, X1a, and X3, R3and R4can each be H.

[0063] One example of a compound of the formulae (III) and / or (IIIA) is a compound of the formula:TEC2025-0036 3000.222W01

[0064] The disclosure also relates to a compound of the formula (IV) or (IVA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2cis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2ctogether with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.

[0065] In the compounds of the formulae (IV) and (IVA), R1can be halo, such as Cl.

[0066] Alternatively or in addition to the option for R1, R2ccan be halo, such as Cl.

[0067] Alternatively or in addition to the option for R1and R2c, R5is halo, such as Cl.TEC2025-0036 3000.222W01

[0068] Alternatively or in addition to the option for R1, R2c, and R5, R6can be H.

[0069] Alternatively or in addition to the option for R1, R2c, R5, and R6, X1can be N. Or X2can be OR9. Or X1is N and X2is CR9. In one example, R9can be H.

[0070] Alternatively or in addition to the option for R1, R2c, R5, R6, X1, and X2, X3can be O.

[0071] Alternatively or in addition to the option for R1, R2c, R5, R6, X1, X2, and X3, R3and R4can each be H.

[0072] One example of a compound of the formulae (IV) and / or (IVA) is a compound of the formula:ci

[0073] The disclosure also relates to a compound of the formula (V) or (VA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl;R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;TEC2025-0036 3000.222W01X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.

[0074] In the compounds of the formulae (V) and (VA), R1can be alkyl, such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, including methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like.

[0075] Alternatively or in addition to the options for R1, R2can be H or C(O)R7, wherein R7is alkyl or alkoxy, or R1and R2together with the atoms to which they are attached, form a ring. In one example, R2can be C(O)R7, wherein R7is alkyl such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, including methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. Or R7can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0076] Alternatively or in addition to the options for R1and R2, R3can be H.

[0077] Alternatively or in addition to the options for R1, R2, and R3, R5can be halo, such as Cl.

[0078] Alternatively or in addition to the options for R1, R2, R3, and R5, R6can be H.

[0079] Alternatively or in addition to the options for R1, R2, R3, R5, and R6, X1can be OR8. Or X2can be CR9. Or X1can be OR8and X2can be OR9.

[0080] Alternatively or in addition to the options for R1, R2, R3, R5, R6, X1, and X2, X3can be NR9. In one example, R9can be H.

[0081] One example of a compound of the formulae (V) and / or (VA) is a compound of the formula:C02Me

[0082] The disclosure also relates to a compound of the formula (VI) or (VIA):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5aand R6aare each independently H, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.

[0083] In the compounds of the formulae (VI) and (VIA), R1can be alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0084] Alternatively or in addition to the options for R1, R2can be H.

[0085] Alternatively or in addition to the options for R1and R2, R3and R4can each be H.

[0086] Alternatively or in addition to the options for R1, R2, R3, and R4, X1can be N. Or X2can be CR9. Or X1can be N and X2can be CR9

[0087] Alternatively or in addition to the options for R1, R2, R3, R4, X1, and X2, X4can be S.

[0088] Alternatively or in addition to the options for R1, R2, R3, R4, X1, X2, and X4, R5acan be H.

[0089] Alternatively or in addition to the options for R1, R2, R3, R4, X1, X2, X4, and R5a, R6acan be alkyl, such as C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl,TEC2025-0036 3000.222W01including methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. In one example, R6ais aryl substituted alkyl, such as optionally substituted aryl alkyl.

[0090] One example of a compound of the formulae (VI) and / or (VIA) is a

[0091] The disclosure also relates to a compound of the formula (VII) or (VIIA):R5aR2(VIIA)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.TEC2025-0036 3000.222W01

[0092] In the compounds of the formulae (VII) and (VIIA), R1can be halo, such as F.

[0093] Alternatively or in addition to the options for R1, R2can be H.

[0094] Alternatively or in addition to the options for R1and R2, R4can be H.

[0095] Alternatively or in addition to the options for R1, R2, and R4, X1can be CR8. Or X2can be CR9. Or X1can be OR8and X2can be OR9.

[0096] Alternatively or in addition to the options for R1, R2, R4, X1, and X2, R5acan be H.

[0097] Alternatively or in addition to the options for R1, R2, R4, X1, X2, and R5a, R6acan be optionally substituted aryl, such as R6ahalo substituted aryl, wherein halo can be F.

[0098] One example of a compound of the formulae (VII) and / or (VIIA) is a compound of the formula:

[0099] The disclosure also relates to a compound of the formula (VIII) or (VI HA):(VIII) oror a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2bis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, formTEC2025-0036 3000.222W01a heterocyclyl group) or R1and R2btogether with the atoms to which they are attached, form a ring;R4is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;R13is C(O)R14, wherein R14is H, alkyl, amino or alkoxy;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.

[0100] In the compounds of the formulae (VIII) and (VIII A), R1can be halo, such as Cl.

[0101] Alternatively or in addition to the options for R1, R2can be H.

[0102] Alternatively or in addition to the options for R1and R2, R4can be H.

[0103] Alternatively or in addition to the options for R1, R2, and R4, X1can be N. Or X2can be CR9. Or X1can be N and X2can be CR9. In one example, R9is H.

[0104] Alternatively or in addition to the options for R1, R2, R4, X1, and X2, R5acan be H.

[0105] Alternatively or in addition to the options for R1, R2, R4, X1, X2, and R5a, R6acan be optionally substituted aryl, such as alkyl substituted aryl.

[0106] Alternatively or in addition to the options for R1, R2, R4, X1, X2, R5a, and R6a, R2bcan be halo.

[0107] Alternatively or in addition to the options for R1, R2, R4, X1, X2, R5a, and R6a, and R2b, R14is alkoxy, such as C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy, including methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, octyloxy, and the like.

[0108] One example of a compound of the formulae (VIII) and / or (VIIIA) is a compound of the formula:ClTEC2025-0036 3000.222W01

[0109] The disclosure also relates to a compound of the formula (IX) or (IXA):R3or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5ais H, alkyl or aryl;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX5is O, acyl or NR9, wherein R9is H or alkyl.

[0110] In the compounds of the formulae (IX) and (IXA), R1can be amino, such as Ci-C8alkyl amino, C2-C5alkyl amino, Ci-C5alkyl amino or C3-C8alkyl amino.

[0111] Alternatively or in addition to the options for R1, R2can be H. Alternatively, R1and R2, together with the atoms to which they are attached, form a ring, such as a five-, six- or seven-membered ring, such as:TEC2025-0036 3000.222W01

[0112] Alternatively or in addition to the options for R1and R2, R3can be H.

[0113] Alternatively or in addition to the options for R1, R2, and R3, R5bcan be aryl, such as halo substituted aryl, such as halo disubstituted aryl including dichloro substituted aryl.

[0114] Alternatively or in addition to the options for R1, R2, R3, and R5b, X5can be C(O).

[0115] Alternatively or in addition to the options for R1, R2, R3, R5b, and X5, X1can be CR8. Or X2can be OR9. Or X1can be OR8and X2can be OR9TEC2025-0036 3000.222W01

[0116] One example of a compound of the formulae (IX) and / or (IXA) is a compound of the formula:

[0117] The disclosure also relates to a compound of the formula (X) or (XA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;Y1is O, S or NR10, wherein R10is H or alkyl; andTEC2025-0036 3000.222W01Y2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.

[0118] The disclosure also relates to a compound of the formula (XI):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X6is CHR15, wherein R15is H, acyl, alkyl, halo or aryl or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl; andY2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.

[0119] In the compounds of the formula (XI), R15can be acyl or acyl substituted alkyl, such as such as acyl substituted C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl, including acyl methyl, ethyl, propyl, ispropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, and the like. For example, acyl can be C(O)OR12, wherein R12is C1-C8alkyl, C2-C5alkyl, C1-C5 alkyl or C3-C8alkyl, including Ci-C8alkyl-C(O)OR12, C2-C5alkyl-C(O)OR12, Ci-C5alkyl-C(O)OR12or C3-C8alkyl-C(O)OR12. In one example, R15can be -(CH2)n-C(O)OR12, wherein n is an integer from 1 to 12 or 1 to 8.

[0120] The disclosure also relates to a compound of the formula (XII):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X, G1, and G2are each independently N, NR10, wherein R10is H or alkyl, C(O) or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;the bonds between X and G1and X and G2are single or double bonds, andY1is O, S or NR10, wherein R10is H or alky.

[0121] In the compounds of the formula (XII), X can be CR8, wherein R8can be H.

[0122] The disclosure also relates to a compound of the formula (XIII):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2dis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group);R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;TEC2025-0036 3000.222W01R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X7is C(O)O; andY1is O, S or NR10, wherein R10is H or alkyl.

[0123] An example of a compound of the formula (XIII) is a compound is of the formula:

[0124] Another example of a compound of the formula (XIII) is a compound of the formula:

[0125] Yet another example of a compound of the formula (XI 11) is a compound of the formula

[0126] The disclosure also includes a compound of the formula A-L-B, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a radical of a compound of the compounds of the disclosure (e.g., compounds of the formulae (I)-TEC2025-0036 3000.222W01(XIII), (IA)-(XA), and (IB)), B is a radical of a protein binding molecule; and L is linker selected from a substituted or unsubstituted, linear or branched chain comprising:(i) 1-50 linker atoms selected from carbon, oxygen, nitrogen, sulfur, silicon, or phosphorus;(ii) optionally one or more heterocyclic or aromatic rings;(iii) optionally one or more repeating units selected from -(CH2)g-, -O-, -NH-, -C(O)-, -S-, -SO-, -SO2-, -C(O)O-, -00(0)-, -C(O)NH-, -NHC(O)-, polyethylene glycol units, alkynyl units, alkenyl units, or combinations thereof;(iv) optionally substituted with one or more substituents selected from halogen, hydroxyl, alkoxy, amino, amide, cyano, thiol, sulfonyl, heteroaryl, or aryl groups;wherein g is independently 1-20; and wherein the total linker length corresponds to a distance sufficient to permit formation of a ternary complex between a target protein and the compound of formula A-L-B; andthe radical of a protein binding molecule is selected from:TEC2025-0036 3000.222W01TEC2025-0036 3000.222W01 oTEC2025-0036 3000.222W01DTAExamples c-Myc Binding MoietiesMeOPDB10058F4Examples of Prion Protein Binding Moietiesamyvid (florbetapir 18F), tauvid (flortaucipir 18F), and thioflavin.The groups “B,” which represent the radical of a protein binding molecule are described in Published U. S. Appl. No. 2025 / 0121068, which incorporated by reference as if fully set forth herein. Examples of linkers L include linkers comprising groups of the formula:TEC2025-0036 3000.222W01, which are described in Published U. S. Appl. No.2025 / 0121068, which incorporated by reference as if fully set forth herein. Target proteins include, but are not limited to tau, a-synuclein, huntingtin, transthyretin (TTR), and DNA binding protein-43 (TDP-43), which are described in Published U. S. Appl. No. 2025 / 0121068, which incorporated by reference as if fully set forth herein. Compounds of the formula A-L-B bind to aggregates of accumulated pathological target proteins. Additional examples of target proteins include:

[0127] Core amyloidogenic proteins: Amyloid-p (Ap) Alzheimer’s disease; Tau (MAPT) Alzheimer’s, frontotemporal dementia (FTD), PSP, CBD; a-Synuclein (SNCA) Parkinson’s disease, Lewy body dementia, MSA; TDP-43 (TARDBP) ALS, FTD; FUS ALS, FTD; Huntingtin (HTT) Huntington’s disease; Ataxin-1 (ATXN1) Spinocerebellar ataxia 1; Ataxin-2 (ATXN2) SCA2, ALS modifier; Ataxin-3 (ATXN3) SCA3 / Machado-Joseph disease; Ataxin-7 (ATXN7) SCA7; C9orf72 DPR proteins ALS / FTD (poly-GA, GR, PR repeats).

[0128] Prion & prion-like proteins: Prion protein (PrP) Creutzfeldt-Jakob disease, Kuru, FFI; SOD1 familial ALS aggregates; Optineurin ALS inclusion bodies; UBQLN2 ALS proteinopathy; VCP / p97 IBMPFD, ALS spectrum.

[0129] RNA-binding proteins: hnRNPAI; hnRNPA2B1; TIA1; MATR3; EWSR1; TAF15.TEC2025-0036 3000.222W01

[0130] Systemic amyloidosis proteins: immunoglobulin light chains (AL amyloidosis); Serum amyloid A (AA amyloidosis); Transthyretin (TTR) familial & age-related amyloidosis; β2-microglobulin dialysis-related amyloidosis; Apolipoprotein A-I; Apolipoprotein A-ll; Lysozyme; Gelsolin; Fibrinogen Aa chain; Cystatin C; Lactoferrin; Prolactin; Insulin (injection-site amyloid).

[0131] Metabolic I enzymatic aggregation diseases: Phenylalanine hydroxylase — PKU misfolding variants; Glucocerebrosidase (GBA1) Gaucher, Parkinson’s risk; Uromodulin kidney amyloidosis; Insulin amyloid deposits; Islet amyloid polypeptide (IAPP / amylin) type 2 diabetes.

[0132] Ocular aggregation diseases: Crystallins (α, β, γ) cataracts; TGFBI protein corneal dystrophies; Keratoepithelin; Lactoferrin corneal amyloid

[0133] kin & epithelial aggregation: Keratin 5 / 14 aggregates epidermolysis bullosa simplex; Filaggrin; Collagen XVII fragments.

[0134] Cancer-associated aggregation: p53 mutants amyloid-like aggregates; RBM45; PTEN misfolding variants.

[0135] Infectious amyloid-like proteins: Prion protein (PrPSc) transmissible; Bacterial curli fibers (cross-seeding implications); Fungal prion proteins.

[0136] This disclosure also contemplates pharmaceutical compositions comprising one or more compounds of the disclosure (e.g., compounds of the formulae (l)-(XII I), (IA)-(XA), and (IB)) and one or more pharmaceutically acceptable excipients. A “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal). Such compositions can be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can be done by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.

[0137] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and / or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R.,TEC2025-0036 3000.222W01Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.

[0138] As used herein “pharmaceutically acceptable carrier” or “excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0139] Pharmaceutical compositions can be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0140] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.TEC2025-0036 3000.222W01

[0141] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present invention can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations can be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present invention can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.

[0142] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms as known in the art. Any biologically-acceptable dosage form known to people of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

[0143] Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrosesaccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[0144] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and / or mannitol and / or sorbitol. TheTEC2025-0036 3000.222W01suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0145] The amount of active compound in a therapeutic composition according to various embodiments of the present invention can vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.

[0146] A “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the present invention or an appropriate pharmaceutical composition thereof are effective, the compounds of the present invention can be administered in an effective amount. The dosages suitable for this invention can be a composition, a pharmaceutical composition or any other compositions described herein.

[0147] For each of the recited embodiments, the dosage is typically administered once, twice, or thrice a day, although more frequent dosing intervals are possible. The dosage can be administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and / or every 7 days (once a week). In one embodiment, the dosage can be administered daily for up to and including 30 days, preferably between 7-10 days. In another embodiment, the dosage can be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage can be administered for as long as signs and / or symptoms persist. The patient can require "maintenance treatment" where the patient is receiving dosages every day for months, years, or the remainder of their lives. In addition, the composition of this invention can be to effect prophylaxis of recurring symptoms. For example, the dosage can be administered once or twice a day to prevent the onset of symptoms in patients at risk, especially for asymptomatic patients.TEC2025-0036 3000.222W01

[0148] The absolute weight of a given compound included in a unit dose for administration to a subject can vary widely. For example, about 0.0001 to about 1 g, or about 0.001 to about 0.5 g, of at least one compound of this disclosure, or a plurality of compounds can be administered. Alternatively, the unit dosage can vary from about 0.001 g to about 2g, from about 0.005 g to about 0.5 g, from about 0.01 g to about 0.25 g, from about 0.02 g to about 0.2 g, from about 0.03 g to about 0.15 g, from about 0.04 g to about 0.12 g, or from about 0.05 g to about 0.1 g.

[0149] Daily doses of the compounds can vary as well. Such daily doses can range, for example, from about 0.01 g / day to about 10 g / day, from about 0.02 g / day to about 5 g / day, from about 0.03 g / day to about 4 g / day, from about 0.04 g / day to about 3 g / day, from about 0.05 g / day to about 2 g / day, and from about 0.05 g / day to about 1 g / day.

[0150] It will be appreciated that the amount of compound(s) for use in treatment will vary not only with the particular carrier selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient. Ultimately the attendant health care provider may determine proper dosage.

[0151] The compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. The preferred routes of administration are buccal and oral. The administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease. Local administration can be administration to, for example, tissue, organ, and / or organ system, which encompasses and / or is affected by the disease, and / or where the disease signs and / or symptoms are active or are likely to occur. Administration can be topical with a local effect. The composition can be applied directly where its action is desired. Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract. Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract.

[0152] The compositions can include the compounds described herein in a “therapeutically effective amount.” Such a therapeutically effective amount is anTEC2025-0036 3000.222W01amount sufficient to obtain the desired physiological effect, such as a reduction of at least one symptom of cancer or an inflammatory disease or condition.

[0153] The compositions contemplated herein can contain other ingredients such as chemotherapeutic agents, anti-inflammatory agents, anti-viral agents, antibacterial agents, antimicrobial agents, immunomodulatory drugs, such as lenalidomide, pomalidomide or thalidomide, histone deacetylase inhibitors, such as panobinostat, preservatives or combinations thereof.

[0154] This disclosure also includes methods for treating neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS, comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., compounds of the formulae (l)-(XIII), (IA)-(XA), and (IB)) to a subject in need thereof. This disclosure also includes methods for reducing, substantially eliminating or eliminating dysregulation of proteostasis comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., compounds of the formulae (l)-(XI 11), (IA)-(XA), and (IB)) to a subject in need thereof. This disclosure also includes methods for reducing, substantially eliminating or eliminating the accumulation of intrinsically disordered proteins (e.g., a-syn) comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., compounds of the formulae (I)-(XIII), (IA)-(XA), and (IB)) to a subject in need thereof. This disclosure also includes methods for reducing, substantially eliminating or eliminating the expression of E5, E6, and / or E7 viral oncoproteins in host cells comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., compounds of the formulae (l)-(XI 11), (IA)-(XA), and (IB)) to a subject in need thereof.

[0155] The disclosure also includes a method for:(a) enhancing 20S proteasome activity and inducing the proteolytic degradation of intrinsically disordered proteins (IDPs), including α-synuclein (α-syn);(b) reducing I DP accumulation and / or preventing IDP aggregation to prevent or reduce neurodegeneration and treating Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease, and / or multiple system atrophy; (c) preventing neurodegeneration to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy; (d) enhancing 20S proteasome activity and inhibiting IDP aggregation to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy;(e) treating diseases or conditions caused by accumulated proteopathies, including a-synucleinopathies and tauopathies, to treat Alzheimer’s disease andTEC2025-0036 3000.222W01related dementias, Parkinson's disease and related dementia, amyotrophic lateral sclerosis, fronto-temporal dementia, Huntington's disease, multiple system atrophy, muscle atrophy diseases (including muscular dystrophies), progressive supranuclear palsy, Pick's disease, spinocerebellar ataxias, prion diseases, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, cancer, cancer metastasis, ageing and diseases relevant to core amyloidogenic proteins, prion and prion-like proteins, RNA-binding proteins, systemic amyloidosis proteins, metabolic / enzymatic aggregation diseases, ocular aggregation-diseases, kin and epithelial aggregation, cancer-associated aggregation and / or infectious amyloid-like proteins; and(f) treating diseases or conditions caused by infections disease (diseases caused by viral and bacterial infections), including HPV-positive cancers and HIV;the method comprising administering a therapeutically effective amount of at least one compound of the formula (I), (IA), (IC) or (ID):or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are eachTEC2025-0036 3000.222W01independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy;R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is 0 or NR9, wherein R9is H or alkyl; andY1is 0, S or NR10, wherein R10is H or alkyl; orone or more compounds of the disclosure (e.g., compounds of the formulae (I)-(XIII), (IA)-(XA), and (IB)); oror a pharmaceutical composition comprising one or more compounds of the disclosure (e.g., compounds of the formulae (I)-(XIII), (IA)-(XA), and (IB));to a subject in need thereof.

[0156] As used herein, the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, treatment that merely reduces symptoms, and / or delays disease progression is also contemplated.

[0157] The pharmaceutical compositions disclosed herein can have the ability to effectively treat new patient segments where proteasome inhibition and reduced toxicity is desired or warranted.

[0158] The compounds and methods described herein can be used prophylactically or therapeutically. The term “prophylactic” or “therapeutic” treatment refers to administration of a drug to a host before or after onset of a disease or condition. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom). Administering the compounds describedTEC2025-0036 3000.222W01herein (including enantiomers and salts thereof) is contemplated in both a prophylactic treatment (e.g. to patients at risk for disease, such as elderly patients who, because of their advancing age, are at risk for arthritis, cancer, and the like) and therapeutic treatment (e.g. to patients with symptoms of disease or to patients diagnosed with disease).

[0159] The term “therapeutically effective amount” as used herein, refers to that amount of one or more compounds of the various examples of the present invention that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some examples, the therapeutically effective amount is that which can treat or alleviate the disease or symptoms of the disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.

[0160] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having from 1 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 1 to 10 carbons atoms, 1 to 8 carbon atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 1 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 1 to 5 carbon atoms, or 1 to 3 carbon atoms. Examples of straight chain mono-valent (C1-C20)-alkyl groups include those with from 1 to 8 carbon atoms such as methyl (i.e., CH3), ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl groups. Examples of branched mono-valent (C1-C20)-alkyl groups include isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, and isopentyl. Examples of straight chain bi-valent (C1-C20)alkyl groups include those withTEC2025-0036 3000.222W01from 1 to 6 carbon atoms such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-. Examples of branched bi-valent alkyl groups include -CH(CH3)CH2- and -CH2CH(CH3)CH2-. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cyclooctyl, bicyclo[1,1.1]pentyl, bicyclo[2.1.1 ]hexyl, and bicyclo[2.2.1]heptyl. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. In some embodiments, alkyl includes a combination of substituted and unsubstituted alkyl. As an example, alkyl, and also (C1)alkyl, includes methyl and substituted methyl. As a particular example, (C1)alkyl includes benzyl. As a further example, alkyl can include methyl and substituted (C2-C8)alkyl. Alkyl can also include substituted methyl and unsubstituted (C2-C8)alkyl. In some embodiments, alkyl can be methyl and C2-C8linear alkyl. In some embodiments, alkyl can be methyl and C2-C8branched alkyl. The term methyl is understood to be -CH3, which is not substituted. The term methylene is understood to be -CH2-, which is not substituted. For comparison, the term (Ci)alkyl is understood to be a substituted or an unsubstituted -CH3or a substituted or an unsubstituted -CH2-. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, cycloalkyl, heterocyclyl, aryl, amino, haloalkyl, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. As further example, representative substituted alkyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. In some embodiments, representative substituted alkyl groups can be substituted from a set of groups including amino, hydroxy, cyano, carboxy, nitro, thio and alkoxy, but not including halogen groups. Thus, in some embodiments alkyl can be substituted with a non-halogen group. For example, representative substituted alkyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. In some embodiments, representative substituted alkyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups. For example, alkyl can be trifluoromethyl, difluoromethyl, or fluoromethyl, or alkyl can be substituted alkyl other than trifluoromethyl, difluoromethyl or fluoromethyl. Alkyl can be haloalkyl or alkyl can be substituted alkyl other than haloalkyl. The term “alkyl” also generallyTEC2025-0036 3000.222W01refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain. Thus, for example, “alkyl” also encompasses groups such as -[(CH2)pO]qH and the like.

[0161] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having at least one carbon-carbon double bond and from 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. The double bonds can be trans or cis orientation. The double bonds can be terminal or internal. The alkenyl group can be attached via the portion of the alkenyl group containing the double bond, e.g., vinyl, propen-1 -yl and buten-1-yl, or the alkenyl group can be attached via a portion of the alkenyl group that does not contain the double bond, e.g., penten-4-yl. Examples of mono-valent (C2-C2o)-alkenyl groups include those with from 1 to 8 carbon atoms such as vinyl, propenyl, propen-1 -yl, propen-2-yl, butenyl, buten-1-yl, buten-2-yl, sec-buten-1-yl, sec-buten-3-yl, pentenyl, hexenyl, heptenyl and octenyl groups. Examples of branched mono-valent (C2-C2o)-alkenyl groups include isopropenyl, iso-butenyl, sec-butenyl, t-butenyl, neopentenyl, and isopentenyl. Examples of straight chain bi-valent (C2-C20)alkenyl groups include those with from 2 to 6 carbon atoms such as -CHCH-, -CHCHCH2-, -CHCHCH2CH2-, and -CHCHCH2CH2CH2-. Examples of branched bi-valent alkyl groups include -C(CH3)CH- and -CHC(CH3)CH2-. Examples of cyclic alkenyl groups include cyclopentenyl, cyclohexenyl and cyclooctenyl. It is envisaged that alkenyl can also include masked alkenyl groups, precursors of alkenyl groups or other related groups. As such, where alkenyl groups are described it, compounds are also envisaged where a carboncarbon double bond of an alkenyl is replaced by an epoxide or aziridine ring. Substituted alkenyl also includes alkenyl groups which are substantially tautomeric with a non-alkenyl group. For example, substituted alkenyl can be 2-aminoalkenyl, 2-alkylaminoalkenyl, 2-hydroxyalkenyl, 2-hydroxyvinyl, 2-hydroxypropenyl, but substituted alkenyl is also understood to include the group of substituted alkenyl groups other than alkenyl which are tautomeric with non-alkenyl containing groups. In some embodiments, alkenyl can be understood to include a combination of substituted and unsubstituted alkenyl. For example, alkenyl can be vinyl and substituted vinyl. For example, alkenyl can be vinyl and substituted (C3-C8)alkenyl. Alkenyl can also include substituted vinyl and unsubstituted (C3-C8)alkenyl. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, forTEC2025-0036 3000.222W01example, monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio, alkoxy, and halogen groups. As further example, representative substituted alkenyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. In some embodiments, representative substituted alkenyl groups can be substituted from a set of groups including monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio and alkoxy, but not including halogen groups. Thus, in some embodiments alkenyl can be substituted with a non-halogen group. In some embodiments, representative substituted alkenyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. For example, alkenyl can be 1-fluorovinyl, 2-fluorovinyl, 1,2-difluorovinyl, 1,2,2-trifluorovinyl, 2,2-difluorovinyl, trifluoropropen-2-yl, 3,3,3-trifluoropropenyl, 1 -fluoropropenyl, 1 -chlorovinyl, 2-chlorovinyl, 1,2-dichlorovinyl, 1,2,2-trichlorovinyl or 2,2-dichlorovinyl. In some embodiments, representative substituted alkenyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups.

[0162] The term “alkynyl” as used herein, refers to substituted or unsubstituted straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 50 carbon atoms, 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. Examples include, but are not limited to ethynyl, propynyl, propyn-1 -yl, propyn-2-yl, butynyl, butyn-1 -yl, butyn-2-yl, butyn-3-yl, butyn-4-yl, pentynyl, pentyn-1-yl, hexynyl, Examples include, but are not limited to –C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.

[0163] The term “aryl” as used herein refers to substituted or unsubstituted univalent groups that are derived by removing a hydrogen atom from an arene, which is a cyclic aromatic hydrocarbon, having from 6 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 20 carbon atoms, 6 to about 10 carbon atoms or 6 to 8 carbon atoms. Examples of C6-C20aryl groups include phenyl, napthalenyl, azulenyl, biphenylyl,TEC2025-0036 3000.222W01indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, anthracenyl groups. Examples include substituted phenyl, substituted napthalenyl, substituted azulenyl, substituted biphenylyl, substituted indacenyl, substituted fluorenyl, substituted phenanthrenyl, substituted triphenylenyl, substituted pyrenyl, substituted naphthacenyl, substituted chrysenyl, and substituted anthracenyl groups. Examples also include unsubstituted phenyl, unsubstituted napthalenyl, unsubstituted azulenyl, unsubstituted biphenylyl, unsubstituted indacenyl, unsubstituted fluorenyl, unsubstituted phenanthrenyl, unsubstituted triphenylenyl, unsubstituted pyrenyl, unsubstituted naphthacenyl, unsubstituted chrysenyl, and unsubstituted anthracenyl groups. Aryl includes phenyl groups and also non-phenyl aryl groups. From these examples, it is clear that the term C6-C20aryl encompasses mono- and polycyclic C6-C20aryl groups, including fused and non-fused polycyclic C6-C20aryl groups such as fused and non-fused polycyclic C6-C10groups.

[0164] The term “heterocyclyl” as used herein refers to substituted aromatic, unsubstituted aromatic, substituted non-aromatic, and unsubstituted non-aromatic rings containing 3 or more atoms in the ring, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 2 to 5 carbon atoms (C2-C5), 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6) or 6 to 8 carbon atoms (C6-C8). A heterocyclyl group designated as a C2-heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to piperidynyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups. For example, heterocyclyl groups include, without limitation:TEC2025-0036 3000.222W01C20)alkyl, (C3-C2o)aryl or an amine protecting group (e.g., a t-butyloxycarbonyl group) and wherein the heterocyclyl group can be substituted or unsubstituted. A nitrogencontaining heterocyclyl group is a heterocyclyl group containing a nitrogen atom as an atom in the ring. In some embodiments, the heterocyclyl is other than thiophene or substituted thiophene. In some embodiments, the heterocyclyl is other than furan or substituted furan.

[0165] The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. Thus, alkyoxy also includes an oxygen atom connected to an alkyenyl group and oxygen atom connected to an alkynyl group. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0166] The term “aryloxy” as used herein refers to an oxygen atom connected to an aryl group as are defined herein.

[0167] The term “aralkyl” and “arylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl, biphenylmethyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in whichTEC2025-0036 3000.222W01a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0168] The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0169] The term “amine” and “amino” as used herein refers to a substituent of the form -NH2, -NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.

[0170] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, group or the like. The carbonyl carbon atom can also be bonded to a nitrogen or an oxygen atom, for example to form an amide (e.g., amido as defined herein), a carboxylic acid (e.g., a carboxy group as defined herein) or an ester, such as an alkyl ester.

[0171] The term “formyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to a hydrogen atom.

[0172] The term “alkoxycarbonyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyl group. Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyenyl group. Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkynyl group. In a further case, which is included in the definition of alkoxycarbonyl as the term is defined herein, and is also included in the term “aryloxycarbonyl,” the carbonyl carbon atom is bonded to an oxygen atom which is bonded to an aryl group instead of an alkyl group.

[0173] The term “arylcarbonyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to an aryl group.

[0174] The term “alkylamido” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. TheTEC2025-0036 3000.222W01carbonyl carbon atom is also bonded to a nitrogen group which is bonded to one or more alkyl groups. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more aryl group instead of, or in addition to, the one or more alkyl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to an nitrogen atom which is bonded to one or more alkenyl group instead of, or in addition to, the one or more alkyl and or / aryl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more alkynyl group instead of, or in addition to, the one or more alkyl, alkenyl and / or aryl group.

[0175] The term “carboxy” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to a hydroxy group or oxygen anion so as to result in a carboxylic acid or carboxylate. Carboxy also includes both the protonated form of the carboxylic acid and the salt form. For example, carboxy can be understood as COOH or CO2H.

[0176] The term “amido” as used herein refers to a group having the formula C(O)NRR, wherein R is defined herein and can each independently be, e.g., hydrogen, alkyl, aryl or each R, together with the nitrogen atom to which they are attached, form a heterocyclyl group.

[0177] The term “alkylthio” as used herein refers to a sulfur atom connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0178] The term “arylthio” as used herein refers to a sulfur atom connected to an aryl group as defined herein.

[0179] The term “alkylsulfonyl” as used herein refers to a sulfonyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0180] The term “alkylsulfinyl” as used herein refers to a sulfinyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0181] The term “dialkylaminosulfonyl” as used herein refers to a sulfonyl group connected to a nitrogen further connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.

[0182] The term “dialkylamino” as used herein refers to an amino group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.TEC2025-0036 3000.222W01

[0183] The term “dialkylamido” as used herein refers to an amido group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.

[0184] The term “substituted” as used herein refers to a group that is substituted with one or more groups including, but not limited to, the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CH2OH), OC(O)N(R)2, ON, NO, NO2, ONO2, azido, CF3, OCF3, methylenedioxy, ethylenedioxy, (C3-C20)heteroaryl, N(R)2, Si(R)3, SR, SOR, SO2R, SO2N(R)2, SO3R, P(O)(OR)2, OP(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, C(O)N(R)OH, OC(O)N(R)2, C(S)N(R)2, (CH2)O-2N(R)C(O)R, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, or C(=NOR)R wherein R can be hydrogen, (C1-C20)alkyl, (C6-C20)aryl, heterocyclyl or polyalkylene oxide groups, such as polyalkylene oxide groups of the formula -(CH2CH2O)f-R-OR, -(CH2CH2CH2O)g-R-OR, -(CH2CH2O)f(CH2CH2CH2O)g-R-OR each of which can, in turn, be substituted or unsubstituted and wherein f and g are each independently an integer from 1 to 50 (e.g., 1 to 10, 1 to 5, 1 to 3 or 2 to 5). Substituted also includes a group that is substituted with one or more groups including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido. Where there are two or more adjacent substituents, the substituents can be linked to form a carbocyclic or heterocyclic ring. Such adjacent groups can have a vicinal or germinal relationship, or they can be adjacent on a ring in, e.g., an orthoarrangement. Each instance of substituted is understood to be independent. For example, a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl. It is envisaged that a substituted group can be substituted with one or more non-fluoro groups. As another example, a substituted group can be substituted with one or more non-cyano groups. As another example, a substituted group can be substituted with one or more groups other than haloalkyl. As yet another example, a substituted group can be substituted with one or more groups other than tert-butyl. As yet a further example, a substituted group can be substituted with one or more groups other than trifluoromethyl. As yetTEC2025-0036 3000.222W01even further examples, a substituted group can be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than thiophenyl, or other than nitrophenyl, or groups meeting a combination of such descriptions. Further, substituted is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups.

[0185] In some instances, the compounds described herein (e.g., compounds of the formulae (l)-(XIII), (IA)-(XA), and (IB)) can contain chiral centers. All diastereomers of the compounds described herein are contemplated herein, as well as racemates.

[0186] As used herein, the term “salts” and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0187] Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences,TEC2025-0036 3000.222W0117th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.

[0188] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0189] The term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0190] As used herein, the term “subject” or “patient” refers to any organism to which a composition described herein can be administered, e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Subject refers to a mammal receiving the compositions disclosed herein or subject to disclosed methods. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs.

[0191] Each embodiment described above is envisaged to be applicable in each combination with other embodiments described herein. For example, embodiments corresponding to formula (I) are equally envisaged as being applicable to formulae (ll)-(XIII) and (IB). Likewise, embodiments corresponding to formula (IB) are equally envisaged as being applicable to compounds of the formulae (l)-(XI 11) and (IA)-(XA) and so forth.

[0192] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1 % to about 5%” or “about 0.1 % toTEC2025-0036 3000.222W015%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0193] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0194] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1 % of a stated value or of a stated limit of a range.

[0195] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0196] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present disclosure. Thus, it should be understood that although the present disclosure has been specifically disclosed by specific embodiments and optional features, modification and variation of the concepts herein disclosed can be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present disclosure

[0197] The invention is now described with reference to the following Examples. The following working examples therefore, are provided for the purpose ofTEC2025-0036 3000.222W01illustration only and specifically point out certain embodiments of the present invention and are not to be construed as limiting in any way the remainder of the disclosure. Therefore, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0198] The disclosure provides for the following example embodiments, the numbering of which is not to be construed as designating levels of importance:1. A compound of the formula (I), (IA), (IC) or (ID):or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;TEC2025-0036 3000.222W01R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy; R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;provided that:X2is not N when R1is NH2and R1is not Cl when X1and X2are both simultaneously N;R2is not H when R5is Cl,R2is not H when RBis methyl;R2is not H when R1is Cl or F;R4is not CH3when R6is optionally substituted phenyl;R6is not phenoxy or CF3when R1methoxy;R6is not CF3when R1is aminomethyl or pyrrolidinyl;R6is not optionally substituted phenyl or phenoxy when Y1is S;R6is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl;X2is not N when R18is NH2and R18is not Cl when X1and X2are both simultaneously N;R2is not H when R21is Cl,R2is not H when R22is methyl;R2is not H when R18is Cl or F;R4is not CH3when R22is optionally substituted phenyl;R22is not phenoxy or CF3when R18methoxy;R22is not CF3when R18is aminomethyl or pyrrolidinyl;R22is not optionally substituted phenyl or phenoxy when Y1is S;R22is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl.2. The compound of Embodiment 1, wherein R1 / R18is halo or alkyl.3. The compound of Embodiment 1 or 2, wherein R1 / R18is halo.TEC2025-0036 3000.222W014. The compound of Embodiment 3, wherein halo is Cl.5. The compound of Embodiment 1 or 2, wherein R1is alkyl.6. The compound of Embodiment 5, wherein alkyl is substituted alkyl.7. The compound of Embodiment 6, wherein substituted alkyl is halo substituted alkyl.8. The compound of Embodiment 7, wherein halo substituted alkyl is fluoro substituted alkyl.9. The compound of Embodiment 8, wherein fluoro substituted alkyl is perfluoro substituted alkyl.10. The compound of Embodiment 9, wherein perfluoro substituted alkyl is CF3.11. The compound of any preceding Embodiment, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.12. The compound of Embodiment 11, wherein R7is alkyl.13. The compound of Embodiment 11, wherein R7is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.14. The compound of Embodiment 11, wherein R7is alkoxy.15. The compound of Embodiment 11, wherein R7is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.16. The compound of any preceding Embodiment, wherein R3and R4are each independently H.17. The compound of any of Embodiments 1 -15, wherein R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring.TEC2025-0036 3000.222W0118. The compound of Embodiment 17, wherein the five- and the six membered heterocyclyl ring is of the formula:Y1and Y1, respectively, each of which is optionally substituted.19. The compound of any preceding Embodiment, wherein R5 / R21is H.20. The compound of any preceding Embodiment, wherein R5 / R21is halo.21. The compound of Embodiment 20, wherein halo is Cl or F.22. The compound of any of Embodiments 1 -18, wherein R5 / R21is alkoxy.23. The compound of Embodiment 22, wherein R5 / R21is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.24. The compound of any preceding Embodiment, wherein Rsis H.25. The compound of any of Embodiments 1-23, wherein R6 / R22is alkyl.26. The compound of Embodiment 25, wherein R6 / R22is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.27. The compound of any of Embodiments 1-23, wherein R6 / R22is aryloxy.28. The compound of Embodiment 27, wherein aryloxy is a C6-C10aryloxy group.29. The compound of Embodiment 28, wherein aryloxy is phenoxy.30. The compound of any of Embodiments 1-23, wherein R6 / R22is alkoxy.31. The compound of Embodiment 30, wherein R6 / R22is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.32. The compound of Embodiment 30 or 31, wherein alkoxy is substituted alkoxy.TEC2025-0036 3000.222W0133. The compound of Embodiment 32, wherein substituted alkoxy is halo substituted alkoxy.34. The compound of Embodiment 33, wherein halo substituted alkoxy is fluoro substituted alkoxy.35. The compound of Embodiment 34, wherein fluoro substituted alkoxy is perfluoro substituted alkoxy.36. The compound of Embodiment 35, wherein perfluoro substituted alkoxy is OCF3.37. The compound of any of Embodiments 1-23, wherein R6 / R22is heteroaryloxy.38. The compound of Embodiment 37, wherein heteroaryloxy is C2-C5heteroaryloxy.39. The compound of Embodiment 37, wherein C2-C5 heteroaryloxy is pyridyl.40. The compound of Embodiment 37, wherein the heteroaryloxy is substituted with one or more halo and acyl.41. The compound of Embodiment 37, wherein acyl is C(O)OR12, wherein R12is C1-C8alkyl, C2-C5 alkyl, C1-C5 alkyl or C3-C8alkyl.42. The compound of Embodiment 37, wherein R6 / R22is a heteroaryloxy group of the formula:, which is optionally substituted.43. The compound of any of Embodiments 1-23, wherein R6 / R22is halo.44. The compound of Embodiment 43, wherein halo is Cl or F.45. The compound of Embodiment 44, wherein halo is Cl.46. The compound of any of Embodiments 1-23, wherein R6 / R22is cyano.TEC2025-0036 3000.222W0147. The compound of any of Embodiments 1 -23, wherein R5and R6or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group.48. The compound of Embodiment 47, wherein the heterocyclyl group is a C3-C5 heterocyclyl group.49. The compound of Embodiment 47, wherein the heterocyclyl group is a C3 heterocyclyl group of the formula:50. The compound of any preceding Embodiment, wherein Y1is O.51. The compound of any of Embodiments 1 -46, wherein Y1is S.52. The compound of any preceding Embodiment, wherein X1is N and X2is CR9.53. The compound of Embodiment 52, wherein R9is H.54. The compound of any of Embodiments 1 -51, wherein X1is CR8and X2is N.55. The compound of Embodiment 54, wherein R8is H.56. The compound of any of Embodiments 1 -51, wherein X1is N and X2is N.57. The compound of Embodiment 1, wherein X3is S.58. The compound of Embodiment 1, wherein:X3is O; andTEC2025-0036 3000.222W01R1 / R18R2R5 / R21R6 / R22X1X2R3R4Cl COOEt Cl H N C H H Cl H Cl H N C H H H H Cl H N C H H Cl H H H N C H H Cl H F H N C H H Cl H OCH3H N C H H Cl H Cl H C C H H Cl H Cl H N C H H Cl H Cl H N C Me H Cl H Cl H N C H Me Cl H Cl H N C Me Me Cl H Cl H C N H H CF3H Cl H C N H H ClCl H H N C H H WCl COOEt H N C H HCl H H OPh N C H H Cl H H OCF3N C H H Cl H H OMe N C H H Cl H H r°>N CH H Cl H H t-Bu N C H H Cl COOEt H t-Bu N C H H Cl H H CN N C H H Cl H H Cl N C H H Cl H Cl t-Bu N C H HTEC2025-0036 3000.222W0159. A compound of the formula (II) or (HA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.60. The compound of Embodiment 59, wherein R1is alkoxy.61. The compound of Embodiment 59, wherein R1is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.62. The compound of any of Embodiments 59-61, wherein R2is H.TEC2025-0036 3000.222W0163. The compound of any of Embodiments 59-62, wherein R3and R4are each H.64. The compound of any of Embodiments 59-63, wherein X1is CR8and X2is N.65. The compound of any of Embodiments 59-64, wherein X3is NR9.66. The compound of any of Embodiments 59-65, wherein R5is H.67. The compound of any of Embodiments 59-66, wherein R6is alkyl.68. The compound of Embodiment 67, wherein R6is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.69. The compound of Embodiment 59, wherein the compound is of the formula:70. A compound of the formula (III) or (I II A):R1R3R4R1aR2R2a(| 11 A)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1and R1aare each independently halo, alkyl, alkoxy, aryloxy or amino;R2and R2aare each independently H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2or R1aand R2a, together with the atoms to which they are attached, form a ring;TEC2025-0036 3000.222W01R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X1ais N or CR8a, wherein R8ais H, halo, alkyl, alkoxy, aryloxy or amino;X2ais N or CR9a, wherein R9ais H, halo, alkyl, alkoxy, aryloxy or amino, or R8aand R9a, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;X3ais O or NR9a, wherein R9ais H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.71. The compound of Embodiment 70, wherein R1and R,aare each independently halo.72. The compound of Embodiment 71, wherein R1and R1aare each chloro.73. The compound of any of Embodiments 70-72, wherein X1and X1aare each N and X2and X2aare each CR9.74. The compound of any of Embodiments 70-73, wherein X3and X3aare each O.75. The compound of any of Embodiments 70-74, wherein R3and R4are each H.76. The compound of Embodiment 70, wherein the compound is of the formula:77. A compound of the formula (IV) or (IVA):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2cis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2ctogether with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.78. The compound of Embodiment 77, wherein R1is halo.79. The compound of Embodiment 77 or 78, wherein R1is Cl.80. The compound of any of Embodiments 77-79, wherein R2° is halo.81. The compound of any of Embodiments 77-80, wherein R2cis Cl.82. The compound of any of Embodiments 77-81, wherein R5is halo.83. The compound of any of Embodiments 77-82, wherein R5is Cl.84. The compound of any of Embodiments 77-83, wherein R6is H.TEC2025-0036 3000.222W0185. The compound of any of Embodiments 77-84, wherein X1is N and X2is CR9.86. The compound of any of Embodiments 77-85, wherein X3is O.87. The compound of any of Embodiments 77-86, wherein R3and R4are each H.88. The compound of Embodiment 77, wherein the compound is of the formula:Cl89. A compound of the formula (V) or (VA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl;R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.90. The compound of Embodiment 89, wherein R1is alkyl.91. The compound of Embodiment 89, wherein R1is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.92. The compound of any of Embodiments 89-91, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.93. The compound of Embodiment 92, wherein R7is alkoxy.94. The compound of Embodiment 93, wherein R7is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.95. The compound of any of Embodiments 89-94, wherein R3is H.96. The compound of any of Embodiments 89-95, wherein R5is halo.97. The compound of any of Embodiments 89-96, wherein R5is Cl.98. The compound of any of Embodiments 89-97, wherein R6is H.99. The compound of any of Embodiments 89-98, wherein X1is CR8and X2is CR9.100. The compound of any of Embodiments 89-99, wherein X3is NR9.101. The compound of Embodiment 89, wherein the compound is of the formula:H HN^NCO2MeTEC2025-0036 3000.222W01102. A compound of the formula (VI) or (VIA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group);R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5aand R6aare each independently H, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.103. The compound of Embodiment 102, wherein R1is alkoxy.104. The compound of Embodiment 102, wherein R1is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.105. The compound of any of Embodiments 102-104, wherein R2is H.TEC2025-0036 3000.222W01106. The compound of any of Embodiments 102-105, wherein R3and R4are each H.107. The compound of any of Embodiments 102-106, wherein X1is N and X2is CR9.108. The compound of any of Embodiments 102-107, wherein X4is S.109. The compound of any of Embodiments 102-108, wherein R5ais H.110. The compound of any of Embodiments 102-109, wherein R6ais alkyl.111. The compound of Embodiment 110, wherein R6ais C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.112. The compound of Embodiment 110, wherein R6ais aryl substituted alkyl.113. The compound of Embodiment 110, wherein R6ais optionally substituted aryl alkyl.114. The compound of Embodiment 102, wherein the compound is of the formula:115. A compound of the formula (VII) or (VI I A):R5a(VII) orTEC2025-0036 3000.222W01R5aR2(VI I A)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.116. The compound of Embodiment 115, wherein R1is halo.117. The compound of Embodiment 116, wherein R1is F.118. The compound of any of Embodiments 115-117, wherein R2is H.119. The compound of any of Embodiments 115-118, wherein R4is H.120. The compound of any of Embodiments 115-119, wherein X1is CR8and X2is CR9.121. The compound of any of Embodiments 115-120, wherein R5ais H.TEC2025-0036 3000.222W01122. The compound of any of Embodiments 115-121, wherein R6ais optionally substituted aryl.123. The compound of Embodiment 122, wherein R6ais halo substituted aryl.124. The compound of Embodiment 115, wherein the compound is of the formula:125. A compound of the formula (VIII) or (VI II A):(VIII) or(VI 11 A)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2bis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2btogether with the atoms to which they are attached, form a ring;R4is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;TEC2025-0036 3000.222W01R13is C(O)R14, wherein R14is H, alkyl, amino or alkoxy;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.126. The compound of Embodiment 125, wherein R1is halo.127. The compound of Embodiment 126, wherein R1is Cl.128. The compound of any of Embodiments 125-127, wherein R2is H.129. The compound of any of Embodiments 125-128, wherein R4is H.130. The compound of any of Embodiments 125-129, wherein X1is N and X2is CR9.131. The compound of any of Embodiments 125-130, wherein R9is H.132. The compound of any of Embodiments 125-131, wherein R5ais H.133. The compound of any of Embodiments 125-132, wherein R6ais optionally substituted aryl.134. The compound of Embodiment 133, wherein R6ais alkyl substituted aryl.135. The compound of any of Embodiments 125-134, wherein R2bis halo.136. The compound of any of Embodiments 125-135, wherein R14is alkoxy.137. The compound of Embodiment 136, wherein R14is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy138. The compound of Embodiment 125, wherein the compound is of the formula:TEC2025-0036 3000.222W01ci139. A compound of the formula (IX) or (IXA):R5b(IX) orR3or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5ais H, alkyl or aryl;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX5is O, acyl or NR9, wherein R9is H or alkyl.140. The compound of Embodiment 139, wherein R1is amino.TEC2025-0036 3000.222W01141. The compound of Embodiment 140, wherein R1is C1-C8alkyl amino, C2-C5alkyl amino, C1-C5alkyl amino or C3-C8alkyl amino.142. The compound of any of Embodiments 139-141, wherein R2is H.143. The compound of any of Embodiments 139-142, wherein R3is H.144. The compound of any of Embodiments 139-143, wherein R5bis aryl.145. The compound of any of Embodiments 139-144, wherein R5ais halo substituted aryl.146. The compound of any of Embodiments 139-145, wherein X5is C(O).147. The compound of any of Embodiments 139-146, wherein R1and R2together with the atoms to which they are attached, form a ring.148. The compound of Embodiment 147, wherein the ring is a five-, six- or seven-membered ring.149. The compound of any of Embodiments 139-148, wherein X1is OR8and X2is CR9.150. The compound of Embodiment 149, wherein the compound is of the formula:151. A compound of the formula (X) or (XA):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;Y1is O, S or NR10, wherein R10is H or alkyl; andY2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.152. A compound of the formula (XI):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X5is CHR15, wherein R15is H, acyl, alkyl, halo or aryl or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl; andY2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.153. The compound of Embodiment 152, wherein R15acyl or acyl substituted alkyl.154. The compound of Embodiment 153, wherein acyl is C(O)OR12, wherein R12is C1-C8alkyl, C2-C5alkyl, C1-C5 alkyl or C3-C8alkyl.155. A compound of the formula (XII):R3R4or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(0)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they areTEC2025-0036 3000.222W01attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X, G1, and G2are each independently N, NR10, wherein R10is H or alkyl, C(O) or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;the bonds between X and G1and X and G2are single or double bonds, and Y1is O, S or NR10, wherein R10is H or alky.156. The compound of Embodiment 155, wherein X is OR8.157. A compound of the formula (XIII):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2dis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X7is C(O)O; andY1is O, S or NR10, wherein R10is H or alkyl.TEC2025-0036 3000.222W01158. The compound of Embodiment 157, wherein the compound is of the formula:159. The compound of Embodiment 157, wherein the compound is of the formula:160. The compound of Embodiment 157, wherein the compound is of the formula:161. A pharmaceutical composition comprising at least one compound of any preceding Embodiment and at least one pharmaceutically acceptable excipient.162. A method for treating a neurodegenerative disease comprising administering a therapeutically effective amount of at least one compound of the formula (IB):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamide or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;Rsis H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and Rs, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of any of Embodiments 1-160; ora pharmaceutical composition of Embodiment 161;to a subject in need thereof.163. The method of Embodiment 162, wherein the neurodegenerative disease is at least one of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS.164. A method for reducing, substantially eliminating or eliminating dysregulation of proteostasis comprising administering a therapeutically effective amount of at least one compound of the formula (IB):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamide or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;Rsis H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and Rs, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of any of Embodiments 1-160; ora pharmaceutical composition of Embodiment 161;to a subject in need thereof.165. A method for reducing, substantially eliminating or eliminating the accumulation of intrinsically disordered proteins comprising administering a therapeutically effective amount of at least one compound of the formula (IB):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamido or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R6is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of any of Embodiments 1-160; ora pharmaceutical composition of Embodiment 161;to a subject in need thereof.166. The method of Embodiment 165, wherein the intrinsically disordered proteins comprise a-syn.167. A method for reducing, substantially eliminating or eliminating the expression of E5, E6, and / or E7 viral oncoproteins in host cells comprising administering a therapeutically effective amount of at least one compound of the formula (IB):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamido or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R6is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of any of Embodiments 1-160; ora pharmaceutical composition of Embodiment 161;to a subject in need thereof.168. A method for:(a) enhancing 20S proteasome activity and inducing the proteolytic degradation of intrinsically disordered proteins (IDPs), including α-synuclein (α-syn);(b) reducing I DP accumulation and / or preventing IDP aggregation to prevent or reduce neurodegeneration and treating Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease, and / or multiple system atrophy;(c) preventing neurodegeneration to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy;TEC2025-0036 3000.222W01(d) enhancing 20S proteasome activity and inhibiting IDP aggregation to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy;(e) treating diseases or conditions caused by accumulated proteopathies, including a-synucleinopathies and tauopathies, to treat Alzheimer’s disease and related dementias, Parkinson's disease and related dementia, amyotrophic lateral sclerosis, fronto-temporal dementia, Huntington's disease, multiple system atrophy, muscle atrophy diseases (including muscular dystrophies), progressive supranuclear palsy, Pick's disease, spinocerebellar ataxias, prion diseases, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, cancer, cancer metastasis, ageing and diseases relevant to core amyloidogenic proteins, prion and prion-like proteins, RNA-binding proteins, systemic amyloidosis proteins, metabolic / enzymatic aggregation diseases, ocular aggregation-diseases, kin and epithelial aggregation, cancer-associated aggregation and / or infectious amyloid-like proteins; and(f) treating diseases or conditions caused by infections disease (diseases caused by viral and bacterial infections), including HPV-positive cancers and HIV; the method comprising administering a therapeutically effective amount of at least one compound of the formula (I), (IA), (IC) or (ID):or a pharmaceutically acceptable salt or solvate thereof,TEC2025-0036 3000.222W01wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy; R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl; ora compound of any of Embodiments 59-160; oror a pharmaceutical composition of Embodiment 161;to a subject in need thereof.169. The method of Embodiment 168, wherein R1 / R18is halo or alkyl.170. The method of Embodiment 168 or 169, wherein R1 / R18is halo.171. The method of Embodiment 170, wherein halo is Cl.172. The method of Embodiment 168 or 169, wherein R1 / R18is alkyl.173. The method of Embodiment 172, wherein alkyl is substituted alkyl.TEC2025-0036 3000.222W01174. The method of Embodiment 173, wherein substituted alkyl is halo substituted alkyl.175. The method of Embodiment 174, wherein halo substituted alkyl is fluoro substituted alkyl.176. The method of Embodiment 175, wherein fluoro substituted alkyl is perfluoro substituted alkyl.177. The method of Embodiment 176, wherein perfluoro substituted alkyl is CF3.178. The method of any of Embodiments 168-177, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.179. The method of Embodiment 178, wherein R7is alkyl.180. The method of Embodiment 179, wherein R7is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.181. The method of Embodiment 180, wherein R7is alkoxy.182. The method of Embodiment 180, wherein R7is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.183. The method of any of Embodiments 168-182, wherein R3and R4are each independently H.184. The method of any of Embodiments 168-182, wherein R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring.185. The method of Embodiment 184, wherein the five- and the six membered heterocyclyl ring is of the formula:TEC2025-0036 3000.222W01respectively, each of which is optionally substituted.186. The method of any of Embodiments 168-185, wherein R5 / R21is H.187. The method of any of Embodiments 168-185, wherein R5 / R21is halo.188. The method of Embodiment 187, wherein halo is Cl or F.189. The method of any of Embodiments 168-185, wherein R5 / R21is alkoxy.190. The method of Embodiment 189, wherein R5 / R21is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.191. The method of any of Embodiments 168-190, wherein R6 / R22is H.192. The method of any of Embodiments 168-190, wherein R6 / R22is alkyl.193. The method of Embodiment 192, wherein R6 / R22is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.194. The method of any of Embodiments 168-190, wherein R6 / R22is aryloxy.195. The method of Embodiment 194, wherein aryloxy is a C6-C10aryloxy group.196. The method of Embodiment 195, wherein aryloxy is phenoxy.197. The method of any of Embodiments 168-190, wherein R6 / R22is alkoxy.198. The method of Embodiment 197, wherein R6 / R22is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.199. The method of Embodiment 197 or 198, wherein alkoxy is substituted alkoxy.TEC2025-0036 3000.222W01200. The method of Embodiment 199, wherein substituted alkoxy is halo substituted alkoxy.201. The method of Embodiment 200, wherein halo substituted alkoxy is fluoro substituted alkoxy.202. The method of Embodiment 201, wherein fluoro substituted alkoxy is perfluoro substituted alkoxy.203. The method of Embodiment 202, wherein perfluoro substituted alkoxy is OCF3.204. The method of any of Embodiments 168-190, wherein R6 / R22is heteroaryloxy.205. The method of Embodiment 204, wherein heteroaryloxy is C2-C5 heteroaryloxy.206. The method of Embodiment 204, wherein C2-C5 heteroaryloxy is pyridyl.207. The method of Embodiment 204, wherein the heteroaryloxy is substituted with one or more halo and acyl.208. The method of Embodiment 204, wherein acyl is C(O)OR12, wherein R12is C1-C8alkyl, C2-C5 alkyl, C1-C5 alkyl or C3-C8alkyl.209. The method of Embodiment 204, wherein R6is a heteroaryloxy group of the formula:°O N, which is optionally substituted.210. The method of any of Embodiments 168-190, wherein R6 / R22is halo.211. The method of Embodiment 210, wherein halo is Cl or F.TEC2025-0036 3000.222W01212. The method of Embodiment 211, wherein halo is Cl.213. The method of any of Embodiments 168-190, wherein R6 / R22is cyano.214. The method of any of Embodiments 168-190, wherein R5and R6or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group.215. The method of Embodiment 214, wherein the heterocyclyl group is a C3-C5 heterocyclyl group.216. The method of Embodiment 214, wherein the heterocyclyl group is a C3heterocyclyl group of the formula:>217. The method of any of Embodiments 168-216, wherein Y1is O.218. The method of any of Embodiments 168-216, wherein Y1is S.219. The method of any of Embodiments 168-218, wherein X1is N and X2is CR9.220. The method of Embodiment 219, wherein R9is H.221. The method of any of Embodiments 168-218, wherein X1is CR8and X2is N.222. The method of Embodiment 221, wherein R8is H.223. The method of any of Embodiments 168-218, wherein X1is N and X2is N.224. The method of Embodiment 168, wherein X3is S.225. The method of Embodiment 168, wherein:TEC2025-0036 3000.222W01X3is O; andTEC2025-0036 3000.222W01R1 / R18R2R5 / R21R6 / R22X1X2R3R4Cl COOEt Cl H N C H H Cl H Cl H N C H H H H Cl H N C H H Cl H H H N C H H Cl H F H N C H H Cl H OCH3H N C H H Cl H Cl H C C H H Cl H Cl H N C H H Cl H Cl H N C Me H Cl H Cl H N C H Me Cl H Cl H N C Me Me Cl H Cl H C N H H CF3H Cl H C N H H ClCl H H N C H H WCl COOEt H N C H HCl H H OPh N C H H Cl H H OCF3N C H H Cl H H OMe N C H H Cl H H r°>N CH H Cl H H t-Bu N C H H Cl COOEt H t-Bu N C H H Cl H H CN N C H H Cl H H Cl N C H H Cl H Cl t-Bu N C H HTEC2025-0036 3000.222W01226. A compound of the formula A-L-B, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a radical of a compound of any of Embodiments 1 - 167, B is a radical of a protein binding molecule; and L is linker selected from a substituted or unsubstituted, linear or branched chain comprising:(v) 1 -50 linker atoms selected from carbon, oxygen, nitrogen, sulfur, silicon, or phosphorus;(vi) optionally one or more heterocyclic or aromatic rings;(vii) optionally one or more repeating units selected from -(CH2)g-, -O-, -NH-, -C(O)-, -S-, -SO-, -SO2-, -C(O)O-, -00(0)-, -C(O)NH-, -NHC(O)-, polyethylene glycol units, alkynyl units, alkenyl units, or combinations thereof;(viii) optionally substituted with one or more substituents selected from halogen, hydroxyl, alkoxy, amino, amide, cyano, thiol, sulfonyl, heteroaryl, or aryl groups;wherein g is independently 1 -20; and wherein the total linker length corresponds to a distance sufficient to permit formation of a ternary complex between a target protein and the compound of formula A-L-B; andthe radical of a protein binding molecule is selected from:TEC2025-0036 3000.222W01TEC2025-0036 3000.222W01 oTEC2025-0036 3000.222W01s10058F4Examples of Prion Protein Binding MoietiesCompound 55HOOHnTRD22EXAMPLES

[0199] The present disclosure can be better understood by reference to the following examples which are offered by way of illustration. The disclosure is not limited to the examples given herein.Example 1: Synthesis of compounds of the disclosureTEC2025-0036 3000.222W01

[0200] FIG. 1 is a scheme showing a general synthesis of compounds disclosed herein. The key for each synthetic step in FIG. 1 is as follows:aCS2CO3(1.2 equiv.), CH3CN, 80°C, 40h (85%);bSnCI2.2H2O (5.0 equiv.), ethyl acetate (EtOAc), 70°C, 2 hours (h) (95%);cParaformaldehyde (1.5 equiv), KOH (2 equiv.), CH3OH, 65°C, 3h then NaBH4(2.0 equiv.), 0-65°C, 4h (87%);dPhCH3, room temperature (r.t.), 3 - 6 h (65% to quant.);6Triphosgene (0.37 equiv.), dichloromethane (DCM); then first aniline substrate, NEt3(2.2 equiv.), DCM over 20 min; then second aniline substrate, NEt3(2.2 equiv.), DCM, 30 min (65% to 78%);fcarbonyldiimidazole (CDI) (0.5 equiv.), tetrahydrofuran (THF), 66°C, 18h (72%);gNaH (3.0 equiv.), THF, 0°C to r.t., 1 h then Mel (3.0 equiv.), r.t., 12h (quant.)ExperimentalMaterials and Reagents

[0201] All chemical reagents and solvents were purchased from Sigma, ThermoScientific, and Oakwood chemicals unless otherwise stated. Commercially available chemical reagents were used without additional purification. Oven dried glassware were equilibrated to room temperature under the flow of nitrogen gas. Dry solvents were used for all reactions. The reactions were performed under nitrogen gas. All NMR spectra were recorded using 500 MHz instrument. Mass spectrometer with ESI ionization method, and a Quadrupole detector was used. A Jasco Series 6600 FTIR spectrometer was used for recording the Infrared spectra.General procedure for the synthesis of urea:

[0202] Procedure 1: The corresponding isocyanate (1.2 equiv.) was added to a mixture of amine / aniline (1.0 equiv.) in toluene (2 ml). The mixture stirred at room temperature under N2atmosphere until completion. The reaction mixture was then filtered using vacuum filtration. The residue on the filter paper was dried under vacuum pump to give a white solid without further purification.

[0203] Procedure 2: A mixture of the first aniline substrate (1 equiv.) and triethyl amine (2.2 equiv.) in (3 ml) dichloromethane was slowly added to a stirring solution of triphosgene (0.37 equiv.) in dichloromethane (2 ml) over 20 minutes. The solution was stirred for 5 more minutes before a mixture of the second aniline substrate (1 equiv.) and triethyl amine (2.2 equiv.) in dichloromethane (2ml) was added. The reaction mixture was allowed to stir for 30 minutes. After evaporating the solvent under vacuo, the concentrate was redissolved in ethyl acetate (15 ml) and washed with 10 ml of a 5% aqueous solution of sodium bicarbonate (NaHCO3). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica columnTEC2025-0036 3000.222WO1chromatography to give a white solid.Synthesis of 2-((5-chloropyridin-3-yl) oxy)-5-nitrobenzoic acid (Compound 1a)

[0204] A mixture of 2-chloro-5-nitrobenzoic acid (0.20 g, 1 mmol), 5-chloropyridin-3-ol (0.13 g, 1 mmol) and cesium carbonate (0.72 g, 2.2 mmol) in acetonitrile (3 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The reaction mixture was then cooled to room temperature. The solvent was evaporated. 10 ml water was added, and the pH was adjusted to 2.0 using 1N HCI. The product and unreacted starting materials were extracted using (3x15) ml I ethyl acetate. The organic layer was washed with brine once (20 ml) and dried over sodium sulfate. The solvent was concentrated in vacuo. The product was crystallized using ethyl acetate.COOHY N J T ^J^LNO2

[0205] Pink solid (70%). M. P: 211-213°C;1H NMR (500 MHz, DMSO-d6) 0 13.74 (s, 1 H), 8.64 (d, J = 3.0 Hz, 1 H), 8.51 (d, J = 2.2 Hz, 1 H), 8.41 (dd, J = 9.8, 2.5 Hz, 2H), 7.81 (t, J = 2.2 Hz, 1 H), 7.36 (d, J = 9.8 Hz, 1 H).13C{1H} NMR (125 MHz, DMSO-d6) 5 164.40, 159.14, 152.93, 143.96, 143.40, 139.39, 131.49, 129.03, 127.31, 126.13, 124.42, 121.46; FTIR (cm1): 3109, 3070, 1696; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C12H8ClN2O5295.0122; Found 295.0122.Synthesis of ethyl 2-((5-chloropyridin-3-yl) oxy)-5-nitrobenzoate (Compound 1 b)

[0206] To a solution of 2-((5-chloropyridin-3-yl) oxy)-5-nitrobenzoic acid (Compound 1 a) (1 equiv.) in ethanol was added SOCI2(2.5 equiv.) dropwise. The solution was stirred in reflux condition for 24 hours under N2atmosphere. The reaction mixture was then cooled to room temperature. The solvent was evaporated. 10 ml water was added, and the pH was adjusted between 7-8 using aqueous solution of sodium bicarbonate. The product was extracted using (3x15) ml ethyl acetate. The organic layer was washed with brine once (20 ml) and dried over sodium sulfate. The solvent was concentrated on vacuo. The product was isolated without no further purification as a brownish solid.COOEt

[0207] Brownish solid (76%). M. P: 44-46°C;1H NMR (500 MHz, DMSO-d6) 5 8.65 (d, J = 2.9 Hz, 1 H), 8.51 (d, J = 2.2 Hz, 1 H), 8.46 (dd, J = 9.1, 2.9 Hz, 1 H), 8.43 (d, J= 2.2 Hz, 1 H), 7.81 (t, J = 2.2 Hz, 1 H), 7.42 (d, J = 9.1 Hz, 1 H), 4.27 (q, J = 7.1TEC2025-0036 3000.222WO1Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).13C{1H} NMR (125 MHz, DMS0-d6) 5 162.80, 158.88, 152.92, 143.99, 143.50, 139.23, 131.51, 129.42, 127.18, 125.94, 123.47, 121.74, 61.77, 13.84; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C14H12ClN2O5323.0435; Found 323.0468.Synthesis of ethyl 5-amino-2-((5-chloropyridin-3-yl) oxy) benzoate (Compound 1c)

[0208] A solution of ethyl 2-((5-chloropyridin-3-yl) oxy)-5-nitrobenzoate (Compound 1b) (1.25 g, 5 mmol) in ethyl acetate (10 ml) was prepared. Tin chloride dihydrate (4.74 g, 25 mmol) was added to the solution. The solution was then heated and stirred at 70°C for 2 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml). The pH of the solution was adjusted between 6-7 using 10% sodium hydroxide solution (added dropwise until the desired pH). The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 70:30) and gave 95% yield after multiple rinsing with diethyl ether and drying under the vacuum pump.COOEt

[0209] Brown solid (95%). M. P: 110-113°C;1H NMR (500 MHz, DMSO-d6) 5 8.27 (d, J = 2.2 Hz, 1 H), 8.15 (d, J = 2.2 Hz, 1 H), 7.20 (t, J = 2.2 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 6.84 (dd, J = 8.6, 2.8 Hz, 1 H), 5.49 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 5 173.92, 164.68, 156.37, 146.99, 141.73, 140.76, 136.79, 130.98, 124.04, 121.84, 119.06, 115.41, 60.62, 13.75; FTIR (cm1): 3087, 2985, 1723; HRMS (ESI / Q-TOF) m / z:[M + H]+Calculated for C14H14CIN2O3293.0693; Found 293.0732.Synthesis of ethyl 5-(3-(3-chlorophenyl) ureido)-2-((5-chloropyridin-3-yl) oxy) benzoate (Compound 1)

[0210] Following procedure 1 for urea synthesisCOOEt

[0211] White solid (quant.). M. P: 162-163°C;1H NMR (500 MHz, DMSO-d6) 5 9.15 (s, 1 H), 8.99 (s, 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.22 (d, J = 2.2 Hz, 1 H), 8.10 (d, JTEC2025-0036 3000.222W01= 2.6 Hz, 1 H), 7.73 - 7.71 (m, 2H), 7.36 - 7.27 (m, 4H), 7.04 (dt, J = 6.7, 2.6 Hz, 1 H), 4.17 (q, J = 7.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 5 164.21, 155.57, 152.44, 146.88, 141.51, 141.08, 137.41, 137.16, 133.22, 131.15, 130.47, 124.24, 124.01, 123.75, 122.63, 121.75, 120.93, 117.82, 116.93, 61.05, 13.78; FTIR (cm1): 3924, 1725; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C21H18Cl2N3O4446.0674; Found 446.0678.Synthesis of 3-chloro-5-(4-nitrophenoxy) pyridine (Compound 2a)

[0212] A mixture of 1-chloro-4-nitrobenzene (1.58 g, 10 mmol), 5- chloropyridin-3-ol (1.30 g, 10 mmol) and cesium carbonate (3.91 g, 12 mmol) in acetonitrile (15 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml) to get rid of the inorganic impurities. The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 80:20) to give 85% yield.

[0213] Light yellow solid (85%). Rf: 0.59 (EtOAc: Hexane 3:10); M. P: 81-83°C;1H NMR (500 MHz, DMSO-d6) 58.58 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.5 Hz, 1 H), 8.29 - 8.26 (m, 2H), 7.97 - 7.96 (m, 1 H), 7.30 - 7.27 (m, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 0161.57, 151.59, 144.94, 143.17, 140.74, 131.57, 128.00, 126.31, 118.24, FTIR (cm-1): 3060, 1486, 1339; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C11H8ClN2O3251.0223; Found 251.0231.Synthesis of 4-((5-chloropyridin-3-yl) oxy) aniline (Compound 2b)

[0214] A solution of 3-chloro-5-(4-nitrophenoxy) pyridine (Compound 2a) (1.25 g, 5 mmol) in ethyl acetate (10 ml) was prepared. Tin chloride dihydrate (4.74 g, 25 mmol) was added to the solution. The solution was then heated and stirred at 70°C for 2 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml). The pH of the solution was adjusted between 6-7 using 10% sodium hydroxide solution (added dropwise until the desired pH). The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 70:30) and gave 80% yield after multiple rinsing with diethyl ether and drying under the vacuum pump.TEC2025-0036 3000.222W01

[0215] Orange solid (95%). Rf: 0.31 (EtOAc: Hexane 4:10); M. P: 40-44°C;1H NMR (500 MHz, DMSO-d6) 0 8.30 - 8.29 (m, 1 H), 8.23 - 8.22 (m, 1 H), 7.31 - 7.30 (m, 1 H), 6.87-6.84 (m, 2H), 6.63 - 6.60 (m, 2H), 5.13 (s, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 5 155.90, 146.50, 144.06, 141.23, 137.58, 131.09, 122.78, 121.02, 114.94; FTIR (cm1): 3417, 3379, 3297, 3068; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C11H10ClN2O 221.0482; Found 221.0490.Synthesis of 1-(3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 2)

[0216] Following procedure 1 for urea synthesis

[0217] White solid (91%). Rf: 0.21 (EtOAc: Hexane 4:10); M. P: 189-191 °C;1H NMR (500 MHz, DMSO-d6) 0 8.91 (s, 1 H), 8.85 (s, 1 H), 8.38 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 2.4 Hz, 1 H), 7.71 (t, J = 2.0 Hz, 1 H), 7.54 - 7.52 (m, 2H), 7.51 (t, J=2.0 Hz, 1 H), 7.30 (t, J=8.3 Hz, 1 H), 7.28 (dt,3J= 8.3,4J= 2 Hz,1 H), 7.13 - 7.10 (m, 2H), 7.03 (dt,3J= 7.5,4J= 2 Hz,1 H).13C{1H} NMR (125 MHz, DMSO-d6) 0 154.67, 152.44, 149.45, 142.27, 141.26, 138.41, 136.51, 133.20, 131.23, 130.43, 124.26, 121.48, 120.24, 120.19, 117.58, 116.69; FTIR (cm1): 3265, 3062, 1642; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H14Cl2N3O2374.0463; Found 374.0475.Synthesis of 3-(4-nitrophenoxy) pyridine (Compound 3a)

[0218] A mixture of 1 -chloro-4-nitrobenzene (1.58 g, 10 mmol), pyridin-3-ol (0.95 g, 10 mmol) and cesium carbonate (3.91 g, 12 mmol) in acetonitrile (15 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The solvent was evaporated. 15 ml water was added to dissolve the inorganic cesium carbonate. The product and remained starting materials were extracted using (3x15) ml ethyl acetate. The organic layer was washed with brine once (20 ml) and dried over sodium sulfate. The solvent was concentrated on vacuo. The product was achieved after purification using silica column chromatography (hexane / ethyl acetate 80:20) to give 85% yield.N °ONNOO?

[0219] Orange solid (85%). M. P: 108-110°C;1H NMR (500 MHz, DMSO-d6) 0 8.54 - 8.52 (m, 2H), 8.29 - 8.26 (m, 2H), 7.71 - 7.69 (ddd, J = 8.4, 2.9, 1.3 Hz, 1 H),TEC2025-0036 3000.222W017.55 (dd, J = 8.4, 4.7 Hz, 1 H), 7.24 -7.17 (m, 2H).13C{1H} NMR (125 MHz, DMS0-d6) 5 162.25, 151.17, 146.56, 142.75, 142.49, 128.13, 126.31, 125.16, 117.69; FTIR (cnr1): 3112, 3064, 1488, 1337; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C11H9N2O3217.0613; Found 217.0614.Synthesis of 4-(pyridin-3-yloxy) aniline (Compound 3b)

[0220] A solution of 3-(4-nitrophenoxy) pyridine (Compound 3a) (1.08 g, 5 mmol) in ethyl acetate (10 ml) was prepared. Tin chloride dihydrate (4.74 g, 25 mmol) was added to the solution. The solution was then heated and stirred at 70°C for 2 hours under N2atmosphere. The reaction mixture was then cooled to room temperature. The reaction mixture was concentrated under the vacuo and redissolved in water (20 ml). The pH of the solution was adjusted between 6-7 using 10% sodium hydroxide solution (added dropwise until the desired pH). The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 70:30) and gave 95% yield after drying under the vacuum pump.

[0221] Orange solid (95%). M. P: 106-108°C;1H NMR (500 MHz, DMSO-d6) 5 8.25 - 8.22 (m, 2H), 7.33 (dd, J = 8.4, 4.6 Hz, 1 H), 7.21 (ddd, J = 8.4, 2.9, 1.4 Hz, 1 H), 6.82 - 6.79 (m, 2H), 6.61 - 6.58 (m, 2H), 5.06 (s, 2H).13C{1H} NMR (125 MHz, DMSO- d6) 5 155.38, 146.02, 144.77, 142.93, 139.21, 124.39, 123.10, 120.85, 114.91; FTIR (cm1): 3382, 3272, 3051; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C11H11N2O 187.0871; Found 187.0877.Synthesis of 1-(3-chlorophenyl)-3-(4-(pyridin-3-yloxy) phenyl) urea (Compound 3)

[0222] Following procedure 1 for urea synthesis

[0223] White solid (quant.). M. P: 141 -143°C;1H NMR (500 MHz, DMSO-d6) 5 8.90 (s, 1 H), 8.82 (s, 1 H), 8.34 - 8.31 (m, 2H), 7.70 (t, J = 2.1 Hz, 1 H), 7.50 - 7.48 (m, 2H), 7.39 - 7.26 (m, 4H), 7.05 - 7.01 (m, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 5 154.15, 152.47, 150.22, 143.97, 141.31, 140.20, 135.96, 133.21, 130.43, 124.62, 124.58, 121.45, 120.23, 119.82, 117.56, 116.67; FTIR (cm1): 3278, 3039, 1670; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H15CIN3O2 340.0853; FoundTEC2025-0036 3000.222W01340.0855.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-phenylurea (Compound 4)

[0224] Following procedure 1 for urea synthesisH HhL0O

[0225] White solid (quant.). M. P: 183-186°C;1H NMR (500 MHz, DMSO-d6) 0 8.77 (s, 1 H), 8.68 (s, 1 H), 8.38 (d, J = 2.2 Hz, 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 7.53 - 7.49 (m, 3H), 7.46 - 7.44 (m, 2H), 7.29 - 7.26 (m, 2H), 7.12 - 7.10 (m, 2H), 6.98 - 6.96 (m, 1 H).13C{1H} NMR (125 MHz, DMSO-d6) 0 154.75, 152.59, 149.18, 142.21, 139.68, 138.37, 136.87, 131.23, 128.83, 124.17, 121.88, 120.24, 119.99, 118.23; FTIR (cm1): 3318, 3042, 1647; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H15CIN3O2 340.0853; Found 340.0872.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(3-fluorophenyl) urea (Compound 5)

[0226] Following procedure 1 for urea synthesisH H ISL. NOO

[0227] White solid (quant.). M. P: 185-188°C;1H NMR (500 MHz, DMSO-d6) 0 8.95 (s, 1 H), 8.86 (s, 1 H), 8.39 (d, J = 2.3 Hz, 1 H), 8.34 (d, J = 2.3 Hz, 1 H), 7.54 - 7.48 (m, 5H), 7.31 - 7.28 (q, J = 8.2 Hz, 1 H), 7.13 - 7.11 (m, 3H), 6.78 (td, J = 8.2, 2.6 Hz, 1 H).13C{1H} NMR (125 MHz, DMSO-d6) 163.37 (d, J= 239 Hz, CF), 154.69, 152.46, 149.42, 142.26, 141.64, 141.54, 138.41, 136.54, 131.24, 130.40 (d, J= 10 Hz, CCCF), 124.25, 120.21, 113.96, 108.25 (d, J= 20 Hz, CCF), 104.97 (d, J= 26.2 Hz, CCF); FTIR (cm-1): 3287, 3028, 1642; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H14ClFN3O2358.0759; Found 358.0771.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(3-methoxyphenyl) urea (Compound 6)

[0228] Following procedure 1 for urea synthesisH H ISL ^. N.0.OO

[0229] White solid (quant.). M. P: 188-190°C;1H NMR (500 MHz, DMSO-d6) 0 8.75 (S, 1 H), 8.69 (s, 1 H), 8.38 (d, J = 2.2 Hz, 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 7.53 - 7.49TEC2025-0036 3000.222W01(m, 3H), 7.19 - 7.16 (m, 2H), 7.12 - 7.09 (m, 2H), 6.94 (dd, J = 8.2, 2.2 Hz, 1 H), 6.55 (dd, J = 8.2, 2.2 Hz, 1 H), 3.73 (s, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 6 159.70, 154.74, 152.52, 149.22, 142.22, 140.90, 138.36, 136.78, 131.23, 129.58, 124.17, 120.22, 120.06, 110.54, 107.25, 103.99, 54.94; FTIR (cm1): 3318, 1646; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H17CIN3O3370.0959; Found 370.0972.Synthesis of 1-chloro-3-(4-nitrophenoxy) benzene (Compound 7a)

[0230] A mixture of 1-chloro-4-nitrobenzene (1.58 g, 10 mmol), 3-chlorophenol (1.30 g, 10 mmol) and cesium carbonate (3.91 g, 12 mmol) in acetonitrile (15 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml) to get rid of the inorganic impurities. The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 80:20) to give 85% yield.T T T 1

[0231] White solid (85%). M. P: 55-56°C;1H NMR (500 MHz, DMSO-d6) 58.29 - 8.25 (m, 2H), 7.52 (t, J = 8.1 Hz, 1 H), 7.38 - 7.34 (m, 2H), 7.20 - 7.17 (m, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 0 162.14, 155.39, 142.74, 134.37, 131.95, 126.28, 125.49, 120.59, 119.15, 117.98; FTIR (cm1): 3074; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C12H9CINO3250.0271; Found 250.0331.Synthesis of 4-(3-chlorophenoxy) aniline (Compound 7b)

[0232] A solution of 1 -chloro-3-(4-nitrophenoxy) benzene (Compound 7a) (1.25 g, 5 mmol) in ethyl acetate (10 ml) was prepared. Tin chloride dihydrate (4.74 g, 25 mmol) was added to the solution. The solution was then heated and stirred at 70°C for 2 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml). The pH of the solution was adjusted between 6-7 using 10% sodium hydroxide solution (added dropwise until the desired pH). The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 70:30) and gave 80% yield after multiple rinsing with diethyl ether and drying under the vacuum pump.TEC2025-0036 3000.222WO1

[0233] White solid (95%). M. P: 36-39°C;1H NMR (500 MHz, DMSO-d6) 67.33 - 7.30 (m, 1 H), 7.06 - 7.05 (m, 1 H), 6.83 - 6.78 (m, 4H), 6.61 - 6.59 (m, 2H), 5.07 (s, 2H);13C{'H} NMR (125 MHz, DMSO-d6) 5 160.21, 146.12, 144.51, 133.75, 131.20, 121.60, 121.29, 115.99, 115.02, 114.89; FTIR (cm1): 3404, 3329, 3229, 3065; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C12H11ClNO 220.0529; Found 220.0541. Synthesis of 1-(4-(3-chlorophenoxy) phenyl)-3-(3-chlorophenyl) urea (Compound 7)

[0234] Following procedure 1 for urea synthesis

[0235] White solid (quant.). M. P: 165-166°C;1H NMR (500 MHz, DMSO-d6) 0 8.90 (S, 1 H), 8.82 (s, 1 H), 7.71 - 7.70 (m, 1 H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 8.2 Hz, 1 H), 7.31 - 7.25 (m, 2H), 7.15 (d, J = 8.2 Hz, 1 H), 7.05 - 6.97 (m, 4H), 6.91 (dd, J = 8.2, 2.5 Hz, 1 H);13C{1H} NMR (125 MHz, DMSO-d6) 5 158.91, 152.48, 149.88, 141.31, 136.12, 133.93, 133.22, 131.43, 130.45, 122.64, 121.47, 120.41, 120.24, 117.58, 117.23, 116.68, 116.05; FTIR (cm1): 3924, 1641; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H15Cl2N2O2373.0511; Found 373.0524.Synthesis of 1-(3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) thiourea (Compound 8)

[0236] Following procedure 1 for urea synthesisH H

[0237] White solid (quant.). M. P: 114-116°C;1H NMR (500 MHz, DMSO-d6) 5 10.01 (s, 1 H), 9.91 (s, 1 H), 8.42 (d, J = 2.2 Hz, 1 H), 8.35 (d, J = 2.2 Hz, 1 H), 7.67 (t, J = 2.0 Hz, 1 H), 7.58 (t, J = 2.2 Hz, 1 H), 7.57 - 7.50 (m, 2H), 7.40 (dt, J = 7.9, 1.6 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.25 (d, J = 7.9 Hz, 1 H), 7.15- 7.12 (m, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 0 179.76, 154.15, 151.92, 142.70, 141.05, 138.83, 135.91, 132.53, 131.27, 130.06, 125.99, 124.91, 124.08, 123.09, 122.05, 119.52; FTIR (cm1): 3130, 2959; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H14Cl2N3OS 390.0235; Found 390.0242.Synthesis of 4-((5-chloropyridin-3-yl) oxy)-N-methylaniline (Compound 9a)

[0238] Paraformaldehyde (225 mg, 7.5 mmol) was first added to methanol (10TEC2025-0036 3000.222W01ml), followed by that, potassium hydroxide (561 mg, 10 mmol) was added to the suspension. Then, 4-((5-chloropyridin-3-yl) oxy) aniline (BG-2-10) (1.10 g, 5 mmol) was added to the prepared solution. The solution was stirred and heated at 65°C for 3 hours. The reaction mixture was cooled down to room temperature then to 0°C using an ice bath. Sodium borohydride (76 mg, 10 mmol) was added gradually to the mixture. The reaction temperature increased back to 65°C and stirred for 4 more hours. The mixture was then concentrated in vacuo. The concentrate was redissolved in water (20 ml). The water layer was washed with ethyl acetate (3x20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 80:20) to give 87% yield.H

[0239] Brownish oil (87%). Rf: 0.55 (EtOAc: Hexane 4:10);1H NMR (500 MHz, DMSO-d6) 0 8.30 (d, J = 2.2 Hz, 1 H), 8.24 (d, J = 2.2 Hz, 1 H), 7.31 - 7.30 (m, 1 H), 6.96 - 6.93 (m, 2H), 6.60 - 6.57 (m, 2H), 5.74 (q, J = 5.1 Hz, 1 H), 2.67 (d, J = 5.1 Hz, 3H).13C{'H} NMR (125 MHz, DMSO-d6) 0 155.92, 147.73, 143.99, 141.27, 137.59, 131.10, 122.80, 121.10, 112.58, 29.98; FTIR (cnr1): 3422, 3332, 3043; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C12H12CIN2O 235.0638; Found 235.0644.Synthesis of 3-(3-chlorophenyl)-1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-1-methylurea (Compound 9)

[0240] Following procedure 1 for urea synthesis

[0241] White solid (84%). Rf: 0.24 (EtOAc: Hexane 3:10); M. P: 114-117°C;1H NMR (500 MHz, DMSO-d6)1H NMR (500 MHz, DMSO-d6) 08.43 (d, J = 2.3 Hz, 1 H), 8.41 (d, J = 2.3 Hz, 1 H), 8.31 (s, 1 H), 7.66 (t, J = 2.3 Hz, 1 H), 7.63 (t, J = 2.1 Hz, 1 H), 7.43 - 7.39 (m, 3H), 7.24 (t, J = 8.0 Hz, 1 H), 7.22 - 7.19 (m, 2H), 7.00 (ddd, J = 8.0, 2.1, 0.9 Hz, 1 H), 3.26 (s, 3H);,3C{1H} NMR (125 MHz, DMSO-d6) 5 154.41, 154.21, 153.06, 142.72, 141.73, 140.18, 138.87, 132.68, 131.31, 129.91, 128.78, 124.89, 121.58, 120.43, 119.17, 118.08, 37.66; FTIR (cnr1): 3348, 3053, 1660; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H16CI2N3O2388.0620; Found 388.0633.Synthesis of 3-chloro-N-methylaniline (Compound 10a)

[0242] Paraformaldehyde (225 mg, 7.5 mmol) was first added to methanol (10TEC2025-0036 3000.222W01ml). Followed by that, potassium hydroxide (561 mg, 10 mmol) was added to the suspension. 3-chloroaniline (638 mg, 5 mmol) was added to the prepared solution. The solution was stirred and heated at 65°C for 3 hours. The reaction mixture was cooled down to room temperature then to 0°C using an ice bath. Sodium borohydride (76 mg, 10 mmol) was added gradually to the mixture. The reaction temperature increased back to 65°C and stirred for 4 more hours. The mixture was then concentrated in vacuo. The concentrate was redissolved in water (20 ml). The water layer was washed with ethyl acetate (3x20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 80:20) to give 85% yield.1H

[0243] Colorless liquid (85%). Rf: 0.78 (EtOAc: Hexane 4:10);1H NMR (500 MHz, DMSO-d6) 57.08 - 7.04 (m, 1 H), 6.52 - 6.50 (m, 2H), 6.48 - 6.46 (m, 1 H), 5.99 (q, J = 5.0 Hz, 1 H), 2.65 (d, J = 5.0 Hz, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 5 151.34, 133.68, 130.31, 114.72, 110.53, 110.43, 29.48; FTIR (cm1): 3425, 3080; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C7HgCIN 142.0424; Found 142.0428.N-(3-chlorophenyl)-N-methyl-1H-imidazole-1 -carboxamide (Compound 10b)

[0244] N, N’-Carbonyl diimidazole (1.78 g, 11 mmol) was added to a solution of 3-chloro-N-methylaniline (Compound 10a) (708 mg, 5 mmol) in THF (10 ml). The reaction mixture was heated and stirred at 66°C for 48 hours under N2atmosphere. The reaction mixture was concentrated in the vacuo. The concentrate was redissolved in water (20 ml) and extracted with ethyl acetate (3x20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate and concentrated to give the carbamoyl imidazole product in 92% yield without further purification.CI^ 1^ 1N^ AN^Me l=ss /

[0245] Yellowish oil (92%).1H NMR (500 MHz, DMSO-d6) 0 7.70 (t, J = 1.2 Hz, 1 H), 7.50 (m, 1 H), 7.39 - 7.38 (m, 2H), 7.26-7.24 (m, 1 H), 7.05 (t, J = 1.2 Hz, 1 H), 6.82 (dd, J = 1.6, 0.9 Hz, 1 H), 3.39 (s, 3H).

[0246] 1H NMR (500 MHz, CDCI3) 0 7.61 (t, J = 1.1 Hz, 1 H), 7.30 - 7.27 (m, 2H), 7.19 - 7.14 (m, 1 H), 6.97 (m, 1 H), 6.88 - 6.82 (m, 2H), 3.46 (s, 3H);13C{1H} NMR (125 MHz, CDCh) 0 150.17, 144.20, 137.70, 135.88, 131.29, 129.44, 128.37, 126.16, 124.23, 118.40, 77.41, 77.16, 76.91, 40.19; FTIR (cm1): 3017, 1696; HRMS (ESI / Q-TEC2025-0036 3000.222W01TOF) m / z: [M + H]+Calculated for C11H11ClN3O 236.0591; Found 236.0598.Synthesis of 1-(3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl)-1-methylurea (Compound 10)

[0247] Following procedure 2 for urea synthesis

[0248] White solid (65%). M. P: 162-163°C;1H NMR (500 MHz, DMSO-d6) 0 8.52 (s, 1 H), 8.37 (d, J = 2.2 Hz, 1 H), 8.30 (d, J = 2.2 Hz, 1 H), 7.53 - 7.50 (m, 2H), 7.48 (t, J = 2.2 Hz, 1 H), 7.45 (t, J = 2.0 Hz, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.31 - 7.27 (m, 2H), 7.08 - 7.05 (m, 2H), 3.29 (s, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 0 154.67, 154.62, 149.62, 145.58, 142.25, 138.44, 137.07, 133.15, 131.22, 130.61, 126.00, 125.41, 124.65, 124.29, 121.89, 119.63, 37.40; FTIR (cm1): 3222, 3051, 1654; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H16CI2N3O2 388.0620; Found 388.0640.Synthesis of 1-(3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl)-1,3-dimethylurea (Compound 11)

[0249] 1-(3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (0.75 g, 2 mmol) was dissolved in THF (4 ml). The temperature of the prepared suspension was decreased to 0 °C. Then, sodium hydride (0.24 g, 6 mmol) was added to the suspension. The reaction temperature was increased to room temperature and stirred for 1 hour. Methyl iodide (374 jxl, 6 mmol) was then added. The mixture stirred at room temperature overnight for 12 hours under N2atmosphere. The reaction mixture was then quenched with ice cold water (20 ml) and ammonium chloride (20 ml). The product was extracted from the aqueous phase using ethyl acetate (3x 30 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate and concentrated to give a white solid powder.I I

[0250] White solid (quant.). M. P: 102-104°C;1H NMR (500 MHz, DMSO-d6) 5 8.40 (d, J = 2.2 Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 7.32 (t, J = 2.2 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7.03-7.01 (m, 1 H), 7.00 - 6.97 (m, 3H), 6.92 - 6.89 (m, 3H), 3.16 (s, 3H), 3.13 (s, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 5 159.05, 154.28, 151.31, 146.47, 142.46, 141.74, 138.39, 132.82, 131.22, 130.03, 126.93, 124.39, 123.99, 123.82, 122.96, 119.93, 38.77, 38.31. FTIR (cm1): 3065, 3053, 2915, 1656; HRMS (ESI / Q-TEC2025-0036 3000.222WO1TOF) m / z: [M + H]+Calculated for C20H18CI2N3O2402.0776; Found 402.0819.Synthesis of 4-((4-chloropyridin-2-yl) oxy) aniline (Compound 12a)

[0251] A mixture of 4-aminophenol (1.09 g, 10 mmol), 2,4-dichloropyridine (1.48 g, 10 mmol) and cesium carbonate (3.91 g, 12 mmol) in acetonitrile (15 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The solvent was evaporated. 15 ml water was added to dissolve the inorganic cesium carbonate. The product and remained starting materials were extracted using (3x15) ml ethyl acetate. The organic layer was washed with brine once (20 ml) and dried over sodium sulfate. The solvent was concentrated on vacuo. The product was achieved after purification using silica column chromatography (hexane / ethyl acetate 70:30).

[0252] Pink solid (87%). M. P: 84-85°C;1H NMR (500 MHz, DMSO-d6) 5 8.24 (d, J = 5.7 Hz, 1 H), 6.88 - 6.84 (m, 4H), 6.64 - 6.61 (m, 2H), 5.20 (s, 2H).13C{1H} NMR (125 MHz, DMSO-d6) 5 167.47, 151.43, 151.09, 147.05, 142.60, 121.47, 114.84, 111.13, 110.80; FTIR (cm1): 3450, 3342, 3327, 3090; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C11H10ClN2O 221.0482; Found 221.0484.Synthesis of 1-(3-chlorophenyl)-3-(4-((4-chloropyridin-2-yl) oxy) phenyl) urea (Compound 12)

[0253] Following procedure 1 for urea synthesis

[0254] White solid (quant.). M. P: 165-170°C;1H NMR (500 MHz, DMSO-d6) 5 8.94 (d, J = 10.2 Hz, 2H), 8.29 (d, J = 5.7 Hz, 1 H), 7.71 (t, J = 1.9 Hz, 1 H), 7.58 - 7.56 (m, 2H), 7.31 - 7.28 (m, 2H), 7.18 - 7.16 (m, 2H), 7.02 (dt, J = 7.4, 1.9 Hz, 1 H), 6.96 - 6.92 (m, 2H).13C{1H} NMR (125 MHz, DMSO-d6) 5 166.62, 152.43, 151.55, 151.29, 147.44, 141.22, 137.43, 133.22, 130.45, 121.55, 121.37, 120.20, 117.62, 116.73, 111.42, 111.34; FTIR (cm1): 3319, 3087, 1699; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H14Cl2N3O2374.0463; Found 374.0455.Synthesis of 4-((4-(trifluoromethyl) pyridin-2-yl) oxy) aniline (Compound 13a)

[0255] A mixture of 4-aminophenol (1.09 g, 10 mmol), 2-chloro-4-(trifluoromethyl) pyridine (1.82 g, 10 mmol) and cesium carbonate (3.91 g, 12 mmol) in acetonitrile (15 ml) was heated and stirred at 80°C for 40 hours under N2atmosphere. The reaction mixture was then cooled to room temperature, concentrated under the vacuo, and redissolved in water (20 ml) to get rid of the inorganic impurities.TEC2025-0036 3000.222W01The water layer was washed with ethyl acetate (3 x 20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate, and concentrated in vacuo. The concentrate was purified using silica column chromatography (hexane / ethyl acetate 70:30) and gave a light-yellow solid after multiple rinsing with diethyl ether.

[0256] Light yellow solid (80%). Rf: 0.19 (EtOAc: Hexane 3:10); M. P: 78-80°C;1H NMR (500 MHz, DMSO-d6) 5 8.38 (d, J = 5.3 Hz, 1 H), 7.41 - 7.40 (m, 1 H), 7.23 -7.22 (m, 1 H), 6.85 - 6.82 (m, 2H), 6.61 - 6.58 (m, 2H), 5.06 (s, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 6 164.74, 149.52, 146.34, 142.95, 140.39 (q, J= 33.3 Hz, CCF3), 125.91 (q, J= 273.7 Hz, CF3), 121.97, 114.52, 113.59 (q, J=3.3 Hz, CCCF3), 106.78 (q, J= 4.1 Hz, CCCF3); FTIR (cm1): 3476, 3452, 3351, 3089; HRMS (ESI / Q-TOF) m / z:[M + H]+Calculated for C12H10F3N2O 255.0745; Found 255.0783.Synthesis of 1-(3-chlorophenyl)-3-(4-((4-(trifluoromethyl) pyridin-2-yl) oxy) phenyl) urea (Compound 13)

[0257] Following procedure 1 for urea synthesis

[0258] White solid (92%). Rf: 0.33 (EtOAc: Hexane 4:10); M. P: 206-208°C;1H NMR (500 MHz, DMSO-d6) 5 8.91 (s, 1 H), 8.82 (s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 7.72 (t, J = 2.0 Hz, 1 H), 7.51 - 7.47 (m, 2H), 7.46 (dd, J = 5.2, 1.5 Hz, 1 H), 7.41 (d, J = 1.5 Hz, 1 H), 7.30- 7.28 (m, 2H), 7.14 - 7.12 (m, 2H), 7.02 (dt, J = 7.3, 2.0 Hz, 1 H);13C{1H} NMR (125 MHz, DMSO-d6) 0 164.03, 152.49, 149.43, 147.67, 141.32, 140.37 (q, J= 32.8 Hz, C-CF3), 136.61, 133.22, 130.42, 125.89 (q, J= 274.0 Hz, CF3), 121.95, 121.45, 119.80, 117.56, 116.66, 114.13 (q, J= 3.2 Hz, C-C-CF3), 107.55 (q, J= 4.4 Hz, C-C-CF3); FTIR (cm1): 3328, 3276, 3082, 1651; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H14ClF3N3O2408.0727; Found 408.0740.Synthesis of 1,3-bis(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 14)

[0259] N, N’-Carbonyl diimidazole (0.41 g, 2.5 mmol) was added to a solution of 4-((5-chloropyridin-3-yl) oxy) aniline (Compound 2b) (1.10 g, 5 mmol) in THF (6 ml). The reaction mixture was heated and stirred at 66°C for 18 hours under N2atmosphere. The reaction mixture was concentrated in vacuo. The concentrate was redissolved in water (20 ml) and extracted with ethyl acetate (3x20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate andTEC2025-0036 3000.222W01concentrated. A white solid was isolated after subjecting the concentrate to silica column chromatography.

[0260] White solid (72%). M. P: 177-180°C;1H NMR (500 MHz, DMSO-d6) 0 8.79 (s, 2H), 8.38 (d, J = 2.2 Hz, 2H), 8.31 (d, J = 2.2 Hz, 2H), 7.57 - 7.48 (m, 6H), 7.15 - 7.08 (m, 4H).13C{1H} NMR (125 MHz, DMSO-d6) 0 154.74, 152.64, 149.22, 142.22, 138.37, 136.82, 131.23, 124.18, 120.24, 120.05; FTIR (cm-1): 3303, 1633; HRMS (ESI / Q-TOF) m / z: [M + H]+ Calculated for C23H17CI2N4O3 467.0678; Found 467.0743.Synthesis of diethyl 5,5'-(carbonylbis (azanediyl)) bis(2-((5-chloropyridin-3-yl) oxy) benzoate) (Compound 15)

[0261] N, N’-Carbonyl diimidazole (0.41 g, 2.5 mmol) was added to a solution of ethyl 5-amino-2-((5-chloropyridin-3-yl) oxy) benzoate (Compound 1b) (1.10 g, 5 mmol) in THF (6 ml). The reaction mixture was heated and stirred at 66°C for 18 hours under N2atmosphere. The reaction mixture was concentrated in vacuo. The concentrate was redissolved in water (20 ml) and extracted with ethyl acetate (3x20 ml). The organic layers were combined, washed with brine once (20 ml), dried over sodium sulfate and concentrated. A white solid was isolated after subjecting the concentrate to silica column chromatography.COOEt COOEt

[0262] White solid (72%). M. P: 180-186°C;1H NMR (500 MHz, DMSO-d6) 5 9.13 (s, 2H), 8.34 (d, J = 2.3 Hz, 2H), 8.23 (d, J = 2.3 Hz, 2H), 8.12 (d, J = 2.8 Hz, 2H), 7.76 (dd, J = 8.8, 2.8 Hz, 2H), 7.36 (t, J = 2.3 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 4.17 (q, J = 7.1 Hz, 4H), 1.07 (t, J = 7.1 Hz, 6H).13C{1H} NMR (125 MHz, DMSO-d6) 5 164.22, 155.56, 152.58, 146.87, 141.50, 137.44, 137.15, 131.14, 124.32, 124.00, 123.75, 122.61, 121.01, 61.04, 13.78; FTIR (cm-1): 3312, 2983, 1731; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C29H25CI2N4O7611.1100; Found 611.1111.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(4-phenoxyphenyl) urea (Compound 16)

[0263] Following procedure 1 for urea synthesisTEC2025-0036 3000.222W01

[0264] White solid (quant.). M. P: 182-184°C;1H NMR (500 MHz, DMSO-d6) 5 8.76 (s, 1 H), 8.71 (s, 1 H), 8.38 (s, 1 H), 8.31 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.49 -7.47 (m, 3H), 7.36 (t, J = 8.0 Hz, 2H), 7.12 -7.07 (m, 3H), 6.99 - 6.95 (m, 4H).13C{1H} NMR (125 MHz, DMSO-d6) 6 157.68, 154.75, 152.67, 150.66, 149.15, 142.20, 138.36, 136.91, 135.69, 131.23, 129.95, 124.16, 122.78, 120.24, 119.99, 119.84, 117.61; FTIR (cnr1): 3298, 3040, 1639; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C24H19CIN3O3432.1115; Found 432.1127.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(3-(trifluoromethoxy) phenyl) urea (Compound 17)

[0265] Following procedure 2 for urea synthesis

[0266] White solid (78%). M. P: 171-174°C;1H NMR (500 MHz, DMSO-d6) 0 8.90 (s, 1 H), 8.82 (s, 1 H), 8.38 (d, J = 2.1 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.57 - 7.50 (m, 5H), 7.30- 7.28 (m, 2H), 7.12 - 7.11 (m, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 0 154.69, 152.53, 149.36, 142.60, 142.24, 139.01, 138.39, 136.63, 131.23, 124.22, 121.77, 121.22 (q, J= 256.0 Hz, CF3), 120.21, 120.17, 119.43; FTIR (cm1): 3294, 3047, 1639; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H14CIF3N3O3 424.0676; Found 424.0685.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(4-methoxyphenyl) urea (Compound 18)

[0267] Following procedure 1 for urea synthesis

[0268] White solid (quant.). M. P: 178-180°C;1H NMR (500 MHz, DMSO-d6) 0 8.69 (s, 1 H), 8.49 (s, 1 H), 8.38 (d, J = 2.1 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.53 - 7.48 (m, 3H), 7.37 - 7.34 (m, 2H), 7.11 - 7.09 (m, 2H), 6.88 - 6.85 (m, 2H), 3.71 (s, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 6 154.79, 154.49, 152.79, 148.99, 142.17, 138.33, 137.10, 132.68, 131.22, 124.11, 120.22, 120.08, 119.87, 114.00, 55.18; FTIR (cm1): 3288, 3047, 1661; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H17ClN3O3370.0959; Found 370.0961.TEC2025-0036 3000.222W01Synthesis of 1-(benzo[d] [1,3] dioxol-5-yl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 19)

[0269] Following procedure 1 for urea synthesis

[0270] White solid (quant.). M. P: 179-181 °C;1H NMR (500 MHz, DMSO-d6) 5 8.70 (s, 1 H), 8.57 (s, 1 H), 8.38 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.51 - 7.48 (m, 3H), 7.19 (d, J = 2.0 Hz, 1 H), 7.10 - 7.08 (m, 2H), 6.83 (d, J = 8.4 Hz, 1 H), 6.76 (dd, J = 8.4, 2.1 Hz, 1 H), 5.97 (s, 2H); FTIR (cm-1): 3320, 3255 2919, 2849,1645; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H15CIN3O4 384.0751; Found 384.0758.Synthesis of 1 -(4-(tert-butyl) phenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 20)

[0271] Following procedure 1 for urea synthesis

[0272] White solid (quant.). M. P: 178-180°C;1H NMR (500 MHz, DMSO-d6) 0 8.73 (S, 1 H), 8.60 (S, 1 H), 8.38 (s, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.53 - 7.48 (m, 3H), 7.37 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 1.26 (s, 9H).13C{1H} NMR (125 MHz, DMSO-d6) 0 154.78, 152.64, 149.06, 144.17, 142.18, 138.33, 137.03, 136.99, 131.22, 125.41, 124.12, 120.24, 119.89, 118.10, 33.91, 31.28; FTIR (cm1): 3310, 2958, 1647; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C22H23CIN3O2396.1479; Found 396.1486.Synthesis of ethyl 5-(3-(4-(tert-butyl) phenyl) ureido)-2-((5-chloropyridin-3-yl) oxy) benzoate (Compound 21)

[0273] Following procedure 1 for urea synthesisCOOEt

[0274] White solid (quant.). M. P: 163-166°C;1H NMR (500 MHz, DMSO-d6) 0 8.99 (S, 1 H), 8.64 (s, 1 H), 8.32 (d, J = 2.2 Hz, 1 H), 8.22 (d, J = 2.2 Hz, 1 H), 8.10 (d, J = 2.8 Hz, 1 H), 7.73 (dd, J = 8.8, 2.8 Hz, 1 H), 7.40 - 7.37 (m, 2H), 7.34 (t, J = 2.2 Hz, 1 H), 7.32 - 7.29 (m, 2H), 7.26 (d, J = 8.8 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2H), 1.26 (s,TEC2025-0036 3000.222W019H), 1.05 (t, J = 7.1 Hz, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 5 164.24, 155.63, 152.57, 146.52, 144.43, 141.42, 137.82, 137.10, 136.81, 131.12, 125.43, 123.99, 123.88, 123.74, 122.52, 120.58, 118.33, 61.00, 33.93, 31.27, 13.76; FTIR (cm1): 3301, 2956, 2923, 2869, 1708; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C25H27CIN3O4468.1690; Found 468.1696.Synthesis of 1-(4-((5-chloropyridin-3-yl) oxy) phenyl)-3-(4-cyanophenyl) urea (Compound 22)

[0275] Following procedure 1 for urea synthesis

[0276] White solid (quant.). M. P: 195-198°C;1H NMR (500 MHz, DMSO-d6) 5 9.23 (s, 1 H), 8.97 (s, 1 H), 8.39 (d, J = 2.0 Hz, 1 H), 8.32 (d, J = 2.6 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.54 - 7.50 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H).13C{1H} NMR (125 MHz, DMSO-d6) 0 154.61, 152.17, 149.68, 144.22, 142.32, 138.45, 136.23, 133.33, 131.24, 124.33, 120.41, 120.20, 119.35, 118.07, 103.26; FTIR (cm1): 3342, 3270, 3069, 1643; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H14CIN4O2 365.0805; Found 365.0811.Synthesis of 1-(4-(tert-butyl)-3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 23)

[0277] Following procedure 1 for urea synthesis

[0278] White solid (quant.). M. P: 197-198°C;1H NMR (500 MHz, DMSO-d6) 5 8.83 (s, 1 H), 8.80 (s, 1 H), 8.38 (d, J = 2.2 Hz, 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 7.54 - 7.47 (m, 5H), 7.34- 7.32 (m, 2H), 7.12 - 7.10 (m, 2H);13C{1H} NMR (125 MHz, DMSO-d6) 5 154.70, 152.50, 149.34, 142.25, 138.71, 138.39, 136.66, 131.23, 128.66, 125.37, 124.22, 120.21, 120.15, 119.76; FTIR (cm1): 3289, 3055, 1629; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C18H14CI2N3O2374.0463; Found 374.0473.Synthesis of 1-(4-(tert-butyl)-3-chlorophenyl)-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 24)

[0279] Following procedure 2 for urea synthesisTEC2025-0036 3000.222W01

[0280] White solid (72%). M. P: 115-120°C;1H NMR (500 MHz, DMSO-d6) 6 8.81 (m, 2H), 8.37 (d, J = 2.2 Hz, 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 7.66 (d, J = 2.4 Hz, 1 H), 7.53 - 7.51 (m, 2H), 7.49 (t, J = 2.2 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 1 H), 7.24 (dd, J = 8.7, 2.4 Hz, 1 H), 7.14 - 7.07 (m, 2H), 1.41 (s, 9H);13C{1H} NMR (125 MHz, DMSO-d6) 0154.72, 152.46, 149.33, 142.22, 138.83, 138.81, 138.36, 136.65, 132.48, 131.23, 128.05, 124.17, 120.76, 120.21, 120.17, 116.73, 35.17, 29.59; FTIR (cm1): 3308, 3047, 2953, 1654; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C22H22CI2N3O2 430.1089; Found 430.1099.Synthesis of ethyl 5-(3-(4-(tert-butyl)-3-chlorophenyl) ureido)-2-((5-chloropyridin-3-yl) oxy) benzoate (Compound 25)

[0281] Following procedure 2 for urea synthesis

[0282] White solid (74%). M. P: 75-78°C;1H NMR (500 MHz, DMSO-d6) 69.08 (s, 1 H), 8.87 (s, 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.22 (d, J = 2.2 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.73 (dd, J = 8.7, 2.7 Hz, 1 H), 7.66 (d, J = 2.7 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 1 H), 7.35 (t, J = 2.2 Hz, 1 H), 7.28 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.42 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H);13C{1H} NMR (125 MHz, DMSO-d6); FTIR (cm1): 3320, 2959, 1712; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C25H26CI2N3O4 502.1300; Found 502.1306.Synthesis of 1-(3-chlorophenyl)-3-(4-methoxyphenyl) urea (Compound 26)

[0283] Following procedure 2 for urea synthesis

[0284] Purple solid (quant.). M. P: 197-198°C;1H NMR (500 MHz, DMSO-d6) 68.79 (s, 1 H), 8.54 (s, 1 H), 7.70 (s, 1 H), 7.36 (d, J = 8.4 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.00 (d, J = 7.7 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H);13C{1H} NMR (125 MHz, DMSO-d6) 5 154.66, 152.57, 141.51, 133.18, 132.38, 130.38, 121.21, 120.27, 117.42, 116.51, 114.01, 55.19; FTIR (cm1): 3344, 3229, 3045, 2923, 1629; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C14H14CIN2O2277.0744; Found 277.0788.Synthesis of 1-benzyl-3-(3-chlorophenyl) urea (Compound 27)

[0285] Following procedure 1 for urea synthesisTEC2025-0036 3000.222W01

[0286] White solid (quant.). M. P: 168-171 °C;1H NMR (500 MHz, DMSO-d6) 5 8.80 (s, 1 H), 7.70 (t, J = 2.0 Hz, 1 H), 7.35 - 7.2 (m, 7H), 6.95 (ddd, J = 7.7, 2.1, 1.2 Hz, 1 H), 6.72 (t, J = 6.0 Hz, 1 H), 4.30 (d, J = 6.0 Hz, 2H).13C{1H] NMR (125 MHz, DMSO-d6) 5 155.01, 142.06, 140.19, 133.13, 130.27, 128.34, 127.15, 126.78, 120.69, 117.04, 116.07, 42.75; FTIR (cm1): 3316, 1631; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C14H14ClN2O 261.0717; Found 261.0836.Synthesis of 1-benzyl-3-(4-((5-chloropyridin-3-yl) oxy) phenyl) urea (Compound 28)

[0287] Following procedure 1 for urea synthesis

[0288] White solid (quant.). M. P: 171 -174°C;1H NMR (500 MHz, DMSO-d6) 0 8.68 (s, 1 H), 8.36 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 2.5 Hz, 1 H), 7.49 - 7.44 (m, 3H), 7.35 - 7.31 (m, 4H), 7.26 - 7.22 (m, 1 H), 7.07 - 7.04 (m, 2H), 6.63 (t, J = 6.0 Hz, 1 H), 4.30 (d, J = 6.0 Hz, 2H).13C{1H} NMR (125 MHz, DMSO-d6) 0 155.26, 154.92, 148.50, 142.05, 140.37, 138.22, 137.74, 131.20, 128.33, 127.12, 126.74, 123.92, 120.24, 119.39, 42.75; FTIR (cm1): 3302, 3039, 1634; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated for C19H17ClN3O2354.1009; Found 354.1016.Synthesis of N-((4-((5-chloropyridin-3-yl) oxy) phenyl) carbamoyl)-4- methylbenzenesulfonamide (Compound 29)

[0289] Following procedure 1 for urea synthesis

[0290] White solid (quant.). M. P: 147-148°C;1H NMR (500 MHz, DMSO-d6) 0 10.80 (s, 1 H), 8.94 (s, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 7.85 - 7.84 (m, 2H), 7.49 (t, J = 2.4 Hz, 1 H), 7.41 - 7.37 (m, 4H), 7.08 - 7.05 (m, 2H), 2.39 (S, 3H).13C{1H} NMR (125 MHz, DMSO-d6) 5 154.41, 150.33, 149.47, 143.85, 142.44, 138.52, 137.11, 135.03, 131.23, 129.49, 127.52, 124.49, 120.93, 120.05, 21.09; FTIR (cm-1): 3326, 3058, 1692; HRMS (ESI / Q-TOF) m / z: [M + H]+Calculated forTEC2025-0036 3000.222W01C19H17CIN3O4S 418.0628; Found 418.0638.Example 2: Small Peptide Assay

[0291] To evaluate the activity of compound 1 and its analogues, the compounds were analyzed using a small peptide degradation assay. 20S proteasome solution was prepared in 38 mM TCH-HCI with 100 mM NaCI (pH=7.8) with final concentration of 1 nm. Different concentrations of the compounds being tested were added (1 pL) to black flat / clear bottom 96-well plate containing 89 pL of the 20S proteasome. After 15 minutes incubation at 37 °C, 10 pL of each fluorogenic substrate or combination of them with final concentration of 20 pM was added. Suc-LLVY-AMC, Z-LLE- AMC, and Boc-LRR-AMC were used for testing CT-L, Casp-L and T-L enzymatic activity respectively. SpectraMax M5e spectrometer was set up at 37 °C to measure the increase in fluorescence units per minute for 1 hour at 380 / 460 nm. The enzymatic activity of the samples treated with the compounds was compared and divided by that of the vehicle. The fold change was plotted against the logarithm of drug concentration in GraphPad Prism 9. The small peptide assay data is presented in Table 1 herein, where “EC200” is the concentration at which proteasome enhancement is increased by 200%. In other words, the EC200 is the concentration of drug that induces double the enzymatic activity of the proteasome.R6R2R1R2R5X1X2R3R4EC200Cl COOEt Cl N C H H 2.4±0.1 Compound 2 Cl H Cl H N C H H 4.8±0.7 Compound 3 H H Cl H N C H H 12.7±0.9 Compound 4 Cl H H H N C H H >40 Compound 5 Cl H F H N C H H 14.8±1.4 Compound 6 Cl H OCH3H N C H H 11.6±0.7 Compound 7 Cl H Cl H C C H H 4.8±0.9 Compound 8 Cl H Cl H N C H H 10.0±1.0 Compound 9 Cl H Cl H N C Me H 14.0±3.0 Compound 10 Cl H Cl H N C H Me 13.0±0.4 Compound 11 Cl H Cl H N C Me Me >40 Compound 12 Cl H Cl H C N H H 4.5±0.5 Compound 13 CF3H Cl H C N H H >40ClCompound 14 Cl H H N C H H 1,2±0.4AoXbClCompound 15 Cl COOEt H N C H H 1.2±0.1A0X^NCOOEtCompound 16 Cl H H OPh N C H H 5.7±1.3 Compound 17 Cl H H OCF3N C H H 8.7±1.2Compound 18 Cl H H OMe N C H H 12.1 ±1.6TEC2025-0036 3000.222W01R1R3R45R2R1R2R5R6X1X2R3R4EC200N CCompound 19 H H 20.7±1.9 Compound 20 Cl H H t-Bu N C H H 2.2±0.2 Compound 21 Cl COOEt H t-Bu N C H H 1.3±0.1 Compound 22 Cl H H CN N C H H >40 Compound 23 Cl H H Cl N C H H 5.7±0.7 Compound 24 Cl H Cl t-Bu N C H H 1,7±0.2Compound 25 Cl COOEt Cl t-Bu N C H H 1,6±0.4Example 3: In-Vitro Alpha Synuclein Degradation Assay

[0292] Mixtures of 0.5 pL of the compound (different concentrations) and 22 pL purified 20S proteasome (10 nM) were incubated at 37°C for 45 minutes. Then, 2.5 pL purified a-synuclein (300 nM) was added and further incubated in a water bath for 2.5 hours. The reactions were quenched with concentrated SDS loading buffer. The samples were boiled for 15 minutes. Purified GAPDH (0.5 pL-250 nM) was added to the mixture and boiled for 15 minutes. The samples were resolved on 4-20% SDS-PAGE and immunoblotted with anti-a-synuclein antibody (1:2000), horse radish peroxidase (HRP) conjugated anti-rabbit IgG (1:1000), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (6C5cc) Mouse mAb (HRP Conjugate). Blots were imaged using Azure imager after being developed with ECL Western reagent. The data from the assay is shown in FIGS. 2A-2D. These data show that compound 1 was effective at reducing the percent of remaining a-synuclein as a function of concentration, with the highest concentration (10 pM) reducing the percent of remaining alpha-syn to approximately 25% (see FIG. 2D). These data also indicate that compound 1 was effective in lowing the concentration of the intrinsically disordered protein, a-synuclein, in cells and thereby can prevent a-synuclein induced cell cytotoxicity seen in many neurodegenerative disorders.Example 4: Degradation of Viral Oncoproteins (HPV-infected cancer cells)

[0293] Although the prophylactic HPV vaccine is effective in preventing -90% of HPV infections, they are unable to clear existing infections. Vaccine coverage in globally is less than 50%, resulting in an increase in in infections. Although some HPV-associated cancers can be treated in their early stages, patients with metastatic or advanced HPV-associated cancers therapeutic options have limited success and significant morbidity. Various therapeutic vaccines are in clinical trials, but high risk-HPV positive cells avoid immune destruction by perturbing the expression and trafficking of several immune receptors and mediators, essential for detection and targeting of virus infected cells. The limited effectiveness of existing treatments for HPV-associated tumors and the increasing rates of recurrence has created an urgent need for novel and effective approaches.

[0294] Making reference to FIGS. 3A and 3B, treatment of HPV-16 / 18 positive cervical cancer cells (HeLa cells) with compound 1 at 5 pM and 10 pM concentration for 16 hours resulted in a strong reduction of E7 (FIG. 3A, left) and E6 (FIG. 3A, right) viral oncoproteins concentrations (determined by Western blot, n=3). Treatment of the HeLa cells with a concentration range (40, 20, 10, 5, 2.5, and 1.25 pM) of compound 1 provided an CC5o of 1.5 microM. The compound / drug-induced reduction in the concentration of viral oncoprotein E7 will prevent E7-mediated oncogenic cell growth,TEC2025-0036 3000.222W01and prevent, halt or reduce tumor growth.Example 5: 20S proteasome Enhancement:

[0295] Compounds 1 and 31-45 were synthesized with modifications on ring A, urea core, group W, X, Y, and Z (FIG. 4). The first evaluation of 20S proteasome activation involves small peptide fluorescent probes SUC-LLVY-AMC (Chymotrypsin-like), BOC-LRR-AMC (Trypsin-like), and Z-LLE-AMC (Caspase-like) (FIG. 4).Proteolysis of all three peptides results in a red shift fluorescence that is detectable in the 380-460 nm range. The 20S proteasome was treated with compounds at doseresponse concentrations or with vehicle controls in a 96-well plate, and the fluorescent signal was measured over 1 hour. The fold activation concentration was calculated by comparing wells treated with compounds to vehicle wells. We measured the effective concentration at a 200% increase in activity (EC200). Parameters to evaluate druglikeness of the compounds in the current study include molecular weight (<500 kDa), total polar surface area (tPSA <90 A), and partition coefficient of compounds 46-60, which are also evaluated by computed prediction (clogP<5) and experimental prediction (log KIAM<4) (FIG. 5).

[0296] Overall, the studies indicate that ring A is highly sensitive to modification, whereas substitution at ring C tunes potency. Removal of chlorine in meta-position in ring A depletes activation, while decreasing the logK| Mdown to the 4-5 range (2). On the other hand, the replacement of chlorine with an electronwithdrawing group in the meta-position of ring A (32 and 33) yields a poor potency. Replacement of pyridine with benzene slightly increases EC200 (34), whereas removal of the pyridine ring results in poor potency. This result concludes that the chlorine might have some electronic interaction with the protein residues, while the pyridine nitrogen fine-tunes the protein-small molecule interaction. Interestingly, removal of the ester on ring B slightly decreases potency but is well tolerated, especially in symmetrical urea analogs (43, 44, and 45) and in bulky group substitution in ring C (53 and 58).

[0297] IDP degradation (a-synuclein as example protein) through 20S proteasome enhancement: To test the downstream impact of these compounds on inducing 20S proteasome mediated degradation of intrinsically disordered proteins (IDPs) such as a-synuclein, we quantified the levels of a-synuclein remaining after proteolysis and compared compound treatment with vehicle (FIGS. 6A-6C).Compounds 43, 44, 53, 54, and 58 continued to perform well in purified enzyme assays of recombinant a-syn. Compounds 45 and 56 significantly reduced a-synuclein levels relative to vehicle.

[0298] To test the downstream impact of these compounds on 20S proteasome substrates, we quantified the levels of a-synuclein remaining afterTEC2025-0036 3000.222W01proteolysis and compared compound treatment with vehicle. Compounds 43, 44, 53, 54, and 58 continued to perform well in purified enzyme assays of recombinant a-syn. On the other hand, compounds 45 and 56 (inactive in the peptide degradation assay) significantly reduced a-synuclein levels relative to vehicle. On the other hand, urea or bis-aryl urea compounds are known to modulate IDP aggregation,37-39so it is possible that these compounds might also bind to IDP and likely modulate IDP aggregation.

[0299] Common PD mutations of a-syn are A30P, E46K, H50Q, G51 D, A53E, and A53T.3741Most notably, many studies have demonstrated that the A53T mutation substantially increases the aggregation rate of a-syn.37-42 44Thus, the pathological amplification and aforementioned mutations of a-syn have rendered it an attractive target for PD treatment. To induce a-syn expression in cells, HEK293T cells were transfected in a 96-well plate with a pHM6-A53T-asyn plasmid to induce protein overexpression for 48 hours (FIGS. 7A-7B). After 24 hours of transfection, cells are lysed with RIPA buffer and quantified a-syn levels by ELISA. The plasmid amount was optimized to fit the assay workflow while preventing cellular toxicity from excessive a-syn.

[0300] Following the assay optimization, analogs that induce significant a-syn degradation in the purified enzyme are evaluated at 10 pM in the cellular assay. We screened the cutoff compounds to determine whether any additional cases, such as 45 and 46, were present in the purified enzyme. While 45 and 46 do not induce any enhanced degradation of a-syn in cells, 57 and 42 do have significant degradation of a-syn, even though they did not cause substantial degradation of recombinant a-syn in the previous assay.

[0301] To evaluate the compound impact on a-syn, two sets of compounds were selected for a dose-response study with the parent compound 1 and the control TCH-165 (FIGS. 8A-8D). Set 1 comprises 42, 43, 53, and 58, while set 2 comprises 41, 44, 54, and 57. Set 3 contains inactive 55 and 42 from the 10 pM screen. The IC5o of TCH-165 and 1 were 3.38 ± 1.58 pM and 7.30 ± 2.55 pM, respectively. Most of the analog IC50 values fall into the 5.00-6.00 pM range, indicating better potency than the parent compound 1. The compounds with the lowest IC50 values are 42 and 43, at 1.86±0.79 pM and 2.80±0.13 pM, respectively.

[0302] Control studies were conducted to confirm the mechanism of action for some of these compounds. 300 nM bortezomib was used to inhibit the function of the proteasome and co-treated with 10 pM of the enhancers (FIG. 9A). In the presence of bortezomib, the enhancers did not efficiently lower the level of a-syn, indicating that the compounds require a functional 20S proteasome to induce a-syn degradation (FIG.9A). When co-treating the compounds with 500 nM of bafilomycin, an autophagyTEC2025-0036 3000.222W01inhibitor, it was confirmed that these compounds do not act through autophagy to enhance a-syn degradation as all compounds were still able to reduce the IPD in the presence of an autophagy inhibitor (FIG. 9B).

[0303] Example 6: Derivatives of compound 1 inhibit IDP aggregation directly: IDPs tend to aggregate, which is a pathological hallmark in most neurodegenerative diseases, including Alzheimer’s Disease, Parkinsons Disease, ALS, Huntington’s and many others. To test whether the compounds could directly prevent IDP aggregation, the compounds were added at the beginning of the incubation period and compared to the vehicle and Anle138b67’68(an aggregation inhibitor under clinical evaluation) as a positive control. Pre-formed aggregate standards were included and 125 ng / mL of 2.0 pm-filtered monomers in each replicate.

[0304] Making reference to FIGS. 10A-10B, similar to Anle138b, compounds 42 and 58 can reduce aggregation in a statistically significant manner for most concentrations. Compounds 43 and 53 minimize aggregation at lower concentrations. Compound 1 has no impact on the aggregation. This result is encouraging as we know that most of these compounds are potent 20S proteasome enhancers (with the exception of compound 42).

[0305] Compound 42 failed to induce a-syn proteolysis through proteasome enhancement, with an EC200 > 20 pM. However, compound 42 showed an IC5o of 1.86 ± 0.79 pM in a cellular a-syn degradation assay (independent of changes in autophagy), suggesting that it may improve a-syn degradation via a mechanism distinct from 20S proteasome enhancers.

[0306] Example 7: Combining the 20S enhancer 1 and derivatives thereof with a aggregation inhibitor reduces IDP concentrations. A cellular degradation assay was used to perform co-treatments with 1 and 53, along with a dose response of 13 (FIG. 11). To confirm that degradation occurs normally, TCH-165 was used as a control. Since Anlel 38b was shown not to impact a-syn level in cells, it is not a suitable control for this experiment. Another proteasome inhibitor, carfilzomib, was co-treated with dose response of 42 to determine whether the impact of 42 depends on the presence of the 20S proteasome.

[0307] The dose-response curves of 42 start to diverge at 5 pM. With the 20S proteasome enhancers, the curve shifted downward, showing more degradation of the 20S proteasome substrate. However, the curve shifted upward in the presence of 100 nM carfilzomib.

[0308] In conclusion, this data indicates that the combination of the 20S proteasome enhancer 1 and derivatives thereof with an inhibitor of IDP aggregation provides an additive or synergistic effect on reducing the amount of IDP. a-synucleinTEC2025-0036 3000.222W01was used herein as the example of a disease relevant IDP.

[0309] Example 8

[0310] Human papillomavirus (HPV) types 16 and 18 are well-defined as high-risk genotype for HPV-induced cervical cancer.72Like a-syn, the E6 and E7 proteins of HPV types 16 and 18 are partially disordered, making them susceptible to 20S proteasome-mediated proteolysis.73-75Both are viral oncoproteins. E6 promotes the degradation of the p53 tumor suppressor, thereby promoting cancer.72’7376On the other hand, E7 interacts with and deactivates pRb, another tumor suppressor protein.727376Thus, compound 1 and derivates thereof that enhance the 20S proteasome activity can increase the degradation of (HPV) E6 and E7 proteins, addressing HPV16 and 18-induced cancer.72’7778

[0311] First, compound 1 (also referred to as MM) was evaluated for the induction of degradation of E6 and E7 in Hela cells, which are HPV18 positive. To determine the ability of 1 to degrade E6 / 7 proteins, we treated HeLa cells (HPV18 positive) with 1 and multiple controls for 24 hours and monitored E6 and E7 protein levels by Western blot. As anticipated, treatment of the cells with the 20S / 26S proteasome inhibitor, bortezomib (0.3 mM) as control, increased protein levels for both E6 and E7, supporting prior literature that these proteins are degradation by the proteasome (FIG. 12B). The 20S proteasome enhancer, TCH-165 (5 and 10 mM), was used as a positive control effectively degraded E6 / 7 at 10 mM concentration. Excitingly, Compound 1 significantly reduced E7 protein at 5 mM and dramatically reduced (>85%) both E6 and E7 protein levels at 10 mM (FIG. 12B). Next, we determined whether the degradation induced by Compound 1 was ubiquitin-dependent or ubiquitin-independent. Prior to 26S proteasome mediated protein degradation, proteins need to be ubiquitinated. This step is sequentially mediated by E1-E3 ligases, with the addition of ubiquitin by the E1 enzyme being the first step in the sequence.1-3Therefore, we pre-treated HeLa cells with the cell permeable irreversible E1 ubiquitin activating enzyme inhibitor, PYR-41.4-9Treatment of the cells with PYR-41 prevented ubiquitin-dependent proteasome mediated degradation of E6 and E7 (FIG. 12C).However, the blocking E6 / E7 ubiquitination by PYR-41 had no effect on the ability of 20S proteasome enhancer 1 to degrade E6 and E7, indicating that Compound 1 induces the degradation of viral E6 and E7 in a ubiquitin - / ^dependent mechanism.

[0312] To confirm that HPV16 E7 degradation is enhanced by increased proteasome activity, we initially used Western Blotting. Given the scarcity of anti-HPV16 E7 antibodies, we used ELISA to quantify HPV16 E7. siRNA transfection was used as a control (FIG. 13) and 20S proteasome enhancer TCH-165. The result shows successful transfection, with protein expression decreased to approximately 50%.TEC2025-0036 3000.222W01Interestingly, the compounds induce substantially greater protein degradation, with less than 25% remaining for MM (1) and sorafenib (structural derivative of compound 1).

[0313] Compound 1 induced reduction of E6 and E7 viral protein will return the cell back to typical cell cycle progression. Both HeLa (HPV18+) and CaSki (HPV18 / 16+) cells were tested for viability (cellTiter glo) and toxicity (cellTox green) levels when compounds (TCH-165, MM, and Sorafenib) were added for 72 hours. The results are in FIG. 14. These data indicate that they exert minimal cell toxicity (<25%) at concentrations < 5 microM but significantly slow cell growth, as anticipated by returning the cell back to a typical cell cycle progression.

[0314] Immune response: An immune response to HPV-infected cells that express E6 / E7 proteins is sufficient to clear the infected neoplastic tissue.10Therapeutic vaccines that target E6 and E7 antigen presentation of the HPV16 strain are currently under development.10-15Class I major histocompatibility complex (MHC I) molecules are found on the cell’s surface and bind peptide fragments from proteins that were subject to proteasomal degradation. When peptide fragments from viral protein are presented, the infected cells induce a T-cell immune response that clears the infected cells. Unfortunately, over one third of HPV-associated cervical squamous cell carcinoma’s has clonal or complete loss of MHC class I expression.17HPV-16 E6 contributes to modulating the hosts immune responses by preventing the transactivation of IFN-b expression, reducing type-l interferon production, and inhibiting transcription of kappa interferon.18-21HPV-16 E7 contributes to modulating the hosts immune responses by preventing recognition of foreign DNA through modulation of cGAS-STING pathways and inhibition of type-1 interferon secretions.22-24Therefore, drug-induced degradation of E6 and E7 is anticipated to restore cellular immunoregulation, rendering the infected cells susceptible to detection and clearance by the host immune system.23References:(1) Kwon, Y. T.; Ciechanover, A. The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy. Trends Biochem. Sci. 2017, 42 (11), 873-886. DOI: 10.1016 / j.tibs.2O17.09.002.(2) Komander, D.; Rape, M. The ubiquitin code. Annu Bev Biochem 2012, 81, 203- 229. DOI: 10.1146 / annurev-biochem-060310-170328.(3) Varshavsky, A. The Ubiquitin System, Autophagy, and Regulated Protein Degradation. Annu Rev Biochem 2017, 86, 123-128. DOI: 10.1146 / annurev- biochem-061516-044859.(4) Yang, L.; Zhang, Q.; Yang, Y. L.; Wang, Q. PYR-41, an inhibitor of ubiquitin- activating enzyme E1, attenuates 2,4-dinitrochlorobenzene-induced atopicTEC2025-0036 3000.222W01dermatitis-like skin lesions in mice. Faseb J 2023, 37 (10). DOI: ARTN e2321010.1096 / fj.202200951 RRR.(5) You, X.; Xu, D. D.; Zhang, D.; Chen, J.; Gao, F. G. PYR-41 and Thalidomide Impair Dendritic Cell Cross-Presentation by Inhibiting Myddosome Formation and Attenuating the Endosomal Recruitments of p97 and Sec61 via NF-KB Inactivation. J Immunol Res 2018, 2018. DOI: Artn 507057310.1155 / 2018 / 5070573.(6) Yoshida, K.; Kang, W.; Nakamura, A.; Kawano, N.; Hanai, M.; Miyado, M.;Miyamoto, Y.; Iwai, M.; Hamatani, T.; Saito, H.; et al. Ubiquitin-activating enzyme El inhibitor PYR-41 retards sperm enlargement after fusion to the egg. Reprod Toxicol2018, 76, 71 -77. DOI: 10.1016 / j.reprotox.2018.01.001.(7) Shu, Q.; Lai, S.; Wang, X. M.; Zhang, Y. L.; Yang, X. L.; Bi, H. L.; Li, H. H.Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin Il-induced cardiac remodeling in mice. Biochem Bioph Res Co 2018, 505 (1), 317-324. DOI: 10.1016 / j.bbrc.2O18.09.100.(8) Matsuo, S.; Sharma, A.; Wang, P.; Yang, W. L. Pyr-41, a Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock2018, 49 (4), 442- 450. DOI: 10.1097 / Shk.0000000000000931.(9) Yang, Y.; Kitagaki, J.; Dai, R. M.; Tsai, Y. C.; Lorick, K. L.; Ludwig, R. L.; Pierre, S.A.; Jensen, J. P.; Davydov, I. V.; Oberoi, P.; et al. Inhibitors of ubiquitin-activating enzyme (E1 ), a new class of potential cancer therapeutics. Cancer Res 2007, 67 (19), 9472-9481.(10) Li, Y. L.; Qiu, X. H.; Shen, C.; Liu, J. N.; Zhang, J. Vaccination of full-length HPV16 E6 or E7 protein inhibits the growth of HPV16 associated tumors. Oncol Rep 2010, 24 (5), 1323-1329. DOI: 10.3892 / or_00000989.(11) Mohammadi, M.; Saha, A.; Giles-Davis, W.; Xiang, Z. Q.; Novikov, M.;Hasanpourghadi, M.; Ertl, H. C. J. Preclinical Immunogenicity and Efficacy Studies for Therapeutic Vaccines for Human Papillomavirus-Type-16-Associated Cancer. Vaccines-Basel 2024, 12 (6). DOI: ARTN 61610.3390 / vaccines12060616.(12) Li, X. X.; Wang, H. Y.; Lai, W. J.; Liao, J. R.; Mo, W. Y.; Huang, K. K.; He, L. Q.;Liang, X. M.; Yu, Z. B.; Xu, J.; et al. Prevention and treatment of HPV-related cancer through a mRNA vaccine expressing APC-targeting antigen. Immunology 2024, 172 (3), 375-391. DOI: 10.1111 / imm.13777.(13) Silva, A. J. D.; Moura, I. A.; Gama, M.; Leal, L. R. S.; Pinho, S. S.; Espinoza, B.C. F.; Santos, D. L. D.; Santos, V. E. P.; Sena, M.; Invencao, M.; et al. Advancing Immunotherapies for HPV-Related Cancers: Exploring Novel Vaccine Strategies and the Influence of Tumor Microenvironment. Vaccines (Basel) 2023, 11 (8). DOI: 10.3390 / vaccinesl 1081354 From NLM PubMed-not-MEDLINE.(14) Hewavisenti, R. V.; Arena, J.; Ahlenstiel, C. L.; Sasson, S. C. Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk. Front Immunol 2023, 14. DOI: ARTN 111251310.3389 / fimmu.2023.1112513. (15) Messa, L.; Loregian, A. HPV-induced cancers: preclinical therapeutic advancements. Expert Opin Inv Drug 2022, 31 (1), 79-93. DOI: 10.1080 / 13543784.2021.2010703.(16) Zottnick, S.; Voss, A. L.; Riemer, A. B. Inducing Immunity Where It Matters:Orthotopic HPV Tumor Models and Therapeutic Vaccinations. Front Immunol 2020, 11. DOI: ARTN 175010.3389 / fimmu.2020.01750.TEC2025-0036 3000.222W01(17) Dibbern, M. E.; Bullock, T. N.; Jenkins, T. M.; Duska, L. R.; Stoler, M. H.; Mills, A.M. Loss of MHC Class I Expression in HPV-associated Cervical and Vulvar Neoplasia A Potential Mechanism of Resistance to Checkpoint Inhibition. Am J Surg Pathol 2020, 44 (9), 1184-1191. DOI: 10.1097 / Pas.0000000000001506. (18) Castro-Munoz, L. J.; Rocha-Zavaleta, L.; Lizano, M.; Ramirez-Alcantara, K. M.;Madrid-Marina, V.; Manzo-Merino, J. Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism. Biomedicines 2022, 10 (11). DOI: ARTN 296510.3390 / biomedicines10112965. (19) Reiser, J.; Hurst, J.; Voges, M.; Krauss, P.; Munch, P.; Iftner, T.; Stubenrauch, F.High-Risk Human Papillomaviruses Repress Constitutive Kappa Interferon Transcription via E6 To Prevent Pathogen Recognition Receptor and Antiviral- Gene Expression. J Virol 2011, 85 (21 ), 11372-11380. DOI: 10.1128 / Jvi.05279-11. (20) Ronco, L. V.; Karpova, A. Y.; Vidal, M.; Howley, P. M. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Gene Dev 1998, 12(13), 2061-2072. DOI: DO1 10.1101 / gad.12.13.2061. (21) Chiang, C.; Pauli, E. K.; Biryukov, J.; Feister, K. F.; Meng, M.; White, E. A.;Munger, K.; Howley, P. M.; Meyers, C.; Gack, M. U. The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling. J Virol 2018, 92(6). DOI: ARTN e01737-1710.1128 / JVI.01737- 17.(22) Lau, L.; Gray, E. E.; Brunette, R. L.; Stetson, D. B. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 2015, 350 (6260), 568-571. DOI: 10.1126 / science.aab3291.(23) Lo Cigno, I.; Calati, F.; Girone, C.; Catozzo, M.; Gariglio, M. High-risk HPV oncoproteins E6 and E7 and their interplay with the innate immune response: Uncovering mechanisms of immune evasion and therapeutic prospects. Journal of Medical Virology 2024, 96(6). 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Claims

1. TEC2025-0036 3000.222W01What is Claimed:

1. A compound of the formula (I), (IA), (IO) or (ID):or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy; R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group;TEC2025-0036 3000.222W01X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;provided that:X2is not N when R1is NH2and R1is not Cl when X1and X2are both simultaneously N;R2is not H when R5is Cl,R2is not H when R6is methyl;R2is not H when R1is Cl or F;R4is not CH3when R5is optionally substituted phenyl;R5is not phenoxy or CF3when R1methoxy;R5is not CF3when R1is aminomethyl or pyrrolidinyl;R6is not optionally substituted phenyl or phenoxy when Y1is S;R6is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl;X2is not N when R18is NH2and R18is not Cl when X1and X2are both simultaneously N;R2is not H when R21is Cl,R2is not H when R22is methyl;R2is not H when R18is Cl or F;R4is not CH3when R22is optionally substituted phenyl;R22is not phenoxy or CF3when R18methoxy;R22is not CF3when R18is aminomethyl or pyrrolidinyl;R22is not optionally substituted phenyl or phenoxy when Y1is S;R22is not CF3when R5is Cl or F; andR7is not methoxy when R6is methyl.

2. The compound of claim 1, wherein R1 / R18is halo or alkyl.

3. The compound of claim 1 or 2, wherein R1 / R18is halo.

4. The compound of claim 3, wherein halo is Cl.

5. The compound of claim 1 or 2, wherein R1is alkyl.TEC2025-0036 3000.222W016. The compound of claim 5, wherein alkyl is substituted alkyl.

7. The compound of claim 6, wherein substituted alkyl is halo substituted alkyl.

8. The compound of claim 7, wherein halo substituted alkyl is fluoro substituted alkyl.

9. The compound of claim 8, wherein fluoro substituted alkyl is perfluoro substituted alkyl.

10. The compound of claim 9, wherein perfluoro substituted alkyl is CF3.

11. The compound of claim 1, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.

12. The compound of claim 11, wherein R7is alkyl.

13. The compound of claim 11, wherein R7is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.

14. The compound of claim 11, wherein R7is alkoxy.

15. The compound of claim 11, wherein R7is Ci-C8alkoxy, C2-C5 alkoxy, C1-C5 alkoxy or C3-C8alkoxy.

16. The compound of claim 1, wherein R3and R4are each independently H.

17. The compound of claim 1, wherein R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring.

18. The compound of claim 17, wherein the five- and the six membered heterocyclyl ring is of the formula:Y1and Y1, respectively, each of which is optionally substituted.

19. The compound of claim 1, wherein R5 / R21is H.

20. The compound of claim 1, wherein R5 / R21is halo.TEC2025-0036 3000.222W0121. The compound of claim 20, wherein halo is Cl or F.

22. The compound of claim 1, wherein R5 / R21is alkoxy.

23. The compound of claim 22, wherein R5 / R21is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.

24. The compound of claim 1, wherein R6is H.

25. The compound of claim 1, wherein R6 / R22is alkyl.

26. The compound of claim 25, wherein Re / R22is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.

27. The compound of claim 1, wherein R6 / R22is aryloxy.

28. The compound of claim 27, wherein aryloxy is a C6-C10aryloxy group.

29. The compound of claim 28, wherein aryloxy is phenoxy.

30. The compound of claim 1, wherein R6 / R22is alkoxy.

31. The compound of claim 30, wherein R6 / R22is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.

32. The compound of claim 30 or 31, wherein alkoxy is substituted alkoxy.

33. The compound of claim 32, wherein substituted alkoxy is halo substituted alkoxy.

34. The compound of claim 33, wherein halo substituted alkoxy is fluoro substituted alkoxy.

35. The compound of claim 34, wherein fluoro substituted alkoxy is perfluoro substituted alkoxy.

36. The compound of claim 35, wherein perfluoro substituted alkoxy is OCF3.TEC2025-0036 3000.222W0137. The compound of claim 1, wherein R6 / R22is heteroaryloxy.

38. The compound of claim 37, wherein heteroaryloxy is C2-C5 heteroaryloxy.

39. The compound of claim 37, wherein C2-C5 heteroaryloxy is pyridyl.

40. The compound of claim 37, wherein the heteroaryloxy is substituted with one or more halo and acyl.

41. The compound of claim 37, wherein acyl is C(O)OR12, wherein R12is C1-C8alkyl, C2-C5 alkyl, C1-C5 alkyl or C3-C8alkyl.

42. The compound of claim 37, wherein R6 / R22is a heteroaryloxy group of the formula:, which is optionally substituted.

43. The compound of claim 1, wherein R6 / R22is halo.

44. The compound of claim 43, wherein halo is Cl or F.

45. The compound of claim 44, wherein halo is Cl.

46. The compound of claim 1, wherein R6 / R22is cyano.

47. The compound of claim 1, wherein R5and R6or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group.

48. The compound of claim 47, wherein the heterocyclyl group is a C3-C5 heterocyclyl group.

49. The compound of claim 47, wherein the heterocyclyl group is a C3heterocyclyl group of the formula:TEC2025-0036 3000.222W0150. The compound of claim 1, wherein Y1is O.

51. The compound of claim 1, wherein Y1is S.

52. The compound of claim 1, wherein X1is N and X2is CR9.

53. The compound of claim 52, wherein R9is H.

54. The compound of a of claim 1, wherein X1is CR8and X2is N.

55. The compound of claim 54, wherein R8is H.

56. The compound of claim 1, wherein X1is N and X2is N.

57. The compound of claim 1, wherein X3is S.

58. The compound of claim 1, wherein:X3is O; andTEC2025-0036 3000.222W01R1 / R18R2R5 / R21R6 / R22X1X2R3R4Cl COOEt Cl H N C H H Cl H Cl H N C H H H H Cl H N C H H Cl H H H N C H H Cl H F H N C H H Cl H OCH3H N C H H Cl H Cl H C C H H Cl H Cl H N C H H Cl H Cl H N C Me H Cl H Cl H N C H Me Cl H Cl H N C Me Me Cl H Cl H C N H H CF3H Cl H C N H H ClCl H H N C H H WCl COOEt H N C H HCl H H OPh N C H H Cl H H OCF3N C H H Cl H H OMe N C H H Cl H H r°>N CH H Cl H H t-Bu N C H H Cl COOEt H t-Bu N C H H Cl H H CN N C H H Cl H H Cl N C H H Cl H Cl t-Bu N C H HTEC2025-0036 3000.222W0159. A compound of the formula (II) or (HA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.

60. The compound of claim 59, wherein R1is alkoxy.

61. The compound of claim 59, wherein R1is Ci-C8alkoxy, C2-C5alkoxy, C1-C5 alkoxy or C3-Cs alkoxy.

62. The compound of claim 59, wherein R2is H.TEC2025-0036 3000.222W0163. The compound of claim 59, wherein R3and R4are each H.

64. The compound of claim 59, wherein X1is OR8and X2is N.

65. The compound of claim 59, wherein X3is NR9.

66. The compound of claim 59, wherein R5is H.

67. The compound of claim 59, wherein R6is alkyl.

68. The compound of claim 67, wherein R6is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.

69. The compound of claim 59, wherein the compound is of the formula:

70. A compound of the formula (III) or (I II A):R1R3R4R1aR2R2a(| 11 A)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1and R1aare each independently halo, alkyl, alkoxy, aryloxy or amino;R2and R2aare each independently H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2or R1aand R2a, together with the atoms to which they are attached, form a ring;TEC2025-0036 3000.222W01R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X1ais N or CR8a, wherein R8ais H, halo, alkyl, alkoxy, aryloxy or amino;X2ais N or CR9a, wherein R9ais H, halo, alkyl, alkoxy, aryloxy or amino, or R8aand R9a, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;X3ais O or NR9a, wherein R9ais H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl.

71. The compound of claim 70, wherein R1and R,aare each independently halo.

72. The compound of claim 71, wherein R1and R,aare each chloro.

73. The compound of claim 70, wherein X1and X1aare each N and X2and X2aare each CR9.

74. The compound of claim 70, wherein X3and X3aare each O.

75. The compound of claim 70, wherein R3and R4are each H.

76. The compound of claim 70, wherein the compound is of the formula:

77. A compound of the formula (IV) or (IVA):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2cis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2ctogether with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.

78. The compound of claim 77, wherein R1is halo.

79. The compound of claim 77 or 78, wherein R1is Cl.

80. The compound of claim 77, wherein R2cis halo.

81. The compound of claim 77, wherein R2cis Cl.

82. The compound of claim 77, wherein R5is halo.

83. The compound of claim 77, wherein R5is Cl.

84. The compound of claim 77, wherein R6is H.TEC2025-0036 3000.222W0185. The compound of claim 77, wherein X1is N and X2is CR9.

86. The compound of claim 77, wherein X3is O.

87. The compound of claim 77, wherein R3and R4are each H.

88. The compound of claim 77, wherein the compound is of the formula:Cl89. A compound of the formula (V) or (VA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl;R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or OR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX3is O or NR9, wherein R9is H or alkyl.

90. The compound of claim 89, wherein R1is alkyl.

91. The compound of claim 89, wherein R1is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.

92. The compound of claim 89, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.

93. The compound of claim 92, wherein R7is alkoxy.

94. The compound of claim 93, wherein R7is CrC8alkoxy, C2-C5alkoxy, C1-C5 alkoxy or C3-C8alkoxy.

95. The compound of claim 89, wherein R3is H.

96. The compound of claim 89, wherein R5is halo.

97. The compound of claim 89, wherein R5is Cl.

98. The compound of claim 89, wherein Rsis H.

99. The compound of claim 89, wherein X1is CR8and X2is CR9.

100. The compound of claim 89, wherein X3is NR9.

101. The compound of claim 89, wherein the compound is of the formula:CO2Me102. A compound of the formula (VI) or (VIA):TEC2025-0036 3000.222W01or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group);R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5aand R6aare each independently H, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.

103. The compound of claim 102, wherein R1is alkoxy.

104. The compound of claim 102, wherein R1is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.

105. The compound of claim 102, wherein R2is H.

106. The compound of claim 102, wherein R3and R4are each H.TEC2025-0036 3000.222W01107. The compound of claim 102, wherein X1is N and X2is CR9.

108. The compound of claim 102, wherein X4is S.

109. The compound of claim 102, wherein R5ais H.

110. The compound of claim 102, wherein R6ais alkyl.

111. The compound of claim 110, wherein R6ais Ci-Cs alkyl, C2-C5 alkyl, C,- C5 alkyl or Cs-Cs alkyl.

112. The compound of claim 110, wherein R6ais aryl substituted alkyl.

113. The compound of claim 110, wherein RSais optionally substituted aryl alkyl.

114. The compound of claim 102, wherein the compound is of the formula:

115. A compound of the formula (VII) or (VIIA):R5aR5aR2(VIIA)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.

116. The compound of claim 115, wherein R1is halo.

117. The compound of claim 116, wherein R1is F.

118. The compound of claim 115, wherein R2is H.

119. The compound of claim 115, wherein R4is H.

120. The compound of claim 115, wherein X1is CR8and X2is CR9.

121. The compound of claim 115, wherein R5ais H.

122. The compound of claim 115, wherein R6ais optionally substituted aryl.

123. The compound of claim 122, wherein R6ais halo substituted aryl.

124. The compound of claim 115, wherein the compound is of the formula:TEC2025-0036 3000.222W01125. A compound of the formula (VIII) or (VIIIA):R5aR5aR2(VIIIA)or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2bis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2btogether with the atoms to which they are attached, form a ring;R4is H or alkyl;R5aand R6aare each independently H, aryl, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5aand R6a, together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group;R13is C(O)R14, wherein R14is H, alkyl, amino or alkoxy;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX4is S, O or NR9, wherein R9is H or alkyl.

126. The compound of claim 125, wherein R1is halo.

127. The compound of claim 126, wherein R1is Cl.

128. The compound of claim 125, wherein R2is H.TEC2025-0036 3000.222W01129. The compound of claim 125, wherein R4is H.

130. The compound of claim 125, wherein X1is N and X2is CR9.

131. The compound of claim 125, wherein R9is H.

132. The compound of claim 125, wherein R5ais H.

133. The compound of claim 125, wherein R6ais optionally substituted aryl.

134. The compound of claim 133, wherein R6ais alkyl substituted aryl.

135. The compound of claim 125, wherein R2bis halo.

136. The compound of claim 125, wherein R14is alkoxy.

137. The compound of claim 136, wherein R14is Ci-Cs alkoxy, C2-C5 alkoxy, C1-C5 alkoxy or C3-C8alkoxy138. The compound of claim 125, wherein the compound is of the formula:Cl139. A compound of the formula (IX) or (IXA):R5b(IX) orTEC2025-0036 3000.222W01R3or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3is H or alkyl;R5ais H, alkyl or aryl;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring; andX5is O, acyl or NR9, wherein R9is H or alkyl.

140. The compound of claim 139, wherein R1is amino.

141. The compound of claim 140, wherein R1is Ci-Cs alkyl amino, C2-C5 alkyl amino, C1-C5 alkyl amino or C3-C8alkyl amino.

142. The compound of claim 139, wherein R2is H.

143. The compound of claim 139, wherein R3is H.

144. The compound of claim 139, wherein R5bis aryl.

145. The compound of claim 139, wherein R5ais halo substituted aryl.

146. The compound of claim 139, wherein X5is C(O).

147. The compound of claim 139, wherein R1and R2together with the atoms to which they are attached, form a ring.TEC2025-0036 3000.222W01148. The compound of claim 147, wherein the ring is a five-, six- or seven- membered ring.

149. The compound of claim 139, wherein X1is OR8and X2is CR9.

150. The compound of claim 149, wherein the compound is of the formula:

151. A compound of the formula (X) or (XA):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;TEC2025-0036 3000.222W01X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl;Y1is O, S or NR10, wherein R10is H or alkyl; andY2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.

152. A compound of the formula (XI):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X5is CHR15, wherein R15is H, acyl, alkyl, halo or aryl or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl; andY2is N, NR10or O, wherein R10is H or alkyl and the dashed bond is absent or represents a double bond when Y2is N.

153. The compound of claim 152, wherein R15acyl or acyl substituted alkyl.TEC2025-0036 3000.222W01154. The compound of claim 153, wherein acyl is C(O)OR12, wherein R12is C1-C8alkyl, C2-C6alkyl, C1-C5 alkyl or C3-C8alkyl.

155. A compound of the formula (XII):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X, G1, and G2are each independently N, NR10, wherein R10is H or alkyl, C(O) or OR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;the bonds between X and G1and X and G2are single or double bonds, and Y1is O, S or NR10, wherein R10is H or alky.

156. The compound of claim 155, wherein X is OR8.

157. A compound of the formula (XIII):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01R2dis H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X7is C(O)O; andY1is O, S or NR10, wherein R10is H or alkyl.

158. The compound of claim 157, wherein the compound is of the formula:R3R4159. The compound of claim 157, wherein the compound is of the formula:

160. The compound of claim 157, wherein the compound is of the formula:TEC2025-0036 3000.222W01161. A pharmaceutical composition comprising at least one compound of one of claims 1, 59, 70, 77, 89, 102, 115, 125, 139, 151, 152, 155, and 157 and at least one pharmaceutically acceptable excipient.

162. A method for treating a neurodegenerative disease comprising administering a therapeutically effective amount of at least one compound of the formula (IB):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamido or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R6is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or OR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01X2is N or OR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of one of claims 1, 59, 70, 77, 89, 102, 115, 125, 139, 151, 152, 155, and 157; ora pharmaceutical composition of claim 161;to a subject in need thereof.

163. The method of claim 162, wherein the neurodegenerative disease is at least one of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS.

164. A method for reducing, substantially eliminating or eliminating dysregulation of proteostasis comprising administering a therapeutically effective amount of at least one compound of the formula (IB):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamide or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R6is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;TEC2025-0036 3000.222W01X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of one of claims 1, 59, 70, 77, 89, 102, 115, 125, 139, 151, 152, 155, and 157; ora pharmaceutical composition of claim 161;to a subject in need thereof.

165. A method for reducing, substantially eliminating or eliminating the accumulation of intrinsically disordered proteins comprising administering a therapeutically effective amount of at least one compound of the formula (IB):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamide or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R5is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and Rs, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;TEC2025-0036 3000.222W01X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of one of claims 1, 59, 70, 77, 89, 102, 115, 125, 139, 151, 152, 155, and 157; ora pharmaceutical composition of claim 161;to a subject in need thereof.

166. The method of claim 165, wherein the intrinsically disordered proteins comprise a-syn.

167. A method for reducing, substantially eliminating or eliminating the expression of E5, E6, and / or E7 viral oncoproteins in host cells comprising administering a therapeutically effective amount of at least one compound of the formula (IB):or a pharmaceutically acceptable salt or solvate thereof,wherein:R1is H, halo, alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, acyl, acyloxy, cyano, sulfonamido or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring;R5is H, hydroxy, alkyl, heterocyclyl, halo, amino, acylamino, alkoxy, SR11, wherein R11is alkyl, or sulfonyl;R5is H, halo, alkyl, aryl, hydroxy, aryloxy, alkoxy, cyano or R5and Rs, together with the atoms to which they are attached, form a heterocyclyl group;X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;TEC2025-0036 3000.222W01X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl;a compound of any of claims 1-160; ora pharmaceutical composition of claim 161;to a subject in need thereof.

168. A method for:(a) enhancing 20S proteasome activity and inducing the proteolytic degradation of intrinsically disordered proteins (IDPs), including a-synuclein (a- syn);(b) reducing I DP accumulation and / or preventing I DP aggregation to prevent or reduce neurodegeneration and treating Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease, and / or multiple system atrophy;(c) preventing neurodegeneration to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy;(d) enhancing 20S proteasome activity and inhibiting IDP aggregation to treat Alzheimer’s disease, Parkinsons disease, Amyotrophic Lateral Sclerosis, Hunting’s disease or multiple system atrophy;(e) treating diseases or conditions caused by accumulated proteopathies, including a-synucleinopathies and tauopathies, to treat Alzheimer’s disease and related dementias, Parkinson's disease and related dementia, amyotrophic lateral sclerosis, fronto-temporal dementia, Huntington's disease, multiple system atrophy, muscle atrophy diseases (including muscular dystrophies), progressive supranuclear palsy, Pick's disease, spinocerebellar ataxias, prion diseases, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, cancer, cancer metastasis, ageing and diseases relevant to core amyloidogenic proteins, prion and prion-like proteins, RNA-binding proteins, systemic amyloidosis proteins, metabolic / enzymatic aggregation diseases, ocular aggregation-diseases, kin and epithelial aggregation, cancer-associated aggregation and / or infectious amyloid-like proteins; andTEC2025-0036 3000.222W01(f) treating diseases or conditions caused by infections disease (diseases caused by viral and bacterial infections), including HPV-positive cancers and HIV;the method comprising administering a therapeutically effective amount of at least one compound of the formula (I), (IA), (IC) or (ID):or a pharmaceutically acceptable salt or solvate thereof,wherein:R18is H, halo, alkyl, alkoxy, aryloxy or amino, provided that at least one of R18and R21in formula (IB) is halo;R1is halo, alkyl, alkoxy, aryloxy or amino;R2is H, halo, hydroxy, alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy or NR16R17(wherein R16and R17are each independently H or alkyl or R16and R17, together with the nitrogen atom to which they are attached, form a heterocyclyl group) or R1and R2together with the atoms to which they are attached, form a ring;R3and R4are each independently H or alkyl or R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring; R5is H, hydroxy, halo or alkoxy;R6is H, alkyl, hydroxy, aryloxy, alkoxy, cyano or R5and R6, together with the atoms to which they are attached, form a heterocyclyl group;R21is H, hydroxy, halo, alkoxy or C(O)R7, wherein R7is hydroxy, alkyl, alkoxy;TEC2025-0036 3000.222W01R22is H, hydroxy, alkyl, halo, cyano, alkoxy, aryloxy, heteroaryloxy, or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group; X1is N or CR8, wherein R8is H, halo, alkyl, alkoxy, aryloxy or amino;X2is N or CR9, wherein R9is H, halo, alkyl, alkoxy, aryloxy or amino, or R8and R9, together with the atoms to which they are attached, form a ring;X3is O or NR9, wherein R9is H or alkyl; andY1is O, S or NR10, wherein R10is H or alkyl; ora compound of one of claims 59, 70, 77, 89, 102, 115, 125, 139, 151, 152, 155, and 157; oror a pharmaceutical composition of claim 161;to a subject in need thereof.

169. The method of claim 168, wherein R' / R18is halo or alkyl.

170. The method of claim 168 or 169, wherein R1 / R18is halo.

171. The method of claim 170, wherein halo is Cl.

172. The method of claim 168 or 169, wherein R1 / R18is alkyl.

173. The method of claim 172, wherein alkyl is substituted alkyl.

174. The method of claim 173, wherein substituted alkyl is halo substituted alkyl.

175. The method of claim 174, wherein halo substituted alkyl is fluoro substituted alkyl.

176. The method of claim 175, wherein fluoro substituted alkyl is perfluoro substituted alkyl.

177. The method of claim 176, wherein perfluoro substituted alkyl is CF3.

178. The method of any of claims 168-177, wherein R2is C(O)R7, wherein R7is alkyl or alkoxy.

179. The method of claim 178, wherein R7is alkyl.TEC2025-0036 3000.222W01180. The method of claim 179, wherein R7is C1-C8alkyl, C2-C5alkyl, C1-C5alkyl or C3-C8alkyl.

181. The method of claim 180, wherein R7is alkoxy.

182. The method of claim 180, wherein R7is Ci-C8alkoxy, C2-C5 alkoxy, C1- C5alkoxy or C3-C8alkoxy.

183. The method of any of claims 168-182, wherein R3and R4are each independently H.

184. The method of any of claims 168-182, wherein R3and R4, together with the nitrogen atoms to which they are attached, form a five- or six membered heterocyclyl ring.

185. The method of claim 184, wherein the five- and the six membered heterocyclyl ring is of the formula:Y1and Y1, respectively, each of which is optionally substituted.

186. The method of any of claims 168-185, wherein R5 / R21is H.

187. The method of any of claims 168-185, wherein R5 / R21is halo.

188. The method of claim 187, wherein halo is Cl or F.

189. The method of any of claims 168-185, wherein R5 / R21is alkoxy.

190. The method of claim 189, wherein R5 / R21is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.

191. The method of any of claims 168-190, wherein R6 / R22is H.

192. The method of any of claims 168-190, wherein R6 / R22is alkyl.TEC2025-0036 3000.222W01193. The method of claim 192, wherein R6 / R22is Ci-C8alkyl, C2-C5 alkyl, Ci- C5alkyl or C3-C8alkyl.

194. The method of any of claims 168-190, wherein R6 / R22is aryloxy.

195. The method of claim 194, wherein aryloxy is a C3-Cio aryloxy group.

196. The method of claim 195, wherein aryloxy is phenoxy.

197. The method of any of claims 168-190, wherein R6 / R22is alkoxy.

198. The method of claim 197, wherein R6 / R22is C1-C8alkoxy, C2-C5alkoxy, C1-C5alkoxy or C3-C8alkoxy.

199. The method of claim 197 or 198, wherein alkoxy is substituted alkoxy.

200. The method of claim 199, wherein substituted alkoxy is halo substituted alkoxy.

201. The method of claim 200, wherein halo substituted alkoxy is fluoro substituted alkoxy.

202. The method of claim 201, wherein fluoro substituted alkoxy is perfluoro substituted alkoxy.

203. The method of claim 202, wherein perfluoro substituted alkoxy is OCF3.

204. The method of any of claims 168-190, wherein R6 / R22is heteroaryloxy.

205. The method of claim 204, wherein heteroaryloxy is C2-C5 heteroaryloxy.

206. The method of claim 204, wherein C2-C5 heteroaryloxy is pyridyl.

207. The method of claim 204, wherein the heteroaryloxy is substituted with one or more halo and acyl.TEC2025-0036 3000.222W01208. The method of claim 204, wherein acyl is C(O)OR12, wherein R12is Ci- C8alkyl, C2-C5 alkyl, C1-C5 alkyl or C3-C8alkyl.

209. The method of claim 204, wherein R6is a heteroaryloxy group of the formula:Ntwhich is optionally substituted.

210. The method of any of claims 168-190, wherein R6 / R22is halo.

211. The method of claim 210, wherein halo is Cl or F.

212. The method of claim 211, wherein halo is Cl.

213. The method of any of claims 168-190, wherein R6 / R22is cyano.

214. The method of any of claims 168-190, wherein R5and R6or R21and R22, together with the atoms to which they are attached, form a heterocyclyl group.

215. The method of claim 214, wherein the heterocyclyl group is a C3-C5 heterocyclyl group.

216. The method of claim 214, wherein the heterocyclyl group is a C3heterocyclyl group of the formula:

217. The method of any of claims 168-216, wherein Y1is O.

218. The method of any of claims 168-216, wherein Y1is S.

219. The method of any of claims 168-218, wherein X1is N and X2is CR9.

220. The method of claim 219, wherein R9is H.

221. The method of any of claims 168-218, wherein X1is CR8and X2is N.TEC2025-0036 3000.222W01222. The method of claim 221, wherein R8is H.

223. The method of any of claims 168-218, wherein X1is N and X2is N.

224. The method of claim 168, wherein X3is S.

225. The method of claim 168, wherein:X3is O; andTEC2025-0036 3000.222W01R1 / R18R2R5 / R21R6 / R22X1X2R3R4Cl COOEt Cl H N C H H Cl H Cl H N C H H H H Cl H N C H H Cl H H H N C H H Cl H F H N C H H Cl H OCH3H N C H H Cl H Cl H C C H H Cl H Cl H N C H H Cl H Cl H N C Me H Cl H Cl H N C H Me Cl H Cl H N C Me Me Cl H Cl H C N H H CF3H Cl H C N H H ClCl H H N C H H WCl COOEt H N C H HCl H H OPh N C H H Cl H H OCF3N C H H Cl H H OMe N C H H Cl H H r°>N CH H Cl H H t-Bu N C H H Cl COOEt H t-Bu N C H H Cl H H CN N C H H Cl H H Cl N C H H Cl H Cl t-Bu N C H HTEC2025-0036 3000.222W01226. A compound of the formula A-L-B, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a radical of a compound of any of claims 1 -167, B is a radical of a protein binding molecule; and L is linker selected from a substituted or unsubstituted, linear or branched chain comprising:(i) 1 -50 linker atoms selected from carbon, oxygen, nitrogen, sulfur, silicon, or phosphorus;(ii) optionally one or more heterocyclic or aromatic rings;(iii)optionally one or more repeating units selected from -(CH2)g-, -O-, -NH-, -C(O)-, -S-, -SO-, -SO2-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, polyethylene glycol units, alkynyl units, alkenyl units, or combinations thereof;(iv) optionally substituted with one or more substituents selected from halogen, hydroxyl, alkoxy, amino, amide, cyano, thiol, sulfonyl, heteroaryl, or aryl groups;wherein g is independently 1 -20; and wherein the total linker length corresponds to a distance sufficient to permit formation of a ternary complex between a target protein and the compound of formula A-L-B; andthe radical of a protein binding molecule is selected from:TEC2025-0036 3000.222W01TEC2025-0036 3000.222W01 oTEC2025-0036 3000.222W01 BTAExamples c-Myc Binding MoietiesMeOPDB10058F4Examples of Prion Protein Binding MoietiesCompound 55nTRD22

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