Thiazole derivatives as tau aggregation inhibitors

Abstract

The present invention relates to a compound of general formula (I): [Formula 1] JPEG2025533497000067.jpg27170 (in the formula, R N are independently -H or -Me, and R X is independently C optionally substituted with halo or hydroxy 1~4 Alkyl, -NHR N1 (where R N1 is C 1~4 alkyl) or C 5~10 heteroaryl, and R Y is independently C optionally substituted with methyl, halo, or phenyl 5~10 heteroaryl or neopentyl) or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is useful as a tau aggregation inhibitor (TAI).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates primarily to compounds having activity as tau aggregation inhibitors (TAIs) and their use in methods of treating tauopathies, including but not limited to Alzheimer's disease. [Background technology]

[0002] background Tau protein aggregation, which forms neurofibrillary tangles and senile plaques, correlates with cognitive decline in Alzheimer's disease (AD) [1-3]. Therefore, there is growing interest in developing therapeutics that target this pathology. Hydromethylthionine mesylate (HMTM, formerly known as leucomethylthionine mesylate, LMTM) has been shown to have exposure-dependent pharmacological activity against clinical decline and brain atrophy in both AD and frontotemporal dementia [4, 5].

[0003] A core tau fragment (dGAE), corresponding to one of the species isolated from proteolytically stable AD paired helical fibrils (PHFs), containing residues 297–391, spontaneously assembles in vitro in the absence of polyanionic cofactors to form PHFs identical to native PHFs isolated from brain tissue [6–9]. Hydromethylthionine (HMT) inhibits the assembly of dGAE fibrils in vitro at a protein:HMT stoichiometry of 1:0.1

[10] .

[0004] PHF cores isolated from AD brain tissue are highly stable structures, requiring harsh solvents such as formic acid to prevent proteolysis and release tau protein components

[11] . Assembly of tau aggregates is an autocatalytic process in which core tau oligomers act to nucleate the further conversion of normal, full-length tau into truncated, toxic species that progressively impair neuronal function [12, 13]. The binding affinity of tau capture in vitro is on the order of 20 nM, significantly higher than that of physiological tau tubulin binding (approximately 400 nM,

[14] ). This drives the redistribution of tau protein pools from normal soluble species to pathologically assembled forms

[15] .

[0005] Despite the availability of atomic resolution structures of AD PHF cores and fibril cores present in Pick's disease [16, 17], elucidating the molecular mechanisms underlying the pathological assembly of tau and other proteins in neurodegenerative diseases remains elusive [18-20]. Many precursor and oligomeric states have been identified for some proteins [21-24]. However, the isolation and further characterization of these structurally heterogeneous and transient forms remains a challenge due to uncertainty about how they can be isolated and made amenable to unbiased structural and biochemical analysis.

[0006] We have previously reported an EC of 0.6 μM seen in cellular assays. 50 reported that HMT has clinical pharmacological activity at an estimated steady-state brain concentration of approximately 0.1 μM, which is of the same order of magnitude as the α-heptane concentration [4, 13].

[0007] Given the intractability of the PHF core, it was not clear that it would be possible to design small molecule TAIs that could be expected to act on intracellular targets in the brain at clinically safe and tolerable concentrations.

[0008] The present invention has been devised in light of the above considerations. Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention We used a combination of molecular dynamics (MD) simulations, immunochemistry, biochemistry, and medicinal chemistry to investigate the molecular mechanism of monomer capture by the PHF core oligomer and how HMT binds to the core tau unit of the PHF. We showed that assembly initiation depends on a sequence of steps involving first anchoring the monomer and then unwinding the core unit to form the stable cross-β-sheet structure of the PHF core. HMT acts by binding to a potentially druggable pocket within the core unit, stabilizing it in a compact conformation that cannot participate in the unwinding required for further self-assembly.

[0010] The potential binding pocket identified by the inventors provided the basis for defining a pharmacophore model, which was used to design alternative tau aggregation inhibitors (TAIs). A set of chemically unrelated compounds to the HMT was synthesized to test whether new inhibitors could be rationally designed to function in the druggable pocket and optimize some of the medicinal chemistry features required for inhibitory activity. New inhibitors were found to be active in a previously described cell-based aggregation assay

[13] .

[0011] Thus, in one aspect, the present invention provides novel compounds useful as tau aggregation inhibitors, which compounds contain a thiazole core and have the general formula: [ka] (In the formula, R N are independently -H or -Me; R X is independently C optionally substituted with halo or hydroxy 1~4 Alkyl, -NHR N1 (where R N1 is C 1~4 alkyl) or C 5~10is heteroaryl, R Y is independently C optionally substituted with methyl, halo, or phenyl 5~10 heteroaryl or neopentyl) It is of the type.

[0012] Pharmaceutically acceptable salts, solvates and hydrates of these compounds are also encompassed by the present invention.

[0013] The present invention further relates to methods, uses, compositions and other materials for employing these compounds as tau protein aggregation inhibitors and for the treatment or prevention of diseases associated with tau protein aggregation ("tauopathies"). The present invention further provides processes for making these compounds.

[0014] The present invention includes combinations of the described embodiments and preferred features except where such combinations are expressly not permitted or expressly avoided.

[0015] Diagram Overview Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings. [Brief explanation of the drawings]

[0016] [Figure 1] The structures of compounds whose activity was tested in a cell-based tau aggregation assay

[13] are shown. The corethiazole moiety is shown in the center, the sulfonamide substituents numbered 1–6 are shown above, and the amide substituents numbered 7–12 are shown at the bottom of the schematic. [Figure 2]Figure 1 shows the inhibition of tau aggregation in fibroblasts transfected with constitutive expression of inducible full-length tau 1-441 and truncated tau (residues 295-391) for (A) MT and (B) Compound 9 [13, 25]. Using this data, the concentrations at which there is 50% inhibition of the lower 12 kDa band (EC50 values) were 0.6 μM and 3.65 μM for MT and Compound 9, respectively (results from replicate assays are tabulated in Example 3 below, with an average value of 4.816 μM for Compound 9). [Figure 3] The layered assembly of a key fragment (residues 306–378) of the monomeric dGAE sequence (image) on a single layer (main chain line) of a PHF stack is shown. (A) Approach of hairpin loop residues 337–355 (recognized by 1D12) during assembly initiation, frame 1. (B) Frame 44 shows the unwinding of the stable monomer and extension of the C- and N-termini. (C) Frame 75 shows further interactions of the monomer just prior to flipping of Pro332. (D) Frame 143 shows the truncated dGAE monomer incorporated onto the PHF stack. The sequence of the truncated dGAE monomer used in the Nudged Elastic band (NEB) simulation is shown at the bottom of the figure, along with regions mapping to epitopes recognized by a panel of single-chain antibodies (scAbs, order of decreasing gray: CE2 > 1D12 > 1G2 > CA4). [Figure 4] The HMT-tau binding pose of the HMT-protein complex is shown. The sequence of truncated tau residues 295–391 used in the MD simulations is shown at the bottom of the figure, along with the region mapping to the epitope recognized by the corresponding scAb (order of decreasing gray: CE2>E2E8>1D12>1G2>CA4). [Figure 5]Immunoreactivity of core region scAbs against dGAE assembled in the presence or absence of TAI HMT and compound 9 is shown. dGAE samples were demonstrated for scAb binding in the solution phase by first capturing dGAE with mAb 423 and then detecting bound dGAE with scAb. mAb 423 specifically recognizes the Glu391-dependent C-terminus of the dGAE fragment. Binding profiles of scAbs (A) CA4, (B) 1G2, (C) CE2, and (D) 1D12 were obtained using an anti-human C-kappa HRP-conjugated secondary antibody. Reactivity with soluble dGAE before assembly (dGAE 0h) was included to demonstrate the maximum reactivity of the scAb against nonaggregated dGAE. The reactivity of dGAE was measured after 24 hours of assembly without (dGAE 24h) or in the presence of HMT or compound 9 (C9), which was dissolved in DMSO, which also served as a solvent control. Values ​​are expressed as absorbance at 450 nm (mean ± SE, n = 2, samples run in duplicate). [Figure 6] Immunoblot intensity analysis shows a progressive decrease in binding of the recombinant scAb to the dGAE (tau297-391) epitope over the course of an 8-hour in vitro assembly. Using FIJI, the signal intensity of the dots at each time point was measured and background subtracted. For normalization, if a signal was observed in the blot at time point 0, this was defined as 1, and the remaining time points were quantified relative to this. In some experimental replicates, no signal was observed. These results were incorporated into the final plot data shown, resulting in a time point 0 value of <1.0 for antibodies CE2, CA4, and E2E8, with positive results obtained by 3 / 9, 4 / 8, and 7 / 8 replicates, respectively. If there was no signal in the blot, this was designated as zero, and the intensity at each time point is expressed as the mean ± SEM. Exposure times were used where the observed signal was not saturating and not within the linear range. [Figure 7] 1 shows a schematic diagram of the computer-aided drug design (CADD) method. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention Aspects and embodiments of the present invention are discussed with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated by reference.

[0018] Hydromethylthionine (HMT) is the active site in hydromethylthionine mesylate (HMTM), a potent tau aggregation inhibitor. Hydromethylthionine (HMT) may also be referred to as leucomethylthionium (LMT). For the avoidance of doubt, these two terms are synonymous and may be used interchangeably herein.

[0019] We used a combination of molecular dynamics (MD) simulations, immunochemistry, biochemistry, and medicinal chemistry to investigate the molecular mechanism of monomer capture by the PHF core oligomer and how HMT binds to the core tau unit of the PHF.

[0020] Molecular dynamics offers the advantage of exploring a wide range of conformational space, providing a means to determine the inherent heterogeneity of molecules and the stability of specific states of the molecule. As with dGAE, obtaining direct structural proof for the existence of specific conformations is challenging, especially for molecules with an inherent ability to spontaneously aggregate. However, structural predictions can be made that can be tested using immunochemistry, medicinal chemistry, and biochemistry. Several tools are essential to making this approach feasible: a model system capable of monitoring PHF core assembly, a family of specific monoclonal antibodies that recognize epitopes located in the PHF core domain, and prototype inhibitors that can serve as the basis for defining pharmacophore models for targeted medicinal chemistry. These techniques have been applied to investigate both models of PHF core assembly and pharmacological inhibition of assembly.

[0021] Initial MD analysis of the mode of monomer capture by the assembled PHF core template unfolds in a series of sequential steps. First, the monomer anchors to the template via a tight hairpin loop formed by residues 337–355. Pro332 then conformationally switches, allowing the monomer to unfold and zip its N- and C-termini with the corresponding segments of the pre-existing assembly. This latter event occurs over a short period of time, with the binding of residues 319–331 in a C- to N-terminal direction and the binding of residues 355–367 in an N- to C-terminal direction. This folding sequence is supported by the progressive loss of immunoreactivity with a panel of scAbs that recognize epitopes spanning the PHF core tau unit. Immunoreactivity with CE2 and CA4, which recognize epitopes directly adjacent to the hairpin loop, is lost very early, whereas closure of epitopes recognized by 1G2 and E2E8, located closer to the C-terminus, occurred at a later stage. Although a short fragment encompassing residues 306–311 has been proposed to trigger tau assembly

[26] , our analysis indicates that the process of template monomer capture occurs over a longer distance, which can be modeled in vitro by a short peptide. We show that initial capture occurs via a highly charged hairpin loop corresponding to residues 337–355. This is followed by zip-up of N- and C-terminal segments on the pre-existing template. In this sequence, the N- and C-termini of the core tau unit require flexibility to form the stable cross-β-sheet structure characteristic of the PHF core.

[0022] Because HMT is known to be a potent inhibitor of dGAE assembly, we used it as a molecular probe to determine whether a transiently stable potential ligand-binding pocket exists that can be used for structure-based drug design. Of the 750,000 possible protein conformations of dGAE identified from MD simulations, we were able to identify a single complex in which the HMT remained tightly bound to the protein structure and did not change significantly over the 100 ns of MD simulation time. Comparison with simulations in the absence of HMT revealed that the HMT acts by stabilizing one of the available conformations within the ensemble of possible conformations of the core tau unit. The driving forces responsible for the final, assembly-incompetent conformation are intramolecular hydrogen bond formation and hydrophobic collapse, reducing the water-accessible polar and hydrophobic surface area required for the alignment and adaptation of monomers onto the existing oligomer. We do not know whether different classes of TAIs may be able to act by stabilizing different conformations of the core tau unit. However, from our studies we can conclude that HMT acts by stabilizing a conformation that competes with the unwinding of the N- and C-terminal domains of the monomer required for oligomer extension.

[0023] The identified potential binding pockets provide the basis for defining a pharmacophore model. A detailed discussion of molecular dynamics studies and definition of the pharmacophore model is provided in WO 2022 / 008545 (WisTa Laboratories Ltd.), the entire disclosure of which is incorporated herein by reference.

[0024] Our study provides an explanation for the unexpected clinical efficacy of TMT as a TAI. Essentially, HMT acts by stabilizing the assembly-incompetent endogenous conformation of the PHF core tau unit. We demonstrate that the druggable pocket bounded by HMT within the PHF core provides a basis for the rational design of chemically unrelated TAIs.

[0025] We designed alternative TAIs based on the aforementioned pharmacophore model. They were synthesized and tested using two biological assay systems. The HMT binding pocket is primarily hydrophobic in nature, with some sites favorable for hydrogen bond formation. We synthesized a set of compounds chemically unrelated to HMT to test whether new inhibitors could be rationally designed to function in the druggable pocket and to optimize some of the medicinal chemistry features required for inhibitory activity.

[0026] Several new inhibitors were found to be active in a previously reported cell-based agglutination assay.

[13] The best of these were compared with HMT in a new aqueous-phase immunoassay that examined agglutination-dependent epitope closure for a panel of antibodies.

[0027] Thus, in one aspect, the present invention provides compounds of the general formula: [ka] (In the formula, R N are independently -H or -Me; R X is independently C optionally substituted with halo or hydroxy 1~4 Alkyl, -NHR N1 (where R N1 is C 1~4 alkyl) or C 5~10 is heteroaryl, R Y is independently C optionally substituted with methyl, halo, or phenyl 5~10 heteroaryl or neopentyl) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0028] In some embodiments, R N is -H.

[0029] In some embodiments, R N is -Me.

[0030] In some embodiments, R X is independently C optionally substituted with halo or hydroxy 1~4 It is alkyl.

[0031] In some embodiments, R X is -Me, -Et, -nPr, -iPr, -nBu, -iBu or -tBu optionally substituted with halo or hydroxy.

[0032] In some embodiments, R X is -Me, -Et, -nPr or -iPr optionally substituted with halo or hydroxy.

[0033] In some embodiments, R X is -Me or -Et optionally substituted with halo or hydroxy.

[0034] In some embodiments, R X is -Me optionally substituted with halo or hydroxy.

[0035] In some embodiments, R X is -Me optionally substituted with -F or -Cl.

[0036] In some embodiments, R X is -CH2F.

[0037] In some embodiments, R X is unsubstituted -Me.

[0038] In some embodiments, R X is -Et optionally substituted with hydroxy.

[0039] In some embodiments, R X is -CH2CH2OH.

[0040] In some embodiments, R X independently, -NHR N1 and R N1 is C 1~4 It is alkyl.

[0041] In some embodiments, R N1 is -Me, -Et, -nPr, -iPr, -nBu, -iBu or -tBu.

[0042] In some embodiments, R N1 is -Me, -Et, -nPr or -iPr.

[0043] In some embodiments, R N1 is -Me or -Et.

[0044] In some embodiments, R X are independently -NHMe.

[0045] In some embodiments, R X independently, C 5~10 It is heteroaryl.

[0046] In some embodiments, R X is the nitrogen-containing C 5~10 It is a heteroaryl group.

[0047] In some embodiments, R X is selected from indolyl, benzimidazolyl, pyrrolyl, imidazolyl, pyrazolyl.

[0048] In some embodiments, R X is an indolyl group.

[0049] In some embodiments, R X teeth, [ka] is.

[0050] In some embodiments, R Y is neopentyl (-CH2C(CH3)3).

[0051] In some embodiments, R Y is independently C optionally substituted with methyl, halo, or phenyl 5~10 It is heteroaryl.

[0052] In some embodiments, R Y is a nitrogen-containing C optionally substituted with methyl, halo, or phenyl 5~10 It is heteroaryl.

[0053] In some embodiments, R Y is a nitrogen-containing C optionally substituted with halo or phenyl 5~10 It is heteroaryl.

[0054] In some embodiments, R Y is a nitrogen-containing C optionally substituted with -Me, -Cl, or -Ph 5~10 It is heteroaryl.

[0055] In some embodiments, R Y is a nitrogen-containing C selected from pyrrolyl, imidazolyl, pyrazolyl, indolyl, and benzimidazolyl, optionally substituted with -Me, -Cl, or -Ph; 5~10 It is heteroaryl.

[0056] In some embodiments, R Y is a nitrogen-containing C selected from pyrrolyl, pyrazolyl, and benzimidazolyl, optionally substituted with -Me, -Cl, or -Ph; 5~10 It is heteroaryl.

[0057] In some embodiments, R Y is the unsubstituted C 5~10 It is heteroaryl.

[0058] In some embodiments, R Y is the unsubstituted nitrogen-containing C 5~10 It is heteroaryl.

[0059] In some embodiments, R Y is unsubstituted pyrrolyl, imidazolyl, pyrazolyl, indolyl or benzimidazolyl.

[0060] In some embodiments, R Y is unsubstituted pyrrolyl or indolyl.

[0061] In some embodiments, R Y teeth, [ka] is selected from.

[0062] Preferred compounds In general, the present invention relates to one or more compounds selected from the following compounds and their use in medicine:

[0063] [Table 1]

[0064] [Table 2]

[0065] [Table 3]

[0066] [Table 4]

[0067] In this and all other aspects of the invention, unless the context indicates otherwise, the compound may be selected from the list consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26.

[0068] In one embodiment, the compound may be selected from the list consisting of 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 18, 20, 21 and 23.

[0069] In one embodiment, the compound may be selected from the list consisting of 1, 4, 5, 6, 9, 10, 12, 15, 16 and 20.

[0070] In one embodiment, the compound may be selected from the list consisting of 5, 9, 10, 12 and 20.

[0071] In one embodiment, the compound may be selected from the list consisting of 9, 10, 14 and 25.

[0072] In one embodiment, the compound is compound 9.

[0073] Preferred compounds of the invention are those that exhibit activity in the assays described herein. Particularly preferred compounds have an activity of less than 0.5 in the cell-based aggregation inhibition assay described herein (truncated tau to full-length tau ratio, tested at 2 μM).

[0074] Preferably, the compound has an EC of less than 500, 250, 200, 100 or 50 as determined with reference to the examples herein. 50 Preferably, the compound has a B of less than 750, 500, 200 or 100 as determined with reference to the examples herein. 50 It has.

[0075] Isotope variations In one embodiment, one or more of the carbon atoms of the compound is 11C or 13 C or 14 It is C.

[0076] In one embodiment, one or more of the carbon atoms of the compound is 11 It is C.

[0077] In one embodiment, one or more of the carbon atoms of the compound is 13 It is C.

[0078] In one embodiment, one or more of the carbon atoms of the compound is 14 It is C.

[0079] In one embodiment, one or more of the nitrogen atoms of the compound is 15 It's N.

[0080] Use for reversing or inhibiting the aggregation of tau protein. One aspect of the present invention is the use of thiazole-containing compounds to reverse or inhibit the aggregation of tau protein. This aggregation can be in vitro or in vivo and can be associated with the tauopathy disease states discussed herein. Also provided are methods of reversing or inhibiting the aggregation of tau protein, comprising contacting the aggregate or protein with a compound described herein.

[0081] As discussed below, various tauopathy diseases are recognized, characterized by prominent tau pathology in neurons and / or glia, and the term has been used in the art for several years. Similarities between these pathological inclusions and the characteristic tau inclusions in diseases such as AD indicate shared structural features, and it is the topographic distribution of pathology that accounts for the distinct clinical phenotypes identified. In addition to the specific diseases described below, those skilled in the art can identify tauopathies by further using a combination of cognitive or behavioral symptoms and an appropriate ligand for aggregated tau visualized using PET or MRI, such as those described in WO 2010 / 034982.

[0082] Therapeutic or prophylactic methods and primary and secondary medical uses One aspect of the present invention relates to a method of treating or preventing a tauopathy condition in a patient, comprising administering to the subject a therapeutically effective amount of a thiazole-containing compound described herein.

[0083] An aspect of the present invention relates to "tauopathies." The pathogenesis of neurodegenerative diseases such as Pick's disease and progressive supranuclear palsy (PSP), as well as Alzheimer's disease (AD), appears to correlate with the accumulation of pathological truncated forms of tau in stellate pyramidal cells of the dentate gyrus and neocortex. Other dementias include frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP-17), disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), pallidopontonigral degeneration (PPND), Guam amyotrophic lateral sclerosis, pallidoncroluysian degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic grain dementia (AgD), dementia pugilistica (DP), where neurofibrillary tangles (NFTs) resemble those seen in AD, albeit with a different topography

[27] , chronic traumatic encephalopathy (CTE), tauopathies such as DP, and repetitive and sports-related concussion

[28] . Other examples are described in Wischik et al. 2000

[30] , see especially Table 5.1).

[0084] Abnormal tau in NFTs is also found in Down syndrome (DS)

[31] and dementia with Lewy bodies (DLB).

[32] Tau-positive NFTs are also found in postencephalitic parkinsonism (PEP).

[33] Tau tangles in glial cells are identified in subacute sclerosing panencephalitis (SSPE).

[34]

[0085] Other tauopathies include Niemann-Pick disease type C (NPC)

[35] , Sanfilippo syndrome type B (or mucopolysaccharidosis III B, MPS III B)

[36] , and myotonic dystrophy (DM), DM1

[37] and DM2

[38] .

[0086] Furthermore, there is a growing consensus in the literature that tau pathology may also contribute to cognitive deficits and decline more generally, such as in mild cognitive impairment (MCI) (see, e.g.,

[39] ).

[0087] All of these diseases that are characterized primarily or in part by abnormal tau aggregation are referred to herein as "tauopathies" or "diseases of tau protein aggregation."

[0088] In this and all other aspects of the invention relating to a tauopathy, preferably the tauopathy is selected from the list consisting of the above indications, i.e. AD, Pick's disease, PSP, FTD, FTDP-17, DDPAC, PPND, Guam ALS syndrome, PNLD, CBD, AgD, DS, SSPE, DP, PEP, SSPE, DLB, CTE and MCI.

[0089] In a preferred embodiment, the tauopathy is Alzheimer's disease (AD).

[0090] One aspect of the present invention pertains to compounds, as described herein, for use in a method for the treatment or prevention (eg, of a tauopathy condition in a human or animal body) by therapy.

[0091] One aspect of the present invention pertains to the use of compounds according to the present invention in the manufacture of a medicament for the treatment or prevention of a tauopathy condition.

[0092] A further embodiment is a method of treating or preventing a disease of tau protein aggregation described herein, comprising administering to a subject a compound described herein or a therapeutic composition comprising same, such that the compound inhibits the aggregation of tau protein associated with the disease state.

[0093] Other Methods and Uses In a further embodiment, a compound as described herein or a therapeutic composition comprising the same is disclosed for use in a method for treating or preventing a disease of tau protein aggregation as described above, the method comprising administering to a subject a thiazole-containing compound or composition that inhibits the aggregation of tau protein associated with the disease state.

[0094] In a further embodiment, there is disclosed the use of a compound as described herein in the manufacture of a medicament for use in a method for treating or preventing a disease of tau protein aggregation as described above, the method comprising administering to a subject a medicament that inhibits the aggregation of tau protein associated with said disease state.

[0095] In one embodiment, a method is disclosed for modulating the aggregation of tau protein in the brain of a mammal, wherein said aggregation is associated with a disease state as described above, and wherein the treatment comprises administering to said mammal in need of said treatment a prophylactically or therapeutically effective amount of an inhibitor of said aggregation, wherein the inhibitor is a thiazole-containing compound as described herein.

[0096] One aspect of the invention is a method of inhibiting the production of protein aggregates (e.g., in the form of paired helical filaments (PHFs), optionally neurofibrillary tangles (NFTs)) in the mammalian brain, wherein the treatment is as described herein.

[0097] In one aspect, the present invention provides a pharmaceutical product for treating a disease state associated with tau protein aggregation in a mammal suffering therefrom, the pharmaceutical product comprising a container labeled with or associated with a label indicating that the pharmaceutical product is for treating said disease, the container containing one or more dosage units, each comprising at least one pharmaceutically acceptable excipient and a pure, isolated compound of the present invention as an active ingredient.

[0098] Composition, Formulation and Purity In one embodiment, compounds that are no more than 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, or 90% pure may be provided or used in the compositions.

[0099] One aspect of the invention relates to a dosage unit (e.g., a pharmaceutical tablet or capsule) comprising 20 to 300 mg of a compound described herein (e.g., obtained or obtainable by a method described herein, having a purity described herein, etc.) and a pharmaceutically acceptable carrier, diluent, or excipient.

[0100] In one embodiment, the dosage unit is a tablet.

[0101] In one embodiment, the dosage unit is a capsule.

[0102] Dosage units (eg, pharmaceutical tablets or capsules) comprising 20-300 mg of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient are discussed in more detail below.

[0103] In one embodiment, the amount is 30 to 200 mg.

[0104] In one embodiment, the amount is about 25 mg.

[0105] In one embodiment, the amount is about 35 mg.

[0106] In one embodiment, the amount is about 50 mg.

[0107] In one embodiment, the amount is about 70 mg.

[0108] In one embodiment, the amount is about 125 mg.

[0109] In one embodiment, the amount is about 175 mg.

[0110] In one embodiment, the amount is about 250 mg.

[0111] In one embodiment, the pharmaceutically acceptable carrier, diluent, or excipient is or includes one or both of a glyceride (e.g., Gelucire 44 / 14®, lauroyl macrogol-32 glyceride, PhEur, USP) and colloidal silicon dioxide (e.g., 2% Aerosil 200®, colloidal silicon dioxide PhEur, USP).

[0112] formulation While it is possible for a compound to be used (eg, administered) alone, it is often preferable to present it as a composition or formulation.

[0113] In one embodiment, the composition is a pharmaceutical composition (e.g., formulation, dosage form, medicament) comprising a thiazole-containing compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0114] In one embodiment, the composition is a pharmaceutical composition comprising at least one compound described herein together with one or more other pharmaceutically acceptable ingredients well known to those of skill in the art, including but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents.

[0115] In one embodiment, the composition further comprises another agent, for example, another therapeutic or prophylactic agent.

[0116] Suitable carriers, diluents, excipients, etc. are described in standard pharmaceutical textbooks, see, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000, and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

[0117] Another aspect of the present invention is a pharmaceutical composition comprising at least one compound as defined herein, together with one or more other pharmaceutically acceptable ingredients, such as carriers, diluents, excipients, etc., that will be well known to those skilled in the art. 11 C] radiolabeled thiazole-containing compound. When formulated as discrete units (e.g., tablets), each unit contains a predetermined amount (dosage) of active compound.

[0118] As used herein, the term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are within the scope of sound medical judgment and suitable for use in contact with the tissues of a subject (e.g., a human) in question without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0119] The formulations can be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing the active compound into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with the carrier (e.g., liquid carrier, finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0120] The formulations may be manufactured to provide fast or slow release, immediate, delayed, sustained or extended release, or combinations thereof.

[0121] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solution suspensions) in which the active ingredient is dissolved, suspended, or provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickeners, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Generally, the concentration of the active ingredient in the liquid is from about 1 ng / ml to about 10 μg / ml, e.g., from about 10 ng / ml to about 1 μg / ml. The formulations may be presented in unit-dose or multi-dose hermetically sealed containers, for example ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0122] Dosage Those skilled in the art will understand that appropriate dosages of compounds and compositions containing compounds may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against risk or adverse side effects. The selected dosage level will depend on a variety of factors, including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, the severity of the condition, the patient's species, sex, age, weight, condition, general health, and previous medical history. The amount of compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage will be selected to achieve a local concentration at the site of action and achieve the desired effect without causing substantial harmful or toxic side effects.

[0123] Administration can be carried out continuously in one dose or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those skilled in the art and will vary depending on the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out, with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0124] In general, suitable doses of active compound range from about 100 ng to about 25 mg (more usually about 1 μg to about 10 mg) per kilogram of subject body weight per day. Where the active compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated on the basis of the parent compound, and so the actual amount used will be increased proportionately.

[0125] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 100 mg three times daily.

[0126] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 150 mg twice daily.

[0127] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 200 mg twice daily.

[0128] However, in one embodiment, the compound is administered to a human patient according to the following dosing regimen: about 50 or about 75 mg three or four times daily.

[0129] In one embodiment, the compound is administered to a human patient according to the following dosing regimen: about 100 or about 125 mg twice daily.

[0130] Preferred Combination Therapy Combination treatments and therapies, in which two or more treatments or therapies are combined, for example sequentially or simultaneously, are discussed in more detail below. Accordingly, it will be understood that any of the medical uses or methods described herein may be used in combination therapy.

[0131] In one embodiment, a treatment of the invention (e.g., with a compound of the invention) is used in combination with a cholinesterase inhibitor such as donepezil (Aricept™), rivastigmine (Exelon™), or galantamine (Reminyl™).

[0132] In one embodiment, a treatment of the invention (eg, with a compound of the invention) is used in combination with an NMDA receptor antagonist, such as memantine (Ebixa™, Namenda™).

[0133] In one embodiment, a treatment of the invention (eg, with a compound of the invention) is used in combination with a muscarinic receptor agonist.

[0134] In one embodiment, a treatment of the invention (e.g., using a compound of the invention) is combined with an inhibitor of amyloid precursor protein for beta amyloid (e.g., an inhibitor of amyloid precursor protein processing that enhances the production of beta amyloid).

[0135] Ligands and Labels The thiazole-containing compounds described herein that can inhibit the aggregation of tau protein can also act as ligands or labels for tau protein (or aggregated tau protein). Thus, in one embodiment, the thiazole-containing compound is a ligand for tau protein (or aggregated tau protein).

[0136] Such thiazole-containing compounds (ligands) may incorporate, conjugate, chelate, or otherwise associate with other chemical groups, such as stable and labile detectable isotopes, radioisotopes, positron-emitting elements, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, therapeutic moieties, or any other moiety that may aid in prognostic, diagnostic, or therapeutic applications.

[0137] For example, as noted above, in one embodiment, the compound is as defined above, but with the additional restriction that the compound incorporates, conjugates or chelates or otherwise associates with one or more (e.g., 1, 2, 3, 4, etc.) isotopes, radioisotopes, positron-emitting atoms, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, or therapeutic moieties.

[0138] In one embodiment, the compound is a ligand and a label, e.g., a label of tau protein (or aggregated tau protein), which incorporates, conjugates or chelates or is otherwise associated with one or more (e.g., 1, 2, 3, 4, etc.) detectable labels.

[0139] For example, in one embodiment, the compound is as defined above, but with the additional restriction that the compound incorporates, conjugates, chelates, or otherwise associates with one or more (e.g., 1, 2, 3, 4, etc.) detectable labels.

[0140] The labeled compound (e.g., when ligated to tau protein or aggregated tau protein) may be visualized or detected by appropriate means, and one of skill in the art will recognize that any appropriate detection means known in the art may be used.

[0141] For example, a thiazole-containing compound (ligand label) can be labeled with a positron-emitting atom (e.g., 11 C) (e.g., as a carbon atom of one or more alkyl group substituents, such as a methyl group substituent) and detecting the compound using positron emission tomography (PET) as known in the art.

[0142] treatment The term "treatment" as used herein in relation to the treatment of a medical condition generally relates to treatments and therapies, whether in humans or animals (e.g., in the veterinary field), in which some desired therapeutic effect is achieved, such as slowing the rate of progression, halting the rate of progression, inhibiting the progression of the medical condition, including regression of the medical condition, ameliorating the medical condition, and curing the medical condition, whether in humans or animals (e.g., in the veterinary field). Treatment as a preventative measure (i.e., prevention, prophylaxis) is also encompassed.

[0143] As used herein, the term "therapeutically effective amount" relates to the amount of an active compound or substance, composition or dosage form containing an active compound, that is effective in producing some desired therapeutic effect when administered in accordance with a desired treatment regimen, commensurate with a reasonable benefit / risk ratio.

[0144] Similarly, the term "prophylactically effective amount," as used herein, relates to the amount of an active compound or agent, composition or dosage form containing an active compound, that, when administered in accordance with a desired treatment regimen, is effective in producing some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio.

[0145] The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are used together, e.g., sequentially or simultaneously. Examples of treatments or therapies include, but are not limited to, chemotherapy (administration of active agents, e.g., drugs, antibodies (e.g., in immunotherapy), prodrugs (e.g., in photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), etc.), surgery, radiation therapy, and gene therapy.

[0146] Administration route The thiazole-containing compound or pharmaceutical composition comprising same may be administered to a subject / patient by any convenient route of administration, whether systemic / peripheral / or local (ie, at the intended site of action).

[0147] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (e.g., by patch, plaster, etc.), transmucosal (e.g., by patch, plaster, etc.), intranasal (e.g., by nasal spray), ocular (e.g., by eye drops), pulmonary (e.g., by inhalation, e.g., by aerosol via the mouth or nose, or insufflation therapy), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral administration, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intraarticular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal (e.g., intravascular catheter into the brain), e.g., by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular.

[0148] Subjects / patients The subject / patient can be an animal, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), monotreme (e.g., duckbilled platypus), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0149] Furthermore, the subject / patient may be in any of its forms of development, for example, a fetus.

[0150] In a preferred embodiment, the subject / patient is a human.

[0151] Suitable subjects for the method may be selected based on conventional factors. Thus, initial patient selection may include one or more of: rigorous evaluation by an experienced clinician; exclusion of possible non-AD diagnoses through complementary laboratory and other studies; and objective assessment of the level of cognitive function using a neuropathologically confirmed battery.

[0152] In one embodiment, the subject / patient is not human.

[0153] Synthesis method Methods for chemically synthesizing the compounds of the invention are described herein in the Examples. These and / or other known methods can be modified and / or adapted in known ways to facilitate the synthesis of other compounds of the invention.

[0154] Thus, one aspect of the present invention provides methods for synthesizing compounds of the present invention as described herein or as described or substantially as described with reference to any of the Examples below.

[0155] The present invention further provides compounds of the invention obtained or obtainable by the methods described herein.

[0156] One aspect of the present invention relates to methods for making the thiazole-containing TAI compounds described herein. The present invention also provides intermediate compounds used in making the compounds of the present invention.

[0157] General synthesis method Compounds of formula (I) may be prepared, for example, via the routes described in the general scheme below. [ka] In this scheme and all subsequent schemes in this section, substituents may be generally designated as "R." These substituents may be independently R N , R X and R YIt will be understood that these groups may correspond to protected forms thereof or may additionally represent precursor groups as appropriate throughout the synthetic scheme.

[0158] For example, route (i) can involve reacting a sulfonamide thiazole acid with a suitable alkylamine in an amide-forming step. For example, the acid can be treated with a base (such as diisopropylethylamine DIPEA), a coupling agent (such as HATU), and an amine. Preferably, the reaction is carried out in a polar aprotic solvent such as DMF or MeCN.

[0159] For example, route (ii) may involve reacting an amidothiazolamine with an appropriate sulfonyl chloride in the presence of a base (such as triethylamine or DIPEA). Preferably, the reaction is carried out in a polar aprotic solvent such as THF.

[0160] Starting materials for synthesizing the compounds of the invention may be prepared by known routes and / or may be commercially available. Methods for synthesizing exemplary compounds are described in the Examples herein. These and / or other known methods may be modified and / or adapted in known ways to facilitate the synthesis of other compounds of the invention.

[0161] The features disclosed in the foregoing specification, or the following claims, or the accompanying drawings, whether presented in their specific form or in terms of means for performing a disclosed function or a method or process for achieving a disclosed result, may be used separately or in any combination with such features to realize the invention in various of its forms.

[0162] While the present invention has been described in conjunction with the exemplary embodiments set forth above, many equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes can be made to the described embodiments without departing from the spirit and scope of the invention.

[0163] For the avoidance of doubt, the theoretical explanations provided herein are provided for the purpose of improving the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0164] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0165] Throughout this specification, including the claims which follow, unless the context requires otherwise, the words "comprise" and "comprises" and variations such as "comprises," "including," and "comprising" will be understood to imply the inclusion of a specified integer or step or group of integers or steps but not the exclusion of other integers or steps or groups of integers or steps.

[0166] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. With "about," the numerical value is arbitrary, meaning, for example, + / - 10%. [Example]

[0167] Example Example 1 Modeling of monomer capture by PHF core oligomers; immunochemical analysis of assembly; characterization of the HMT binding pocket Molecular dynamics simulations were performed to explore the conformational landscape of the dGAE monomer, as detailed in WO 2022 / 008545. We further developed a panel of single-chain monoclonal antibody fragments (scAbs) that recognize linear epitopes spanning most of the core tau unit and used these to examine epitope availability in dot immunoblots over the course of dGAE assembly in vitro [6]. We hypothesized that the inhibitory effect of HMT on dGAE assembly could be explained by the stabilization of a transient cryptic ligand-binding pocket by a ligand-induced funnel-shaped conformation

[40] . We ultimately identified a single complex in which HMT remained tightly bound, and the protein structure did not change significantly after 100 ns of MD simulation time. Thus, the HMT-bound complex represents an energy well in which conformation is maintained over a relatively long period of time. The conformation of the tau297-391 core unit stabilized by the HMT is a compact folded state lacking β-sheets, which is very different from the extended conformation required for the monomer to align on the PHF core template.

[0168] Pharmacophore modeling of potential druggable pockets and its use to identify novel inhibitors The site bound by HMT was determined to be 70% druggable

[41] , i.e., possesses a favorable proportion of hydrophobic, solvent-accessible surface area. As also disclosed in WO 2022 / 008545, the inventors developed a pharmacophore model based on key residues that can be used to aid in the rational design of TAIs. The HMT-binding pocket is primarily hydrophobic in nature (Phe378, Phe346, Val350, Leu315, Ile354, Ile371). Many residues have the potential to form hydrogen bonds with molecules bound within this pocket, such as the NH of Lys347, Thr373, Leu315, and Glu372. The inventors utilized the shape, hydrogen bonding, and lipophilicity features identified by HMT to design alternative TAIs in the pharmacophore model.

[0169] Using a computer-aided drug design approach (see below), we identified a thiazole core as a suitable heterocyclic replacement for the central ring of HMT. A representative range of candidates was synthesized and tested in a cell-based tau aggregation screening assay (see below and Figure 1), which measures the ability of compounds to inhibit capture of full-length tau by dGAE and its template truncation by endogenous proteases

[13] . In this model, 1 μM MT reduces aggregation to 9.6% of the aggregation measured in its absence. Of the compounds synthesized and tested, compound 9 reduced the level of tau aggregation to 26.6% of the level measured in the absence of compound. The 50% inhibition (EC ) from one experiment was 1.2%. 50 The concentrations required for MT and compound 9 were 0.6 μM and 3.65 μM, respectively (FIG. 2). Data from replicate experiments are summarized in Example 3 below.

[0170] Comparison of the inhibitory activity of the tested thiazole derivatives reveals that interactions with Lys343 via hydrogen bonds and π-cation interactions are important in determining compound potency. The orientation of the sulfonamide oxygen atom is important for achieving the desired hydrogen bond with the main-chain carbonyl of Lys343. Substitution of the methyl group on amide 7 to form amide 8 results in a change in potency. This is explained by the reorientation of the thiazole amide in compound 2, which forms a critical H-bond to the main-chain NH of Lys347 compared to compound 1. This interaction is disrupted by a new interaction with the pyrrole NH of Thr373. Small alkyl substituents appear to be more suitable for binding within the lipophilic pocket for Phe378. Sulfonamides affect the ability of the amide site to form a hydrogen bond to the NH of Thr373. Both amide substituents 9 and 11 have the ability to form additional hydrogen bonds with proteins, either with the main-chain carbonyl of Asp345 or with Leu315. Compound 9 satisfies many of the required binding features, including the sulfonamide oxygen hydrogen bond to the backbone NH of Glu372, the amide carbonyl forming a hydrogen bond to the backbone NH of Lys347, and the pyrazole forming hydrogen bonds to the NH of Thr373 and the carbonyl backbone of Leu315. Furthermore, the phenyl substituent on the pyrazole is well-positioned to bind tightly in the lipophilic pocket, form a face-edge π-stack with Phe378, and interact with Lys343 through a π-cation interaction. Thus, the pharmacophore model developed based on HMT binding allows for the identification of compounds chemically unrelated to HMT that also have the ability to inhibit tau aggregation.

[0171] Immunochemical confirmation of TAI activity As an additional confirmation of activity, TAI activity in dGAE preparations was measured using an aqueous-phase ELISA assay (see Example 3 below). Immunoreactivity with model antibodies (whose epitopes are illustrated in Figures 3 and 4 ) was measured before and after assembly of dGAE in the presence and absence of HMT and Compound 9. Immunoreactivity across a range of dGAE dilutions indicates that all epitopes were accessible for antibody binding in the soluble, pre-assembly dGAE preparation ( Figure 5 ). In the assembled dGAE preparation, the CA4 and CE2 epitopes became almost completely unavailable, whereas the accessibility of the 1G2 and 1D12 epitopes was substantially reduced, consistent with the immunoblot analysis shown in Figure 6 . When dGAE assembly was performed in the presence of HMT, assembly-dependent occlusion of these epitopes did not occur. The CE2 epitope was more accessible in the HMT-treated sample than in the soluble, pre-assembly sample, suggesting reversal of partial oligomerization in solution before assembly was induced. The 1G2 epitope remained partially blocked in the HMT assembly preparation, consistent with the critical HMT binding site, Thr373 (within the 1G2 epitope). Epitope exposure was less complete for compound 9. While comparable to HMT, there was only partial exposure of the CA4 and 1D12 epitopes, as measured by 1G2 immunoreactivity. HMT binding prevented conformational changes in the CE2 epitope that would cause an early loss of immunoreactivity, but this was not the case for compound 9, a feature that may explain the low potency of this compound in cellular assays.

[0172] Computer-Aided Drug Design (CADD) Energy minimization and 50 ns molecular dynamics simulations were performed on 30 replicas of the unliganded single-stranded filament (Figure 7). Principal component analysis was performed along the simulation trajectory to identify clusters. Representative sample protein conformations were obtained from each cluster, and the RMSD between snapshots was determined. 380 different protein structures were used for docking and identified, resulting in 15,090 ligand poses. The poses were scored, and 178 binding poses for 65 binding sites were found. A short minimization was performed, followed by a 1 ns run for each system. The ligand binding energy was recalculated. The top-scoring ligand was adopted, the simulation time was extended, and the process was repeated numerous times. The trajectory of interest was then processed for analysis.

[0173] Example E2 - Chemical Synthesis All reactions were performed under a positive pressure of argon unless otherwise specified. Glassware was oven-dried at 120 °C or flame-dried under vacuum unless otherwise specified. Anhydrous dichloromethane (DCM), acetonitrile (MeCN), N,N-dimethylformamide (DMF), and pyridine were purchased from Sigma-Aldrich. Anhydrous tetrahydrofuran (THF) was purchased from Acros Organics or Sigma-Aldrich. Other commercially available solvents or reagents were used without further purification unless otherwise specified. Ambient temperatures were 20-21 °C as indicated. Reactions were monitored by thin-layer chromatography (TLC) using precoated silica gel plates from EMD Millipore (TLC Silica Gel 60F254). Flash column chromatography was performed on silica gel 60 (particle size 0.04-0.063 mm) commercially available from Fluorochem or on a Biotage® Selekt instrument using prepacked columns commercially available from Biotage®. 1 H NMR and 13C NMR spectra were recorded on a Bruker Avance II 400 MHz & 600 MHz spectrometer at 298 K, and residual solvent peaks were used as: CDCl, 7.26 ppm ( 1 H) and 77.16 ppm ( 13 C);CD3OD, 3.31 ppm ( 1 H) and 49.00 ppm ( 13 C);DMSO-d6, 2.50 ppm ( 1 H) and 39.52 ppm ( 13 C). NMR data are given in apparent multiplicity: m = multiplet, s = singlet, d = doublet, t = triplet and combinations thereof, with br indicating broad, poorly resolved signals. Mass spectra were obtained on a Waters Xevo® G2 QTOF mass spectrometer. IR spectra were recorded on a PerkinElmer FT-IR Spectrum Two spectrometer equipped with an ATR diamond cell. Melting points were obtained using a Stuart® SMP50 melting point apparatus and are uncorrected.

[0174] Synthesis of tert-butyl 4-(3,3-dimethylbutylcarbamoyl)thiazol-2-ylcarbamate [ka] To a stirred suspension of 2-Boc-aminothiazole-4-carboxylic acid (253 mg, 1.04 mmol) in anhydrous MeCN (20 mL) was added DIPEA (269 mg, 362 μL, 2.08 mmol) under an inert atmosphere. Once the solid was completely dissolved, HATU (407 mg, 1.07 mmol) was added, followed by 3,3-dimethylbutylamine (108 mg, 144 μL, 1.07 mmol). The reaction mixture was heated at 50° C. for 23 h. Water (40 mL) was added and the resulting suspension was cooled to ambient temperature. Additional water (20 mL) was added and the suspension was vacuum filtered. The collected solid was washed with water (3×10 mL) and dried in a vacuum oven at 40° C. for 2 h to afford the title compound (246 mg, 73%) as an off-white solid. 1H (400 MHz, CDCl3) δ 7.73 (br s, 1H), 7.67 (s, 1H), 6.98 (br s, 1H), 3.45-3.39 (m, 2H), 1.55 (s, 11H, including H2O signals), 1.53-1.49 (m, 2H), 0.96 (s, 9H); 13 C(101MHz,CDCl3)δ161.18,158.86,151.96,145.06,117.18,83.43,43.45,36.12,30.13,29.57,28.29

[0175] Synthesis of 2-amino-N-(3,3-dimethylbutyl)thiazole-4-carboxamide [ka] To a stirred solution of tert-butyl 4-(3,3-dimethylbutylcarbamoyl)thiazol-2-ylcarbamate (233 mg, 0.712 mmol) in DCM (6 mL) was added dropwise TFA (2 mL) under an inert atmosphere. The reaction mixture was stirred at 20 °C for 4 h and then concentrated to leave an orange residue, which was dissolved in EtOAc (20 mL). The resulting solution was washed with saturated aqueous NaHCO (10 mL) and brine (10 mL). The organic phase was dried (MgSO), filtered, and evaporated to give a viscous orange oil, which was purified by flash chromatography (SiO, EtOAc:petroleum ether 40 / 60, 7:3) to give the title compound (171 mg) as a yellow oil. The material was used without purification. 1 H(400MHz,CDCl3)δ7.33(s,1H),7.01(br s,1H),4.98(br s,2H),3.42-3.37(m,2H),1.52-1.48(m,2H),0.95(s,9H); 13 C(101MHz,CDCl3)δ168.93,159.42,141.20,112.81,42.86,36.70,30.02,29.44

[0176] Synthesis of methyl 2-(N-(4-(3,3-dimethylbutylcarbamoyl)thiazol-2-yl)sulfamoyl)acetate [ka] To a stirred solution of 2-amino-N-(3,3-dimethylbutyl)thiazole-4-carboxamide (123 mg, 0.541 mmol) in DCM (5 mL) was added pyridine (65 mg, 66 μL, 0.816 mmol) and DMAP (14 mg, 0.115 mmol) under an inert atmosphere. Methyl 2-(chlorosulfonyl)acetate (98 mg, 66 μL, 0.568 mmol) was added dropwise, and the resulting solution was stirred at 20 °C for 43 h. The reaction mixture was diluted with DCM (5 mL) and washed with 0.5 M aqueous HCl (10 mL), water (10 mL), and brine (10 mL). The brine was extracted with EtOAc (10 mL), and the organic extracts were combined, dried (MgSO), filtered, and evaporated to leave a yellow and white material. The crude product was purified by flash chromatography (SiO, DCM:MeOH, 19:1 then 9:1) and the isolated material was further purified by flash chromatography (SiO, EtOAc:MeOH, 98:2 then 9:1) to afford the title compound (112 mg) slightly impure as a pink-orange foam. Material was used without further purification. 1 H (400MHz, CD3OD) δ 7.41 (s, 1H), 4.16 (s, 2H), 3.69 (s, 3H), 3.37-3.33 (m, 3H, containing MeOH), 1.51-1.47 (m, 2H), 0.94 (s, 9H)

[0177] N-(3,3-dimethylbutyl)-2-(2-hydroxyethylsulfonamido)thiazole-4-carboxamide [ka] To a stirred solution of the crude sample of methyl 2-(N-(4-(3,3-dimethylbutylcarbamoyl)thiazol-2-yl)sulfamoyl)acetate (103 mg, 0.283 mmol) in anhydrous THF (5 mL) was added sodium borohydride (43 mg, 1.14 mmol) under an inert atmosphere. The resulting suspension was stirred at 20 °C for 27 h and quenched with saturated aqueous NH4Cl (20 mL). The mixture was extracted with EtOAc (2 × 20 mL). The aqueous layer was acidified with 3 drops of 32% aqueous HCl, saturated with NaCl, and extracted with DCM (3 × 15 mL). The DCM was dried (MgSO4), filtered, and evaporated to leave a white solid. The crude product was dissolved in DCM (15 mL) and quenched with a 3:1 (v / v) mixture of water and saturated aqueous NaHCO3 (20 mL). The aqueous layer was washed with DCM (15 mL) and then acidified with 1 M aqueous HCl to a pH of approximately 1. The acidic solution was extracted with DCM (2 × 15 mL), and the combined DCM extracts were washed with brine (10 mL), dried (MgSO), filtered, and evaporated to leave a white solid. After drying in a vacuum oven at 40 °C for 1.5 h, the title compound (38 mg, 40%, 23% over two steps) was obtained as a white solid. IRu max (cm -1 )3480,3313,3095,2960,1645,1544,1267,1239,1116,1041,896,659,553,535; 1 H(400MHz,DMSO-d6)δ12.71(br s,1H),8.43(br s,1H),7.44(s,1H),4.78(br s,1H),3.73(t,J=6.7Hz,2H),3.24-3.19(m,4H),1.43-1.39(m 2H),0.91(s,9H); 13 C(101MHz,DMSO-d6)δ166.90(br),157.34,132.98(br),111.50(br),55.83,55.41,42.51,35.59,29.65,29.22; HRMS:C 12 H 21For N3NaO4S2, m / z (ESI) calculated: 358.0871 (M+Na) + ;Measured value: 358.0875

[0178] Synthesis of tert-butyl (4-(((1-methyl-1H-pyrrol-2-yl)methyl)carbamoyl)thiazol-2-yl)carbamate [ka] To a stirred solution of 2-Boc-aminothiazole-4-carboxylic acid (526 mg, 2.05 mmol), DIPEA (530 mg, 714 μL, 4.10 mmol), and HATU (779 mg, 2.05 mmol) in a mixture of anhydrous MeCN (15 mL) and DMF (10 mL) under inert atmosphere was added 1-(1-methyl-1H-pyrrol-2-yl)methanamine (226 mg, 2.05 mmol), and the reaction mixture was stirred for 15 h at 20° C. The solvent was evaporated, and the residue was dissolved in EtOAc (40 mL) and washed with water (15 mL) and brine (15 mL). The aqueous washes were extracted with EtOAc (2 × 20 mL) and the combined organic extracts were dried (MgSO), filtered and evaporated to give a solid which was purified by flash chromatography (SiO, hexane / EtOAc, 1:1) to give the title compound (561 mg, 81%) as a cream-colored solid after drying under high vacuum at 20 °C for 3.5 h. 1 H(400MHz,CDCl3)δ7.73(br s,1H),7.72(s,1H),7.10-7.19(m,1H),6.63(s,1H),6.14(s,1H),6.09(s,1H),4.59(d,J=5.3Hz,2H),3.60(s,3H),1.55(s,9H); 13 C(101MHz,CDCl3)δ160.55,158.76,151.84,144.41,128.48,123.10,117.50,108.90,106.95,83.29,34.92,33.80,28.11

[0179] Synthesis of 2-amino-N-((1-methyl-1H-pyrrol-2-yl)methyl)thiazole-4-carboxamide [ka] A solution of tert-butyl (4-(((1-methyl-1H-pyrrol-2-yl)methyl)carbamoyl)thiazol-2-yl)carbamate (265 mg, 0.788 mmol) in 2,2,2-trifluoroethanol (3.5 mL) was placed in a sealed microwave vial and heated to 150° C. with stirring (1000 rpm) for 1.5 h. The solvent was removed by evaporation and the residue was purified by flash chromatography (SiO, hexane / EtOAc, 1:1) to give the title compound (135 mg, 73%) as a white solid after drying at 60° C. for 19 h. 1 H(400MHz,CDCl3)δ7.39(s,1H),7.15(br s,1H),6.62(s,1H),6.13(s,1H),6.08(s,1H),4.88(br s,2H),4.57(d,J=5.6Hz,2H),3.60(s,3H); 13 C(101MHz,CDCl3)δ166.71,160.62,145.50,128.48,123.07,113.85,108.94,106.90,34.91,33.81

[0180] Synthesis of methyl (4-(((1-methyl-1H-pyrrol-2-yl)methyl)carbamoyl)thiazol-2-yl)sulfonyl)acetate [ka] To a stirred solution of 2-amino-N-((1-methyl-1H-pyrrol-2-yl)methyl)thiazole-4-carboxamide (55 mg, 0.233 mmol) and pyridine (28 mg, 28 μL, 0.349 mmol) in anhydrous DCM (5 mL) was added a solution of methyl(chlorosulfonyl)acetate (42 mg, 0.245 mmol) in DCM (150 μL) dropwise under an inert atmosphere, and the resulting solution was stirred at 21° C. for 17 h. The reaction mixture was diluted with DCM (45 mL), washed with 1 M HCl (10 mL), brine (15 mL), and dried (MgSO). After filtration, the solvent was removed by evaporation to give the title compound (74 mg, 85%) as a tan solid after drying in a vacuum oven at 40° C. for 6.5 h. The material was used without further purification. 1 H(400MHz,DMSO-d6)δ13.09(br s,1H),8.80(br s,1H),7.58(s,1H),6.68(s,1H),5.98(s,1H),5.90(s,1H),4.38(d,J=2.7Hz,2H),4.15(s,2H),3.60(s,3H),3.55(s,3H); 13 C(101MHz,DMSO-d6)δ168.74,164.03,156.85,132.27,128.35,122.57,112.42,108.50,106.24,57.35,52.41,34.64,33.37

[0181] Synthesis of 2-(2-hydroxyethylsulfonamido)-N-((1-methyl-1H-pyrrol-2-yl)methyl)thiazole-4-carboxamide [ka] To a stirred solution of methyl (4-(((1-methyl-1H-pyrrol-2-yl)methyl)carbamoyl)thiazol-2-yl)sulfonyl)acetate (74 mg, 0.198 mmol) in anhydrous THF (5 mL) was added sodium borohydride (30 mg, 0.792 mmol), and the resulting solution was stirred at 20° C. under an inert atmosphere for 18 h. The solvent was evaporated, and the residue was dissolved in water (7 mL), acidified with 1 M aqueous HCl (2 mL), saturated with NaCl, and extracted with EtOAc (5×10 mL). The combined organics were washed with brine (15 mL), dried (MgSO), filtered, and evaporated to give a solid that was dissolved in saturated aqueous NaHCO (25 mL) and extracted with EtOAc (3×10 mL). The aqueous phase was acidified by dropwise addition of 32% aqueous HCl, saturated with NaCl, and extracted with EtOAc (4×25 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO), filtered and evaporated to give a solid which was purified by flash chromatography (SiO, EtOAc / MeOH, 10:1) to give the title compound (26 mg, 38%) as a white solid after drying at 60 °C for 3 h. IRu max (cm -1 ):3315,3097,2924,1627,1554,1470,1229,1102,713,504; 1 H (400 MHz, CD3OD) δ 7.42 (s, 1H), 6.56-6.61 (m, 1H), 6.03 (br s, 1H), 5.91-5.96 (m, 1H), 4.49 (s, 2H), 3.94 (t, J = 6.3 Hz, 2H), 3.55 (s, 3H), 3.30 (m, 2H) (signal partially overlaps with CD3OD signal); 13 C(101MHz,CD3OD)δ173.93,164.50,145.35,129.62,123.93,113.63,110.09,107.80,58.13,55.83,36.25,34.14; HRMS:C 12 H 16For N4NaO4S2, m / z (ESI) calculated: 367.0511; found: 367.0522

[0182] Synthesis of sulfonamide thiazole esters: Methyl 2-(2-methoxy-2-oxoethylsulfonamido)thiazole-4-carboxylate [ka] To a stirred suspension of methyl 2-aminothiazole-4-carboxylate (525 mg, 3.15 mmol), pyridine (373 mg, 380 μL, 4.72 mmol), and DMAP (38 mg, 0.315 mmol) in anhydrous DCM (25 mL) was added methyl (chlorosulfonyl)acetate (571 mg, 3.31 mmol) dropwise, and the resulting solution was stirred at 20° C. for 17 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1 M aqueous HCl (40 mL). The aqueous phase was extracted with DCM (3×50 mL), and the combined organic extracts were washed with brine (40 mL), dried (MgSO), filtered, and evaporated to give the title compound (920 mg, 99%) as a pale yellow solid. The material was used without further purification. 1 H(400MHz,DMSO-d6)δ13.52(br s,1H),7.76(s,1H),4.20(s,2H),3.82(s,3H),3.61(s,3H); 13 C(101MHz,DMSO-d6)δ168.89,163.95,157.88,128.49,118.79,57.40,52.69,52.44

[0183] Methyl 2-(2-hydroxyethylsulfonamido)thiazole-4-carboxylate [ka] To a stirred solution of 2-(2-methoxy-2-oxoethylsulfonamido)thiazole-4-carboxylate (750 mg, 2.55 mmol) in a mixture of THF (55 mL) and MeOH (6 mL) was added NaBH (578 mg, 15.29 mmol) in portions over 1.5 h, and the reaction mixture was stirred at 20 °C for 15 h. After this time, NaBH (49 mg, 1.30 mmol) was added, and stirring at ambient temperature was continued for 24 h. The reaction mixture was cooled to 0-5 °C, and brine (25 mL) was added, followed by 1 M aqueous HCl (22 mL). The organic phase was separated, and the aqueous phase was saturated with NaCl and extracted with THF (5 × 35 mL). The combined organic extracts were dried (MgSO), filtered and evaporated to give a residue which was purified by flash chromatography (SiO, DCM / MeOH, 20:1) to give the title compound (403 mg, 59%) as a white solid after drying under high vacuum at 20° C. for 7 h. 1 H(400MHz,DMSO-d6)δ13.09(br s,1H),7.74(s,1H),4.81(br s,1H),3.81(s,3H),3.74(t,J=6.6Hz,2H),3.23(m,2H); 13 C(101MHz,DMSO-d6)δ166.80,158.34,130.04,118.82,55.72,55.45,52.53

[0184] Methyl 2-(methylsulfonamido)thiazole-4-carboxylate [ka] To a stirred solution of methyl 2-aminothiazole-4-carboxylate (801 mg, 5.06 mmol) in anhydrous pyridine (8 mL) was added methanesulfonyl chloride (591 mg, 400 μL, 5.16 mmol) under an inert atmosphere. The reaction mixture was stirred at 20° C. for 20 h and then diluted with EtOAc (40 mL). The suspension was filtered, and the filtrate was washed with 1 M aqueous HCl (3 × 40 mL), water (30 mL), and brine (20 mL). The organic phase was dried (MgSO), filtered, and evaporated to leave methyl 2-(bis(methylsulfonyl)amino)thiazole-4-carboxylate (190 mg, 23%) as an orange solid. The aqueous acid was extracted with DCM (70 mL), and the DCM was washed with water (30 mL) and brine (20 mL), then dried (MgSO), filtered, and evaporated to leave an orange solid. The combined aqueous extracts were saturated with NaCl and extracted with DCM (3 x 30 mL). The combined DCM extracts were washed with brine (20 mL), dried (MgSO), filtered, and evaporated to leave a white solid. The two solids from the DCM extractions were combined and purified by flash chromatography using a Biotage® Selekt (SiO, 5-19% MeOH in DCM) to afford the title compound (586 mg, 49%) as an off-white solid. Methyl 2-(bis(methylsulfonyl)amino)thiazole-4-carboxylate: 1 H(400MHz,DMSO-d6)δ8.74(s,1H),3.86(s,3H),3.69(s,6H); 13 C NMR(101MHz,DMSO-d6)δ160.45,154.18,143.28,134.21,52.43,43.11 Methyl 2-(methylsulfonamido)thiazole-4-carboxylate: 1 H(400MHz,CDCl3)δ7.31(s,1H),3.92(s,3H),3.06(s,3H); 13 C(101MHz,CDCl3)δ166.71,158.04,128.58,116.55,53.25,41.67

[0185] Methyl 2-(fluoromethylsulfonamido)thiazole-4-carboxylate [ka] To a stirred solution of methyl 2-Boc-aminothiazole-4-carboxylate (762 mg, 2.95 mmol) in anhydrous THF (24 mL) was added sodium hydride (60% dispersion in mineral oil, 161 mg, 4.01 mmol) under an inert atmosphere. After bubbling ceased, fluoromethanesulfonyl chloride (351 mg, 2.65 mmol) was added dropwise over 5 min, and the reaction mixture was stirred at 20 °C for 70 h. The solvent was evaporated, and the residue was dissolved in DCM (60 mL). The reaction mixture was cooled to 0-5 °C, TFA (8 mL) was added dropwise, and the resulting solution was stirred at ambient temperature for 22 h. The solvent was removed by evaporation, and saturated aqueous NaHCO3 (50 mL) was added to the residue. The mixture was sonicated for 5 min, vacuum filtered, and the filtrate was extracted with DCM (10 × 50 mL). The aqueous phase was acidified by dropwise addition of 32% aqueous HCl and extracted with EtOAc (4 x 40 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO), filtered, and evaporated to give the title compound (365 mg, 54%) as a white solid after drying in an oven at 60 °C for 2 h. 1 H(400MHz,DMSO-d6)δ13.74(br s,1H),7.78(s,1H),5.33(d,J=46Hz,2H),3.83(s,3H); 13 C(101MHz,DMSO-d6)δ169.70,157.76,128.38,118.96,90.73(d,J=208Hz),52.70

[0186] Synthesis of methyl 2-(methylsulfamoyl)aminothiazole-4-carboxylate [ka] To a stirred solution of methyl 2-aminothiazole-4-carboxylate (499 mg, 3.15 mmol) in anhydrous THF (40 mL) was added DIPEA (449 mg, 605 μL, 3.47 mmol) under an inert atmosphere. N-Methylsulfamoyl chloride (446 mg, 302 μL, 3.44 mmol) was added dropwise, and the resulting solution was heated at 50 °C for 116 h. After cooling to ambient temperature, the THF was evaporated, and the residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO (20 mL). After phase separation, the organic phase was extracted with saturated aqueous NaHCO (10 mL), and the combined aqueous phases were washed with EtOAc (20 mL). The aqueous portion was acidified to pH ∼1 with 2 M aqueous HCl, extracted with DCM (3 × 20 mL), saturated with NaCl, and extracted with THF (3 × 20 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a viscous orange oil. The crude material was purified by flash chromatography (SiO, DCM:MeOH, 94:6) to isolate the title compound (551 mg, 70%) as a viscous pale yellow oil. 1 H(400MHz,CD3OD)δ7.64(s,1H),3.89(s,3H),2.62(s,3H); 13 C(101MHz,CD3OD)δ167.27,160.63,133.61,119.64,53.09,29.47

[0187] Synthesis of methyl 2-(1H-indole-3-sulfonamido)thiazole-4-carboxylate [ka] To a stirred solution of 1H-indole-3-sulfonyl chloride (471 mg, 2.18 mmol) in anhydrous THF (20 mL) was added methyl 2-amino-1,3-thiazole-4-carboxylate (693 mg, 4.38 mmol) under an inert atmosphere. DIPEA (312 mg, 420 μL, 2.41 mmol) was added, and the resulting solution was heated at 50 °C for 116 h. After cooling to ambient temperature, the THF was evaporated, and the residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO (20 mL). After phase separation, the organic phase was extracted with saturated aqueous NaHCO (20 mL), and the combined aqueous extracts were washed with EtOAc (20 mL). The aqueous phase was acidified to pH ∼1 with 2 M aqueous HCl, resulting in the formation of a sticky orange solid that stuck to the glassware. The mixture was extracted with DCM (20 mL), which did not dissolve the sticky solid. Nevertheless, the DCM was dried (MgSO), filtered, and evaporated to leave a viscous yellow oil, which was dissolved in a mixture of DCM and MeOH and concentrated to give the title compound (265 mg, 36%) as a pale yellow foamy solid.

[0188] The aqueous phase was saturated with NaCl and extracted with THF (4 x 20 mL). The combined THF extracts were dried (MgSO), filtered, and evaporated to leave a pink-orange foam, which was purified by flash chromatography using a Biotage® Selekt (SiO, 4-20% MeOH in DCM). Additional title compound (138 mg, 19%) was isolated as a pale yellow solid. Total yield: 403 mg (55%). 1 H NMR(400MHz,CD3OD)δ7.87(s,1H),7.84(d,J=7.7Hz,1H),7.44-7.41(m,2H),7.22-7.17(m,1H),7.16-7.12(m,1H),3.79(s,3H); 13 C(101MHz,CD3OD)δ168.17,159.87,137.95,131.89,130.64,124.74,124.25,122.42,120.72,118.97,115.97,113.20,53.04

[0189] Synthesis of methyl 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylate [ka] To a stirred suspension of 2-(methylamino)thiazole-4-carboxylic acid (501 mg, 3.17 mmol) in MeOH (12 mL) was added concentrated sulfuric acid (1.0 mL) under an inert atmosphere. The resulting solution was heated at reflux for 15 h. After cooling to ambient temperature, MeOH was evaporated and the residue was diluted with DCM (20 mL) and water (10 mL). The aqueous phase was neutralized with saturated aqueous NaHCO3 and the phases were separated. The aqueous phase was extracted with DCM (15 mL) and the combined organic phases were washed with water (15 mL) and brine (15 mL). The DCM was dried (MgSO4), filtered, and evaporated to give methyl 2-(methylamino)thiazole-4-carboxylate (430 mg, 79%) as an off-white solid. 1 H(400MHz,CDCl3)δ8.05(s,1H),7.34(s,1H),3.85(s,3H),3.00(s,3H); 13 C(101MHz,CDCl3)δ172.07,162.16,143.15,115.00,52.05,32.65

[0190] To a stirred suspension of methyl 2-(methylamino)thiazole-4-carboxylate (200 mg, 1.16 mmol) in anhydrous pyridine (4 mL) was added methanesulfonyl chloride (266 mg, 180 μL, 2.32 mmol) under an inert atmosphere. The reaction mixture was stirred at 20° C. for 21 h and then diluted with DCM (20 mL). The mixture was washed with 1 M aqueous HCl (3×20 mL), water (20 mL), and brine (10 mL). The organic phase was dried (MgSO), filtered, and evaporated to give the title compound (227 mg, 78%) as an orange solid. 1 H(400MHz,CDCl3)δ7.84(s,1H),3.91(s,3H),3.58(s,3H),3.03(s,3H); 13 C(101MHz,CDCl3)δ161.70,161.65,142.78,124.53,52.57,37.60,36.85

[0191] Synthesis of sulfonamide thiazole acids: general procedure A. [ka] To the sulfonamide thiazole ester (1 equiv.) was added an aqueous solution of NaOH (3–6 equiv.), and the resulting mixture was stirred at ambient temperature for 3–6 h. The reaction mixture was filtered, the filtrate was washed with EtOAc (15 mL), and the aqueous layer was acidified with 1 M aqueous HCl to pH ∼1. The acidic solution was saturated with NaCl and then extracted with DCM (3 × 10 mL) and THF (3 × 15 mL). The combined THF extracts were washed with brine (10 mL), dried (MgSO), filtered, and evaporated.

[0192] [ka] Following general procedure A using methyl 2-(2-hydroxyethylsulfonamido)thiazole-4-carboxylate (500 mg, 1.88 mmol) and 1 M NaOH (3.2 equiv.) gave 2-(2-hydroxyethylsulfonamido)thiazole-4-carboxylic acid as a white solid (426 mg, 90%). 1 H(400MHz,DMSO-d6)δ12.71-14.16(br s,3H),7.61(s,1H),3.73(t,J=6.8Hz,2H),3.19(t,J=6.6Hz,2H); 13 C(101MHz,DMSO-d6)δ167.43,159.01,130.05,117.55,55.78,55.46

[0193] [ka] Following general procedure A using methyl 2-(methylsulfonamido)thiazole-4-carboxylate (626 mg, 2.65 mmol) and 1 M NaOH (3.3 equiv.) gave 2-(methylsulfonamido)thiazole-4-carboxylic acid as a pale yellow solid (473 mg, 80%). 1 H(400MHz,CD3OD)δ7.52(s,1H),2.99(s,3H); 13 C(101MHz,CD3OD)δ169.48,160.24,131.36,118.13,41.15

[0194] [ka] Following general procedure A using methyl 2-(fluoromethylsulfonamido)thiazole-4-carboxylate (362 mg, 1.42 mmol) and 1 M NaOH (5.6 equiv.) gave 2-(fluoromethylsulfonamido)thiazole-4-carboxylic acid as an off-white solid (317 mg, 93%). 1 H(400MHz,DMSO-d6)δ14.70-11.95(br s,2H),7.67(s,1H),5.31(d,J=46Hz,2H); 13 C(101MHz,DMSO-d6)δ169.90,158.73,129.63,118.06,90.74(d,J=208Hz)

[0195] [ka] Following general procedure A, methyl 2-(methylsulfamoyl)aminothiazole-4-carboxylate (170 mg, 0.677 mmol) and 0.5 M NaOH (5.6 equiv.) was used to give 2-((N-methylsulfamoyl)amino)thiazole-4-carboxylic acid as a white solid (134 mg, 83%). 1 H(400MHz,CD3OD)δ7.57(s,1H),2.62(s,3H); 13 C(101MHz,CD3OD)δ167.70,161.31,134.14,118.90,29.48

[0196] [ka] Following general procedure A, methyl 2-(1H-indole-3-sulfonamido)thiazole-4-carboxylate (399 mg, 1.18 mmol) and 0.5 M NaOH (3.2 equiv.) was used to give 2-(1H-indole-3-sulfonamido)thiazole-4-carboxylic acid as an off-white solid (325 mg, 85%). 1 H(400MHz,DMSO-d6)δ13.21(br s,2H),11.90(br s,1H),7.94(s,1H),7.74(d,J=7.8Hz,1H),7.61(s,1H),7.47(d,J=8.0Hz,1H),7.22(app t,J=7.5Hz,1H),7.16(app t,J=7.4Hz,1H); 13 C(101MHz,DMSO-d6)δ159.20(br),136.17,129.54(br),123.20,122.77,120.99,119.43,117.70(br),115.05(br),112.49(missing 2)

[0197] Synthesis of 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid [ka] To a solution of methyl 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylate (225 mg, 0.899 mmol) in a mixture of MeOH (6 mL) and THF (3 mL) was added 1 M aqueous NaOH (1 mL) under an inert atmosphere. The resulting solution was stirred at 20 °C for 2 h and then concentrated. The residue was diluted with water (10 mL) and extracted with DCM (2 × 10 mL). The aqueous layer was acidified with 1 M aqueous HCl (2 mL) and stirred until a precipitate appeared. The resulting suspension was vacuum filtered, and the collected solid was washed with water (3 × 10 mL) and dried in a vacuum oven at 40 °C for 13.5 h to afford the title compound (174 mg, 82%) as a pale yellow solid. 1 H(400MHz,CD3OD / CDCl3)δ7.95(s,1H),3.54(s,3H),3.11(s,3H); 13 C(101MHz,CD3OD / CDCl3)δ163.85,162.81,143.97,125.36,37.41,36.95

[0198] Synthesis of test inhibitors: General procedure B. [ka] To a stirred suspension of sulfonamidothiazole acid (1.0 equiv.) in anhydrous MeCN or DMF, DIPEA (2.0 equiv.) was added under an inert atmosphere. Once the solid was completely dissolved, HATU (1.0 equiv.) was added, followed by the amine (1.2 equiv.). The reaction mixture was stirred at 20°C or 50°C. Note: When an amine hydrochloride was used, additional DIPEA was added equal to the moles of hydrochloride. Workup procedures vary and are detailed for each compound.

[0199] [ka] According to general procedure B, 2-(2-hydroxyethylsulfonamido)thiazole-4-carboxylic acid (87 mg, 0.345 mmol) and 1-(5(6)-chloro-1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride (96 mg, 0.379 mmol) in anhydrous MeCN (10 mL) and DMF (1 mL) were used at 21 °C for 22 h. Water (15 mL) was added, and the solution was saturated with NaCl and then extracted with EtOAc (4 × 50 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a pale yellow oil, which was dissolved in saturated aqueous NaHCO (25 mL) and extracted with DCM (6 × 40 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl, saturated with NaCl, and extracted with THF (3 × 40 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a solid that was purified by two further rounds of the base dissolution procedure to give, after drying in an oven at 60° C. for 17 hours, N-((5(6)-chloro-1H-benzo[d]imidazol-2-yl)methyl)-2-(2-hydroxyethylsulfonamido)thiazole-4-carboxamide (118 mg, 82%) as an off-white solid. IRu max (cm -1 )3404,3105,1626,1548,1471,1418,1255,1111,1060,1016,841,727,559; 1 H(400MHz,DMSO-d6)δ11.94-12.88(br s,2H),8.85(s,1H),7.56(s,1H),7.50(d,J=8.0Hz,1H),7.40(s,1H),7.16(d,J=8.6Hz,1H),4.45-4.79(br s,1H),4.62(d,J=5.3Hz,2H),3.71(t,J=6.8Hz,2H),3.12(t,J=6.8Hz,2H); 13 C(101MHz,DMSO-d6)δ168.56,161.01,153.87,140.85,137.07(br),125.86,121.75,115.80(br),114.86(br),112.60,56.49,54.45,37.31(missing 2); HRMS:C 14 H 15 m / z (ESI) calculated for ClN5O4S2: 416.0250 (M+H) + ;Measured value: 416.0254

[0200] [ka] According to general procedure B, 2-(2-hydroxyethylsulfonamido)thiazole-4-carboxylic acid (86 mg, 0.341 mmol) and (5-phenyl-1H-pyrazol-3-yl)methanamine (65 mg, 0.375 mmol) in anhydrous MeCN (11 mL) and DMF (0.5 mL) were used at 21 °C for 18 h. Brine (25 mL) was added, and the reaction mixture was extracted with THF (4 × 50 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a pale yellow oil, which was dissolved in saturated aqueous NaHCO (25 mL) and extracted with DCM (10 × 50 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl, saturated with NaCl, and extracted with THF (3 × 25 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a solid that was suspended in DCM (15 mL) and sonicated for 10 min. The solid was collected by vacuum filtration and dried in an oven at 60° C. for 19 h to give 2-(2-hydroxyethylsulfonamido)-N-((5-phenyl-1H-pyrazol-3-yl)methyl)thiazole-4-carboxamide (92 mg, 66%) as a white solid. IRu max (cm -1 )3320,3209,1642,1552,1303,1115,1005,890,764,751,727,660,549; 1H(400MHz,DMSO-d6)δ12.61-13.20(br s,2H),8.95(br s,1H),7.74(d,J=7.6Hz,2H),7.55(s,1H),7.41(app t,J=7.6Hz,2H),7.30(t,J=7.4Hz,1H),6.59(s,1H),4.79(br s,1H),4.44(d,J=4.9Hz,2H),3.73(t,J=6.4Hz,2H),3.21(m,2H); 13 C (101 MHz, DMSO-d6) δ 166.75, 157.74, 146.04, 134.01, 131.15, 128.82, 127.71, 125.02, 112.36, 101.00, 55.84, 55.35, 35.66 (undermeasured 1); HRMS:C 16 H 17 Calculated value of N5NaO4S2, m / z (ESI), 430.0617 (M+Na) + ;Experimental value,430.0620

[0201]

change

[0202] [ka] According to general procedure B, 2-(methylsulfonamido)thiazole-4-carboxylic acid (80 mg, 0.360 mmol) and 1-(5(6)-chloro-1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride (90 mg, 0.355 mmol) in anhydrous DMF (0.5 mL) and MeCN (10 mL) were used at 20 °C for 89 h. Water (25 mL) was added, and the solution was saturated with NaCl and then extracted with EtOAc (4 × 30 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated to give a pale yellow solid, which was dissolved in saturated aqueous NaHCO (25 mL) and extracted with DCM (8 × 35 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl and extracted with THF (3 × 25 mL). The combined organic extracts were dried (MgSO), filtered, evaporated, triturated with DCM / MeO, and dried under vacuum at 50° C. for 7 hours to give N-((5(6)-chloro-1H-benzo[d]imidazol-2-yl)methyl)-2-(methylsulfonamido)thiazole-4-carboxamide (139 mg, “100%)) as an off-white solid. Traces of solvents (DCM, MeOH, and THF) were not reduced by further drying. IRu max (cm -1 )3631,3409,3111,2988,1625,1547,1471,1252,1113,839,558; 1 H(400MHz,DMSO-d6)δ12.42(br s,2H),8.73(br s,1H),7.55(s,1H),7.50(d,J=8.5Hz,1H),7.33(s,1H),7.16(dd,J=1.2,8.5 Hz,1H),4.63(d,J=5.9Hz,2H),2.80(s,3H); 13C(101MHz,DMSO-d6)δ168.54,160.91,153.84,140.72,137.26(br),125.86,121.76,115.75(br),114.83(br),112.58,39.99,37.32(missing 1); HRMS:C 13 H 12 m / z (ESI) calculated for ClN5O3S2: 386.0146 (M+H) + ;Measured value: 386.0148

[0203] [ka] General procedure B was followed using 2-(methylsulfonamido)thiazole-4-carboxylic acid (129 mg, 0.580 mmol) and 3,3-dimethylbutylamine (71 mg, 94 μL, 0.699 mmol) in anhydrous MeCN (10 mL) at 20 °C for 93 h. Water (80 mL) was added, and the resulting mixture was extracted with DCM (3 × 30 mL). The combined organic extracts were washed with 1 M aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried (MgSO), filtered, and evaporated to give a viscous orange oil. The isolated material was partitioned between EtOAc (40 mL) and 1 M aqueous HCl (25 mL), and the organic phase was separated and extracted with NaHCO (2 × 20 mL). The combined basic extracts were acidified with 32% aqueous HCl to pH ∼1 and extracted with DCM (2 × 15 mL). The combined organic extracts were washed with water (15 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated to give N-(3,3-dimethylbutyl)-2-(methylsulfonamido)thiazole-4-carboxamide as a white solid (109 mg, 61%). IRu max (cm -1 )3335,3104,2955,1645,1530,1282,1125,970,886,652,529,518; 1H(400MHz,DMSO-d6)δ12.65(br s,1H),8.42(br s,1H),7.45(s,1H),3.24-3.19(m,2H),2.98(br s,3H),1.43-1.39(m,2H),0.91(s,9H); 13 C(101MHz,DMSO-d6)δ166.59(br),157.43,133.74(br),111.56(br),42.52,40.81,35.55,29.64,29.21; HRMS:C 11 H 19 For N3NaO3S2, m / z (ESI) calculated: 328.0766 (M+Na) + ;Measured value: 328.0772

[0204] [ka] According to general procedure B, 2-(methylsulfonamido)thiazole-4-carboxylic acid (98 mg, 0.441 mmol) and (1H-indol-2-yl)methanamine hydrochloride (96 mg, 0.526 mmol) in anhydrous MeCN (50 mL) were used at 50 °C for 15 h. After cooling to ambient temperature, water (25 mL) was added, and the resulting suspension was cooled in an ice bath for 30 min. The liquid was decanted, and the solid residue was dissolved in MeOH (10 mL). MeOH was evaporated, and the orange residue was dried in a vacuum oven at 40 °C for 80 min. The dried crude material was dissolved in EtOAc (20 mL), and the solution was extracted with 1 M aqueous HCl (20 mL) and saturated aqueous NaHCO (10 mL). The combined aqueous extracts contained a precipitate, which was collected by vacuum filtration. The solid was washed with water (3×10 mL) and dried in a vacuum oven at 40° C. for 16.5 h to give N-((1H-indol-2-yl)methyl)-2-(methylsulfonamido)thiazole-4-carboxamide as a tan solid (47 mg, 30%). IRu max (cm -1)2284,2242,3099,1652,1557,1533,1251,1116,1103,789,734,645,540,513; 1 H(600MHz,DMSO-d6)δ12.75(br s,1H),10.97(s,1H),8.97(br s,1H),7.60(br s,1H),7.45(d,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.05-7.02(m,1H),6.96-6.94(m,1H),6.30(s,1H),4.58(d,J=5.6Hz,2H),2.99(br s,3H); 13 C (151 MHz, DMSO-d6) δ 167.04 (br), 157.76 (br), 136.31, 136.11, 127.87, 120.74, 119.57, 118.88, 112.11 (br), 111.09, 99.32, 40.80, 36.45 (undermeasured 1); HRMS:C 14 H 14 Calculated value of N4NaO3S2, m / z (ESI), 373.0405 (M+Na) + ;Accurate value,373.0408

[0205]

change

[0206] [ka] General procedure B was followed using 2-(methylsulfonamido)thiazole-4-carboxylic acid (100 mg, 0.450 mmol) and 1-(1-methyl-1H-pyrrol-2-yl)methanamine (54 mg, 0.495 mmol) in anhydrous DMF (7 mL) at 20 °C for 20 h. The solvent was removed under high vacuum, the residue was dissolved in 5% aqueous NaHCO (30 mL), and extracted with EtOAc (2 × 30 mL). The aqueous phase was neutralized to pH 6-7 by dropwise addition of 1 M aqueous HCl, and the fine precipitate was removed by vacuum filtration. The filtrate was extracted with EtOAc (5 × 40 mL) and the combined organic extracts were washed with brine (35 mL), dried (MgSO), filtered and evaporated to give 2-(methylsulfonamido)-N-((1-methyl-1H-pyrrol-2-yl)methyl)thiazole-4-carboxamide as a pale tan solid (75 mg, 53%) after drying in a vacuum oven at 40 °C for 21 h. IRu max (cm -1 ):3094,2918,1645,1534,1271,1118,967,839,557,521; 1 H(400MHz,DMSO-d6)δ12.68(br s,1H),8.69(br s,1H),7.54(s,1H),6.68(s,1H),5.97(s,1H),5.87-5.93(m,1H),4.38(d,J=4.4Hz,2H),3.55(s,3H),2.95(br s,3H); 13 C(101MHz,DMSO-d6)δ166.46,157.32,128.49,122.50,112.32,108.38,106.20,40.71,34.54,33.35;(missing 1); HRMS:C 11 H14 For N4NaO3S2, m / z (ESI) calculated: 337.0405 (M+Na) + ;Measured value: 337.0422

[0207] [ka] According to general procedure B, 2-(fluoromethylsulfonamido)thiazole-4-carboxylic acid (76 mg, 0.316 mmol) and 1-(1H-pyrrol-2-yl)methanamine (33 mg, 0.348 mmol) in anhydrous MeCN (14 mL) were used at 20 °C for 20 h. Water (35 mL) was added, and the solution was saturated with NaCl and then extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO), filtered, and evaporated to give a solid, which was dissolved in saturated aqueous NaHCO (25 mL) and extracted with DCM (8 × 40 mL). The aqueous phase was acidified by dropwise addition of 32% aqueous HCl and extracted with EtOAc (4 × 25 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO), filtered, and evaporated to give 2-(fluoromethylsulfonamido)-N-((1H-pyrrol-2-yl)methyl)thiazole-4-carboxamide as a tan solid (102 mg, 102%) after drying in an oven at 60° C. for 14 hours. Traces of EtOAc were not reduced by further drying. IRu max (cm -1 )3328,3097,1644,1531,1271,1127,1116,835,728,557; 1 H(400MHz,DMSO-d6)δ13.30(br s,1H),10.67(s,1H),8.88(s,1H),7.60(s,1H),6.66(s,1H),5.94(s,2H),5.30(d,J=46Hz,2H),4.36(d,J=5.4Hz,2H); 13C(101MHz,DMSO-d6)δ169.46,156.97,132.41,127.79,117.30,112.50,107.36,106.25,90.72(d,J=208Hz),36.04; HRMS:C 10 H 11 For FN4NaO3S2, m / z (ESI) calculated: 341.0154 (M+Na) + ;Measured value: 341.0174

[0208] [ka] According to general procedure B, 2-(fluoromethylsulfonamido)thiazole-4-carboxylic acid (78 mg, 0.323 mmol) and 1-(5(6)-chloro-1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride (90 mg, 0.355 mmol) in anhydrous DMF (1.2 mL) and anhydrous MeCN (12 mL) are used at 20 °C for 96 h. Water (35 mL) is added, and the solution is saturated with NaCl, then extracted with EtOAc (3 × 50 mL). The combined organic extracts are washed with water (40 mL), brine (30 mL), dried (MgSO), filtered, and evaporated to give a pale yellow solid. The aqueous washes are extracted with EtOAc (5 × 80 mL). The combined organic extracts are washed with brine (40 mL), dried (MgSO), filtered, and evaporated to give a yellow solid. The solids were combined, dissolved in saturated aqueous NaHCO3 (35 mL), and extracted with DCM (6 x 40 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (35 mL), dried (MgSO4), filtered, and evaporated to give, after drying in an oven at 60 °C for 20 h, N-((5(6)-chloro-1H-benzo[d]imidazol-2-yl)methyl)-2-(fluoromethylsulfonamido)thiazole-4-carboxamide as a pale tan solid (137 mg, 105%). Traces of DCM and EtOAc were not reduced by further drying. IRu max (cm -1)3410,3104,2972,1648,1542,1466,1265,1224,1123,840,556; 1 H(400MHz,DMSO-d6)δ9.05(br s,1H),7.56(s,1H),7.46-7.54(m,2H),7.50(s,1H),7.17(d,J=8.5Hz,1H),5.22(d,J=47Hz,2H),4.64(d,J=5.1Hz,2H); 13 C (101 MHz, DMSO-d6) δ 169.41, 159.25, 153.60, 139.82, 136.93, 125.93, 121.83, 115.79, 114.73, 113.17, 90.40 (d, J = 208 Hz), 37.28 (undermeasured 1); HRMS:C 13 H 12 ClFN5O3S2 Hikaru, m / z (ESI) calculated value, 404.0054 (M+H) + ;test value,404.0068

[0209]

change

[0210] [ka] According to general procedure B, 2-(fluoromethylsulfonamido)thiazole-4-carboxylic acid (60 mg, 0.250 mmol) and 1-(1H-indol-2-yl)methanamine hydrochloride (50 mg, 0.275 mmol) in anhydrous MeCN (11 mL) and DMF (0.5 mL) were used for 19 h at 20 °C. Water (35 mL) was added, and the solution was saturated with NaCl and then extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO), filtered, and evaporated to give a pale yellow oil, which was dissolved in saturated aqueous NaHCO (35 mL) and extracted with DCM (5 × 40 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl and extracted with EtOAc (4 × 40 mL). The combined organic extracts were washed with brine (35 mL), dried (MgSO), filtered, and evaporated to give a solid that was again dissolved in saturated aqueous NaHCO (20 mL) and extracted with DCM (5 × 40 mL). The aqueous phase was neutralized by dropwise addition of 32% aqueous HCl and extracted with EtOAc (5 × 40 mL). The combined organic extracts were washed with brine (35 mL), dried (MgSO), filtered, and evaporated to give 2-(fluoromethylsulfonamido)-N-(1H-indol-2-ylmethyl)thiazole-4-carboxamide (86 mg, 93%) as a pale orange solid after drying in an oven at 60 °C for 14 h. IRu max (cm -1 )3387,1634,1538,1471,1457,1424,1271,1233,1128,1057,962,840,741,559; 1H(400MHz,DMSO-d6)δ13.36(br s,1H),10.93(s,1H),8.57(br s,1H),7.43(d,J=7.8Hz,1H),7.35(br s,1H),7.33(d,J=7.8Hz,1H),7.02(app t,J=7.8Hz,1H),6.93(app t,J=7.6Hz,1H),6.26(s,1H),5.11(d,J=46Hz,2H),4.54(d,J=5.8Hz,2H); 13 C(101MHz,DMSO-d6)δ169.48,160.05,140.20(br),136.95,136.12,127.87, 120.67,119.57,118.84,112.80,111.11,99.12,90.16(d,J=207Hz),36.21; HRMS:C 14 H 13 For FN4NaO3S2, m / z (ESI) calculated: 391.0311 (M+Na) + ;Measured value: 391.0328

[0211] [ka] General procedure B was followed using 2-(fluoromethylsulfonamido)thiazole-4-carboxylic acid (38 mg, 0.158 mmol) and (5-phenyl-1H-pyrazol-3-yl)methanamine (32 mg, 0.185 mmol) in anhydrous MeCN (5 mL) at 50° C. for 26.5 h. After cooling to ambient temperature, water (20 mL) was added and the resulting suspension was cooled in an ice bath for 15 min. The solid was collected by vacuum filtration, washed with water (3×5 mL), and dried in a vacuum oven at 40° C. for 16 h to give 2-(fluoromethylsulfonamido)-N-((5-phenyl-1H-pyrazol-3-yl)methyl)thiazole-4-carboxamide (48 mg, 77%) as a pale tan solid. IRu max (cm -1)3306,3243,3094,2955,1643,1547,1442,1423,1318,1275,1133,1007,893,766,666,590,508; 1 H(600MHz,DMSO-d6)δ13.16(br s,2H),9.10(br t,J=5.7Hz,1H),7.74(d,J=7.7Hz,2H),7.62(s,1H),7.41(app t,J=7.5Hz,2H),7.30(t,J=7.4Hz,1H),6.60(s,1H),5.31(d,J=46Hz,2H),4.45(d,J=5.7Hz,2H); 13 C (151 MHz, DMSO-d6) δ 169.46, 157.22, 144.00 (br), 132.38, 130.86 (br), 128.83, 127.72, 125.03, 112.63, 101.02, 90.73 (d, J = 207 Hz), 35.76 (br) (undermeasured 1); HRMS:C 15 H 15 N5O3S2F Hikaru, m / z (ESI) calculated value, 396.0600 (M+H) + ;True value,396.0596

[0212]

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[0213] [ka] According to general procedure B, 2-((N-methylsulfamoyl)amino)thiazole-4-carboxylic acid (94 mg, 0.396 mmol) and 1-(5(6)-chloro-1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride (122 mg, 0.479 mmol) in anhydrous MeCN (10 mL) were used at 50 °C for 66.5 h. After cooling to ambient temperature, water (80 mL) was added and the resulting suspension was cooled in an ice bath for 30 min. The liquid was decanted and the solid residue was dissolved in MeOH (15 mL). MeOH was evaporated and the orange residue was dried in a vacuum oven at 40 °C for 13 h. The dried crude material was dissolved in saturated aqueous NaHCO (10 mL) and the aqueous solution was extracted with EtOAc (2 × 10 mL). The aqueous phase was acidified to pH 6 with 2 M aqueous HCl and then extracted with DCM (10 mL) and THF (3 × 10 mL). The combined THF extracts were dried (MgSO), filtered, and evaporated to give a viscous orange oil, which was dried in a vacuum oven at 40 °C for 14 h. N-((5(6)-chloro-1H-benzo[d]imidazol-2-yl)methyl)-2-((N-methylsulfamoyl)amino)thiazole-4-carboxamide (59 mg, 37%) was obtained as a tan solid. IRu max (cm -1 )3245,3098,2968,1649,1543,1454,1260,1116,1059,883,805,562,461; 1 H(400MHz,CD3OD)δ7.67(s,1H),7.50(d,J=2.0Hz,1H),7.46(d,J=8.6Hz,1H),7.18(dd,J=8.6,1.9Hz,1H),4.80(s,2H),2.65(s,3H); 13 C(101MHz,CD3OD)δ163.24,163.13,154.72,144.47,140.32,137.97,129.14,124.00,117.83,116.68,115.66,38.33,29.35; HRMS:C13 H 14 N6O3S2 35 m / z (ESI) calculated for Cl: 410.0257 (M+H) + ;Measured value: 401.0257

[0214] [ka] According to general procedure B, 2-((N-methylsulfamoyl)amino)thiazole-4-carboxylic acid (95 mg, 0.400 mmol) and 3,3-dimethylbutylamine (49 mg, 65 μL, 0.483 mmol) in anhydrous MeCN (10 mL) were used at 50 °C for 18 h. Water (20 mL) and brine (10 mL) were added, and the resulting mixture was cooled to ambient temperature. The mixture was extracted with EtOAc (2 × 15 mL), and the combined organic extracts were evaporated to give a pink oil, which was dissolved in saturated aqueous NaHCO (10 mL). The aqueous solution was extracted with DCM (3 × 15 mL) and acidified to pH ∼1 with 2 M aqueous HCl. The aqueous acid was saturated with NaCl and extracted with THF (2 × 15 mL). The combined THF extracts were dried (MgSO4), filtered and evaporated to give N-(3,3-dimethylbutyl)-2-((N-methylsulfamoyl)amino)thiazole-4-carboxamide as an off-white solid (120 mg, 94%). IRu max (cm -1 )3345,3253,2957,1646,1565,1530,1278,1248,1175,1129,1041,840,667,556,492; 1 H(400MHz,CD3OD)δ7.61(s,1H),3.40-3.34(m,2H),2.65(s,3H),1.54-1.48(m,2H),0.96(s,9H); 13 C(101MHz,CD3OD)δ163.07,162.29,144.09,116.76,43.89,37.10,30.60,29.68,29.28; HRMS:C 11 H 20For N4NaO3S2, m / z (ESI) calculated: 343.0875 (M+Na) + ;Measured value: 343.0876

[0215] [ka] General procedure B was followed using 2-((N-methylsulfamoyl)amino)thiazole-4-carboxylic acid (125 mg, 0.527 mmol) and (1H-indol-2-yl)methanamine hydrochloride (115 mg, 0.630 mmol) in anhydrous MeCN (10 mL) at 50 °C for 23 h. After cooling to ambient temperature, water (80 mL) was added, and the resulting cloudy mixture was cooled in an ice bath for 30 min. The liquid was decanted, and the solid residue was dissolved in MeOH (25 mL). MeOH was evaporated, and the orange residue was dried in a vacuum oven at 40 °C for 16 h. The dried solid was partitioned between DCM (15 mL) and saturated aqueous NaHCO (15 mL), the phases were separated, and the aqueous phase was washed with DCM (15 mL). The aqueous portion was acidified to pH ∼1 with 2 M aqueous HCl, and the resulting precipitate was collected by vacuum filtration. The solid was washed with water (3×15 mL) and then dried in a vacuum oven at 40° C. for 15 h to give N-((1H-indol-2-yl)methyl)-2-((N-methylsulfamoyl)amino)thiazole-4-carboxamide as an off-white solid (46 mg, 24%). IRu max (cm -1 )3300,1652,1539,1340,1289,1122,884,794,750,660,568,466; 1 H(400MHz,CD3OD)δ7.68(s,1H),7.45(d,J=7.9Hz,1H),7.31(d,J=8.1Hz,1H),7.05(app t,J=7.6Hz,1H),6.96(app t,J=7.5Hz,1H),6.35(s,1H),4.69(s,2H),2.63(s,3H); 13 C(101MHz,CD3OD)δ162.84(br),138.16,136.83,136.74* ,129.68,129.60 * ,122.28,120.90,120.87 * ,120.18,117.43(br),111.90,101.07,37.84,37.82 * ,29.28(missing 2); * Peaks appear at approximately half the height of their immediate neighbors, all of which are (indol-2-yl)methyl linked and likely belong to rotamers. HRMS:C 14 H 15 For N5NaO3S2, m / z (ESI) calculated: 388.0514 (M+Na) + ;Measured value: 388.0505

[0216] [ka] General procedure B was followed using 2-((N-methylsulfamoyl)amino)thiazole-4-carboxylic acid (110 mg, 0.464 mmol) and (5-phenyl-1H-pyrazol-3-yl)methanamine (94 mg, 0.543 mmol) in anhydrous MeCN (10 mL) at 50 °C for 40 h. After cooling to ambient temperature, water (60 mL) was added, and the resulting suspension was cooled in an ice bath for 30 min. The solid was collected by vacuum filtration, washed with water (3 × 10 mL), and dried in a vacuum oven at 40 °C for 69 h. The dried solid was suspended in saturated aqueous NaHCO (20 mL) and stirred before being washed with EtOAc (2 × 20 mL). The aqueous phase was acidified to pH ∼1 with 2 M aqueous HCl, saturated with NaCl, and extracted with THF (2 × 15 mL). The combined THF extracts were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give 2-((N-methylsulfamoyl)amino)-N-((5-phenyl-1H-pyrazol-3-yl)methyl)thiazole-4-carboxamide as an off-white solid (91 mg, 50%). IRu max (cm -1)3287,3183,3134,1742,1648,1539,1306,1122,883,769,695,647,574; 1 H(400MHz,CD3OD)δ7.71-7.69(m,3H),7.41(app t,J=7.6Hz,2H),7.32(t,J=7.4Hz,1H),6.60(s,1H),4.60(s,2H),2.64(s,3H); 13 C(101MHz,DMSO-d6)δ159.17(br),146.86(br),146.18(br),131.21(br),128.83,127.74,125.06,114.74(br),100.97,35.58,28.78(undertest 2); HRMS:C 15 H 17 Calculated value of N6O3S2 Hikaru, m / z (ESI), 393.0804 ([M+H] + ); measured value, 393.0807

[0217]

change

[0218] [ka] General procedure B was followed using 2-(1H-indole-3-sulfonamido)thiazole-4-carboxylic acid (84 mg, 0.260 mmol) and (5-phenyl-1H-pyrazol-3-yl)methanamine (55 mg, 0.318 mmol) in anhydrous MeCN (9 mL) at 50° C. for 22 h. After cooling to ambient temperature, water (15 mL) was added and the resulting suspension was transferred to a beaker. The remaining solid in the reaction flask was rinsed with water (15 mL) in the beaker. The suspension was stirred and cooled in an ice bath for 30 min. The solid was collected by vacuum filtration, washed with water (3×15 mL), and dried in a vacuum oven at 40° C. for 20 h to give 2-(1H-indole-3-sulfonamido)-N-((5-phenyl-1H-pyrazol-3-yl)methyl)thiazole-4-carboxamide (105 mg, 84%) as an off-white solid. IR Umax (cm -1 )3297,3105,1642,1546,1509,1424,1289,1113,1014,880,745,679,653,589; 1H(400MHz,DMSO-d6)δ12.80(brs,2H),11.90(s,1H),8.76(brs,1H),7.96( s,1H),7.76(d,J=8.0Hz,1H),7.72(d,J=7.7Hz,2H),7.54(s,1H),7.47(d,J =8.0Hz,1H),7.39(appt,J=7.6Hz,2H),7.29(t,J=7.4Hz,1H),7.21(appt,J=7.6Hz,1H),7.16(appt,J=7.5Hz,1H),6.55(s,1H),4.40(d,J=5.6Hz,2H); 13 C(101MHz,DMSO-d6)δ136.16,129.90(br)128.80,127.68,125.01,123.22,122.78,121.02,119.43,112.50,100.91,35.67(br)(missing 8); HRMS:C 22 H 19 For N6O3S2, m / z (ESI) calculated: 479.0960 ([M+H] + ); Actual value: 479.0962

[0219] General Procedure C. [ka] To a stirred suspension of 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid (1.0 equiv.) in anhydrous MeCN was added DIPEA (2.0 equiv.) under an inert atmosphere. Once the solid was completely dissolved, HATU (1.0 equiv.) was added, followed by the amine (1.05–1.2 equiv.). The reaction mixture was stirred at 20°C or 50°C. Workup procedures varied and are detailed for each compound.

[0220] [ka] General procedure C was followed using 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid (81 mg, 0.344 mmol) and 1-(1H-pyrrol-2-yl)methanamine (36 mg, 0.378 mmol) in anhydrous MeCN (6.5 mL) at 20° C. for 70 h. The reaction mixture was diluted with water (45 mL) and cooled to 0-5° C. for 1 h. The precipitate was collected by vacuum filtration, washed with water (3×10 mL), and dried in an oven at 60° C. for 5 h to give N-((1H-pyrrol-2-yl)methyl)-2-(N,S-dimethylsulfonamido)thiazole-4-carboxamide as an off-white solid (92 mg, 85%). IRu max (cm -1 )3412,3303,1665,1552,1488,1349,1150,977,744,514; 1 H(400MHz,DMSO-d6)δ10.55(s,1H),8.43(t,J=5.4Hz,1H),7.88(s,1H),6.63(s,1H),5.90(s,2H),4.39(d,J=5.9Hz,2H),3.49(s,3H),3.27(s,3H); 13 C(101MHz,DMSO-d6)δ160.91,160.00,145.08,128.82,119.85,117.19,107.08,105.92,37.07,36.24,35.57; HRMS:C 11 H 14 For N4NaO3S2, m / z (ESI) calculated: 337.0405 (M+Na) + ;Measured value: 337.0421

[0221] [ka] General procedure C was followed using 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid (84 mg, 0.356 mmol) and 3,3-dimethylbutylamine (38 mg, 50 μL, 0.372 mmol) in anhydrous MeCN (5 mL) at 50° C. for 15.5 h. Water (40 mL) was added, and the resulting mixture was cooled to ambient temperature. The aqueous solution was decanted, and the residual oil was dissolved in EtOAc (15 mL). The organic solution was dried (MgSO), filtered, and evaporated to give a viscous orange oil. The decanted aqueous solution was extracted with EtOAc (2×25 mL), and the combined EtOAc extracts were washed with 1 M aqueous HCl (20 mL), saturated aqueous NaHCO (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried (MgSO), filtered, and evaporated to give a pale yellow viscous oil. The two isolated oils were combined and purified by flash chromatography (SiO, petroleum ether 40 / 60: EtOAc, 1:1). The oil thus isolated was dried in a vacuum oven at 40°C for 13.5 hours to give N-(3,3-dimethylbutyl)-2-(N,S-dimethylsulfonamido)thiazole-4-carboxamide as a white solid (106 mg, 93%). IRu max (cm -1 )3415,3397,3119,2996,2951,2916,2866,1657,1557,1491,1347,1156,765,514,487; 1 H(600MHz,CDCl3)δ7.69(s,1H),7.03(br t,J=5.9Hz,1H),3.49(s,3H),3.41-3.37(m,2H),3.01(s,3H),1.50-1.47(m,2H),0.92(s,9H); 13 C(151MHz,CDCl3)δ161.08,160.55,145.84,119.12,43.35,37.45,36.51,36.03,30.00,29.43; HRMS:C 12 H 21 For N3NaO3S2, m / z (ESI) calculated: 342.0922 (M+Na) +;Measured value: 342.0925

[0222] [ka] General procedure C was followed using 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid (88 mg, 0.372 mmol) and (5-phenyl-1H-pyrazol-3-yl)methanamine (77 mg, 0.445 mmol) in anhydrous MeCN (5 mL) at 50 °C for 19.5 h. Water (40 mL) was added, and the resulting mixture was cooled to ambient temperature and then cooled in an ice bath for 1 h. The aqueous solution was decanted, and the residual oil was dissolved in EtOAc (15 mL). The organic solution was dried (MgSO), filtered, and evaporated to give a viscous orange oil that was purified by flash chromatography (SiO, DCM:MeOH, 92:8) to give 2-(N,S-dimethylsulfonamido)-N-((5-phenyl-1H-pyrazol-3-yl)methyl)thiazole-4-carboxamide as a white solid (106 mg, 93%). IRu max (cm -1 )3184,3139,3115,3017,1652,1553,1486,1352,1156,959,776,748,699,654,512,495; 1 H(400MHz,CDCl3)δ7.89(br t,J=5.5Hz,1H),7.77(s,1H),7.66(d,J=7.6Hz,2H),7.37(app t,J=7.5Hz,2H),7.30(t,J=7.4Hz,1H),6.50(s,1H),4.68(d,J=5.5Hz,2H),3.41(s,3H),2.96(s,3H); 13 C(101MHz,CDCl3)δ161.41,161.25,147.71(br),146.38(br),145.14,131.19,128.92,128.25,125.54,120.01,101.70,37.47,36.43,35.97; HRMS:C 16 H 18For N5O3S2, m / z (ESI) calculated: 392.0851 ([M+H] + ); Actual value: 392.0849

[0223] [ka] General procedure C was followed using 2-(N,S-dimethylsulfonamido)thiazole-4-carboxylic acid (81 mg, 0.344 mmol) and 1-(1-methyl-1H-pyrrol-2-yl)methanamine (42 mg, 0.378 mmol) in anhydrous MeCN (5.7 mL) for 20 h at 20° C. The reaction mixture was diluted with water (40 mL), saturated with NaCl, and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO), filtered, and evaporated to give a viscous oil that was purified by flash chromatography (SiO, DCM / MeOH, 98:2) to give, after drying under high vacuum at 20° C. for 8.5 h, N-((1-methyl-1H-pyrrol-2-yl)methyl)-2-(N,S-dimethylsulfonamido)thiazole-4-carboxamide as a gummy white solid (76 mg, 68%). IRu max (cm -1 )3394,3076,2924,1669,1546,1483,1346,1151,965,653,513; 1 H(400MHz,CDCl3)δ7.81(s,1H),7.10-7.19(m,1H),6.65(s,1H),6.16(s,1H),6 .08-6.13(m,1H),4.63(d,J=5.6Hz,2H),3.62(s,3H),3.52(s,3H),3.03(s,3H); 13 C(101MHz,CDCl3)δ161.09,159.97,145.19,128.37,123.14,119.85,108.86,106.84,37.26,36.50,34.84,33.81; HRMS:C 12 H 16For N4NaO3S2, m / z (ESI) calculated: 351.0562 (M+Na) + ;Measured value: 351.0590

[0224] Example 3 - Biological Assays Determining the pharmacological activity of inhibitor compounds by dGAE assembly and immunodetection. (a) Sandwich ELISA Recombinant dGAE was produced and assembled in a bacterial expression system in the presence of 10 mM DTT by incubation at 37°C with agitation, as previously described [6]. To test for pharmacological activity, assembly reactions were performed in Protein Lobind tubes (Eppendorf) using 100 μM dGAE and 500 μM tau aggregation inhibitor (compound 9 or HMT). Compound 9 was dissolved in DMSO (final 0.5%) and HMT in 10 mM phosphate buffer (PB) supplemented with 10 mM DTT. Control tubes containing dGAE + DTT in PB and dGAE + DTT in 0.5% DMSO were also set up to compare the extent of aggregation. Following a 24-hour assembly reaction, the contents of each tube were mixed by pipetting, and samples were removed for immunodetection of exposed epitopes using a liquid-phase sandwich ELISA.

[0225] A 96-well Nunc Maxisorp plate was precoated with mAb 423 (10 μg / ml), which specifically recognizes C-terminally truncated tau at Glu391 in the pronase-resistant PHF core

[42] . The plate was washed three times with PBS containing 0.1% Tween 20 (PBST) and then blocked with 2% dry milk (Marvel) in PBS. Two-fold dilutions of dGAE-assembled samples were added from a starting concentration of 10 μg / ml in PBS and incubated for 1 h at 37°C. Bound tau was then detected using scAb (10 μg / ml) and incubated for 1 h at 37°C. An anti-human C-kappa HRP-conjugated secondary antibody was diluted 1:1,000 in 2% dry milk in PBS and incubated for 1 h at 37°C. The reaction was developed using Pierce 1-Step Ultra TMB-ELISA substrate solution, followed by quenching with the addition of 1 M H2SO4. Absorbance was measured at 450 nm.

[0226] (b) Cellular tau aggregation inhibition assay A cell-based tau aggregation assay was performed as previously described [13, 25]. The process is described in more detail in WO 02 / 055720. Essentially, fibroblast cells (3T6) express full-length tau ("T40," the htau40 isoform) and low constitutive levels of the PHF-core tau fragment (12 kDa fragment) under the control of an inducible promoter. When T40 expression is induced, it undergoes intracellular aggregation-dependent truncation at the N-terminus at approximately amino acid residue 295 and the C-terminus at approximately residue 390, thereby producing higher levels of the 12 kDa PHF-core domain fragment. The production of the 12 kDa fragment can be blocked in a dose-dependent manner by tau aggregation inhibitors. Indeed, quantification of the inhibitory activity of compounds against the proteolytic production of the 12 kDa fragment in cells can be generally described in terms of the same parameters that represent the inhibition of tau-tau binding in vitro. Thus, the extent of proteolytic production of the 12 kDa fragment within the cell is determined entirely by the degree of tau-tau binding via the repeat domain, not the availability of the relevant proteases within the cell.

[0227] Compounds were first tested at a single concentration of 2 μM in at least three replicates for the intracellular formation of truncated tau, as detected by immunoblotting of cell lysates separated by SDS-PAGE

[25] . MTC was derived as a reference tau aggregation inhibitor. For single-concentration testing, the ratio of the amounts of both protein bands at different concentrations of TAI was measured to correct for the expression level of full-length tau and cell density, especially at high concentrations of TAI.

[0228] The inhibition rate (IR) is calculated using the formula:

number

[0229] Compound 9 and MTC were further tested over a range of concentrations (0-20 μM for compound 9 and 0-2 μM for MTC, Figure 2), and the ratio of the lower truncated 12 kDa tau to full-length T40 band was calculated. The concentration at which there is 50% inhibition of the 12 kDa band relative to T40 (EC 50 values) were calculated from a graph of the protein band ratios relative to the ratios observed in untreated cells

[25] .

[0230] (c)B 50 In vitro cell-free assay to establish This is described in detail in WO 96 / 30766 and

[25] . Briefly, a fragment of tau corresponding to the core repeat domain, adsorbed to a solid substrate, can capture soluble full-length tau and bind to tau with high affinity. This association confers stability to the aggregated tau molecule against proteolytic digestion. The process is self-propagating and can be selectively blocked by a prototype drug

[12] .

[0231] More specifically, truncated tau (residues 297-390, dGA) diluted in carbonate buffer (pH 9.6) was bound to the assay plate, and another truncated tau species (residues 297-391, dGAE) was added to the aqueous phase. The aqueous phase binding buffer contained 0.05% Tween-20 and 1% gelatin in phosphate-buffered saline (pH 7.4). Bound dGAE was detected using mAb 423, which recognizes a Glu-391-dependent epitope absent from the solid-phase dGA.

[0232] The concentration of compound required to inhibit tau-tau binding by 50% is B 50 is called the value.

[0233] (d) Cellular toxicity - LD 50 The fibroblasts used in the cell-based assays described above were used to assess the toxicity of the compounds described herein and to measure EC 50 Toxicity was measured by cell count after 24 hours of exposure to compounds using the lactate dehydrogenase assay kit TOX-7 (Sigma Biosciences) following lysis of any remaining cells, according to the manufacturer's instructions. Alternatively, a commercially available kit from Promega UK (CytoTox 96) was used, again according to the manufacturer's instructions. LD 50 is determined as the concentration of compound at which 50% of the cells are killed.

[0234] [Table 5]

[0235] References A number of publications are cited above to more fully describe and disclose the present invention and the prior art to which it pertains. Detailed citations for these references are provided below. Each of these references is incorporated herein in its entirety. 1.GK Wilcock, MM Esiri, Plaques, tangles and dementia. A quantitative study. J. Neurol. Sci. 56, 343-356 (1982). 2.PV Arriagada, JH Growdon, ET Hedley-Whyte, BT Hyman, Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 42, 631-639 (1992). 3.R. Smith, A. Puschmann, M. Schoell, T. Ohlsson, J. van Swieten, M. Honer, E. Englund, O. Hansson, 18F-AV-1451 tau PET imaging correlates with tau neuropathology strongly in MAPT mutation carriers. Brain. 139, 2372-2379 (2016). 4.B. O. Schelter, H. Shiells, T. C. Baddeley, C. M. Rubino, H. Ganesan, J. Hammel, V. Vuksanovic, R. T. Staff, A. D. Murray, L. Bracoud, G. Riedel, S. Gauthier, J. Jia, P. Bentham, K. 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Claims

1. General formula: 【Chemical 1】 (In the formula, R Ｎ are independently —H or —Me; R Ｘ is independently C optionally substituted with halo or hydroxy １～４ Alkyl, —NHR Ｎ１ (where R Ｎ１ is C １～４ alkyl) or C ５～１０ is heteroaryl, R Ｙ is independently C optionally substituted with methyl, halo, or phenyl. ５～１０ heteroaryl or neopentyl) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

2. R Ｘ The compound of claim 1, wherein is selected from -Me and -Et optionally substituted with halo or hydroxy.

3. R Ｘ The compound of claim 2, wherein is -Me or -Et substituted with halo.

4. R Ｘ The compound of claim 2, wherein is -Me substituted with -F or -Cl.

5. R Ｘ is -CH ２ The compound of claim 2, wherein:

6. R Ｘ The compound of claim 2, wherein is -Me or -Et substituted by hydroxy.

7. R Ｘ is -CH ２ CH ２ 3. The compound of claim 2, wherein:

8. R Ｘ is -NHR Ｎ１ and R Ｎ１ is C １～４ The compound of claim 1 , wherein the aryl group is alkyl.

9. R Ｎ１ The compound of claim 8, wherein is -Me or -Et.

10. R Ｘ The compound of claim 8, wherein is -NHMe.

11. R Ｘ is C ５～１０ The compound of claim 1 which is heteroaryl.

12. R Ｘ is nitrogen-containing C ５～１０ The compound of claim 11 which is a heteroaryl group.

13. R Ｘ is an indolyl group.

14. R Ｘ teeth, 【Chemistry 2】 14. The compound of claim 13, wherein:

15. R Ｙ is neopentyl (-CH ２ C(CH ３ ) ３ 15. The compound according to any one of claims 1 to 14, wherein

16. R Ｙ is a C optionally substituted with methyl, halo or phenyl ５～１０ The compound of any one of claims 1 to 15, which is heteroaryl.

17. R Ｙ is unsubstituted C ５～１０ 17. The compound of claim 16 which is heteroaryl.

18. R Ｙ is a nitrogen-containing C optionally substituted with —Cl or phenyl ５～１０ 18. The compound of claim 17, which is a heteroaryl group.

19. R Ｙ The compound according to any one of claims 16 to 18, wherein is selected from pyrrolyl, imidazolyl, pyrazolyl, indolyl and benzimidazolyl.

20. R Ｙ teeth, 【Chemistry 3】 20. The compound of claim 19 selected from:

21. R Ｎ The compound of any one of claims 1 to 20, wherein is -H.

22. R Ｎ The compound of any one of claims 1 to 21, wherein is -Me.

23. The following compounds: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 2. The compound of claim 1 selected from:

24. A compound according to any one of claims 1 to 23 for use in a method for the treatment or prevention of a tauopathy or a disease of tau protein aggregation.

25. 25. The compound for use according to claim 24, wherein the method is for the treatment or prevention of Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP-17), disinhibition-dementia-parkinsonism-amystrophy complex (DDPAC), pallidopontonigral degeneration (PPND), Guam ALS syndrome, pallido-nigro-luysian degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic grain dementia (AgD), chronic traumatic encephalopathy (CTE), Down's syndrome (DS), dementia with Lewy bodies (DLB) or mild cognitive impairment (MCI).

26. Use of a compound according to any one of claims 1 to 23 in the manufacture of a medicament for the treatment or prevention of a tauopathy or a disease of tau protein aggregation.

27. 27. The use of claim 26, wherein the medicament is for the treatment or prevention of Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP-17), disinhibition-dementia-parkinsonism-amytrophy complex (DDPAC), pallidopontonigral degeneration (PPND), Guam ALS syndrome, pallido-nigro-luysian degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic grain dementia (AgD), chronic traumatic encephalopathy (CTE), Down's syndrome (DS), dementia with Lewy bodies (DLB) or mild cognitive impairment (MCI).

28. A method for treating or preventing a tauopathy or a disease of tau protein aggregation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 23.

29. 29. The method of claim 28, for treating or preventing Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP-17), disinhibition-dementia-parkinsonism-amytrophy complex (DDPAC), pallidopontonigral degeneration (PPND), Guam ALS syndrome, pallido-nigro-luysian degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic grain dementia (AgD), chronic traumatic encephalopathy (CTE), Down's syndrome (DS), dementia with Lewy bodies (DLB), or mild cognitive impairment (MCI).

30. 24. A pharmaceutical composition for use in the treatment of a tauopathy or a disease of tau protein aggregation, comprising a compound according to any one of claims 1 to 23 and a pharmaceutically acceptable excipient, carrier or diluent.

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