Inhibitors of TTBK1

Abstract

The present application provides a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as described herein. Also provided are pharmaceutical compositions comprising the compound of formula (I), and methods of using said compounds and compositions to treat neurodegenerative diseases.

Description

[Technical field]

[0001] Claiming priority This application claims the benefit of U.S. Provisional Application No. 63 / 197,809, filed June 7, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to thalidomide-based compounds that degrade tau tubulin kinase 1 (TTBK1) and methods of their use to treat tau pathology, and thus Alzheimer's disease and related tauopathies. [Background technology]

[0003] There are many fatal diseases that affect the current human population. For example, neurodegenerative diseases affect a significant segment of the population, especially the elderly. Alzheimer's disease ("AD") and related tauopathies are neurodegenerative disorders that are the most common cause of dementia and the fifth leading cause of death in adults over 65 years of age. The estimated annual socio-economic burden of these disorders is more than $300 billion.

[0004] TTBK1 is involved in various neurodegenerative diseases. See, for example, Nozal V, Martinez A. Tau Tubulin Kinase 1 (TTBK1), a new player in the fight against neurodegenerative diseases. Eur J Med Chem. 2019 Jan 1;161:39-47. doi: 10.1016 / j.ejmech.2018.10.030. and Taylor LM, McMillan PJ, Kraemer BC, Liachko NF. Tau tubulin kinases in proteinopathy. FEBS J. 2019 Jul;286(13):2434-2446. doi: 10.1111 / febs.14866. For example, increased TTBK1 expression has been observed in the brains of subjects with Alzheimer's disease and frontotemporal lobar degeneration (FTLD). See, e.g., Sato, et al., J Neurosci. 2008 Dec 31;28(53):14511-21. doi: 10.1523 / JNEUROSCI.3417-08.2008. TTBK1 transgenic mice, moreover, show elevated levels of tau phosphorylation, accelerated neurodegeneration, and enhanced neuroinflammation when crossed with P301L tau mice. See, e.g., Xu, et al., FASEB J. 2010 Aug;24(8):2904-15. doi: 10.1096 / fj.09-150144. Furthermore, silencing TTBK1 attenuates LPS-stimulated microglia-induced neurodegeneration. See, e.g., Asai, et al., Am J Pathol. 2014 Mar;184(3):808-18. doi: 10.1016 / j.ajpath.2013.11.026. Summary of the Invention

[0005] In one general aspect, the present disclosure provides a compound of formula (I):

[0006] [ka] or a pharma- ceutically acceptable salt thereof, wherein X, L 1 , n, R 1 , m, R 2 , R 3 , R 4 , R 5 and R 6 is as described herein.

[0007] In another general aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0008] In yet another general aspect, the disclosure provides a method of treating a neurodegenerative disease or disorder selected from a tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal lobar degeneration with tau pathology, Huntington's disease, and Parkinson's disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs.Methods and materials are described herein for use in this application; other suitable methods and materials known in the art may also be used.Materials, methods and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries, and other references described herein are incorporated by reference in their entirety.In the case of discrepancies, the present specification, including definitions, will control.

[0010] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 illustrates the structure of TTBK1. [Diagram 2] Figure 1 illustrates the analysis of TTBK1 expression levels (Millipore ABN348 antibody for TTBK1) in post-mortem human brain tissue from control and tauopathy patient samples in comparison to human iPSC-derived neurons within a 4- or 8-week neuronal differentiation window via Western blot of total protein loaded. Full-length TTBK1 (band at 150-200 kDa) was detected along with a lower molecular weight processed TTBK1 form, consistent with literature reports. [Diagram 3] Figure 1 illustrates the analysis of TTBK1 expression levels (Millipore ABN348 antibody for TTBK1) in human iPSC-derived neurons via Western blot of total protein loaded and at the 1-8 week neuronal differentiation window. For full length TTBK1 (band at 150-200 kDa), there was a trend for higher TTBK1 in mutant neurons, but this was not statistically significant. For the predicted lysosomal processed form of TTBK1 (80 kDa band), there was no tau mutation-dependent increase in TTBK1 protein, except at the 2nd week of neuronal differentiation. [Figure 4] FIG. 1 illustrates a map of known tau phosphoepitopes, the kinases associated with each site, and antibody probes suitable for assaying the activity of the cognate kinase. Sites known to be phosphorylated by TTBK1, including S199, S202 / T205, and S422, are known disease-associated sites associated with tauopathies. [Diagram 5] FIG. 1 illustrates the design of the first generation “TTBK-IMiD” for targeted degradation of tau tubulin kinase 1. [Figure 6] Figure 1 illustrates that RAY06-001 does not significantly affect steady-state levels of TTBK1 protein. However, the compound results in a reduction of both AT8 and S422 P-tau, both TTBK1 specific sites, and in contrast has low to no effect on the S396 P site. [Figure 7] FIG. 1 illustrates that the effect of Ray06-002 is consistent with TTBK1 dose-dependent degradation. Along with the reduction in the levels of TTBK1, there was also a reduction in total tau (tau5) and P-tau AT8 and S422. The effect of this TTBK-IMiD on S396 P-tau was less significant, especially in A152T neurons. When examining the P-tau / total tau ratio, the effect of Ray06-002 was only observed at the highest concentration (P301L neurons), suggesting that the reduction in P-tau at lower concentrations occurs in parallel with the reduction in total tau, possibly due to changes in tau oligomerization and degradation propensity. At higher doses, the reduction in tau phosphorylation becomes more pronounced than the process that leads to total tau reduction. [Figure 8] Figure 1 illustrates that the TTBK1 degrader Ray06-003 does not appear to promote TTBK1 degradation, so any effect seen on P-tau levels (and even total tau) must be due to the TTBK1 inhibitory effect carried by the molecule.However, the effect on P-tau is seen mainly / only in P301L neurons. [Figure 9] FIG. 1 illustrates that the effect of Ray06-004 was consistent with a dose-dependent degradation of TTBK1 that was 40% lower than basal levels, and with the same IC50 in both tauopathy neuron models. However, the effect of reduced TTBK1 on P-tau was only observed at higher concentrations of the compound (A152T neurons) or showed less dose-dependence (P301L neurons). Unexpectedly, in this degrader, the effect on P-tau S396 was more pronounced than that on P-tau AT8. [Figure 10]Ray06-005 illustrates that in both neuronal models, TTBK1 levels were reduced in a dose-dependent manner. It also caused a reduction in total tau levels, especially in the A152T model, where the dose-dependent effect is more clear (along with some increase in non-P-tau tau1). Along with the reduced levels of TTBK1, there was also a reduction in P-tau for all epitopes tested, whether TTBK1-dependent (AT8, S422) or not (S396). The most significant reduction was seen for P-tau S422. With regard to Ray06-002, the results suggest that the reduction in P-tau occurs in parallel with the reduction in total tau, possibly due to changes in tau oligomerization and degradation propensity. [Figure 11] Figure 2 illustrates that TTBK1 showed the strongest dose-dependent effect on TTBK1 protein levels, with IC50s between 0.05 and 0.2 μM. With respect to tau, a reduction in total tau was observed with a strong dose-dependent effect in the A152T model. Moreover, there was a reduction in P-tau for all epitopes tested, whether TTBK1-dependent (AT8, S422) or not (S396). The results suggest that the reduction in P-tau occurs in parallel to the reduction in total tau, possibly due to changes in tau oligomerization and degradation propensity. Analysis of P-tau / total tau in A152T suggests that the reduction in tau phosphorylation and in total tau levels was very similar, with the exception of S396 P-tau (non-TTBK1 site). For P301L neurons, the reduction in tau phosphorylation appears to be more pronounced than the effect on total tau. [Figure 12]Figure 2 illustrates that the TTBK1 degrader Ray06-007 showed good dose-dependent effects on TTBK1 protein levels with IC50 of 0.02-0.2 μM. With respect to tau, reductions in total tau were observed mainly in A152T neurons. In this model, reductions in P-tau were more pronounced for the TTBK1-dependent sites AT8 and S422. The % reductions in P-tau and total tau appear to be very similar, probably due to changes in tau oligomerization and degradation propensity as a result of reduced tau phosphorylation. In P301L neurons, the effects on tau and P-tau were less pronounced and were mainly observed at higher TTBK imide concentrations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] TTBK1 has been implicated in tau pathology and thus in Alzheimer's disease and related tauopathies. Published studies demonstrate that TTBK1 levels are increased in postmortem brains of Alzheimer's disease and that TTBK1 phosphorylates tau. TTBK1 has been implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis, through phosphorylation of TDP-43. Finally, TTBK1 has been shown to be involved in neuroinflammation as well. Taken together, selective inhibitors of TTBK1 in development are expected to have versatility in the treatment of multiple human diseases of the nervous system. However, the K for TTBK1 is unclear. m Due to the observation in the literature that ATP is at the lower end of the "normal" range for kinases at about 10 μM, it is problematic for the field to develop pharmacologically acceptable, highly potent ATP-competitive inhibitors, because the cellular concentration of ATP is in the high millimolar range. The present disclosure provides a series of compounds that are heterobifunctional TTBK1 degraders (e.g., the compounds can target TTBK1 for degradation).

[0013] compound In some embodiments, the present disclosure provides a compound of formula (I):

[0014] [ka] or a pharma- ceutically acceptable salt thereof, wherein: n is an integer selected from 1 to 10; Each L 1 is C(=O), N(R N ), S, S(=O), S(=O)2, O, (-C 1~3 Alkylene-O-) x , (-OC 1~3 Alkylene-) x , -C 1~10 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, C 6~10 arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene, where each x is independently an integer from 1 to 10; 1~10 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, C 6~10 The arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene are optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO, CN, halo, amino, and carboxy; Each R N , H, C 1~3 Alkyl, and C 1~3 independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R 1 Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; Each R 2 , R 3 and R 5 H, halo, C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; R 4 and R 6 , H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0015] In some embodiments: n is an integer selected from 1 to 10; Each L 1 is C(=O), N(R N ), S, S(=O), S(=O)2, O, -C 1~3 Alkylene-O-, -OC 1~3 Alkylene-, -C 1~10 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, C 6~10 arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene, 1~10 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, C 6~10 The arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene are optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO, CN, halo, amino, and carboxy; Each RN , H, C 1~3 Alkyl, and C 1~3 independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R 1 Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1-3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; Each R 2 , R 3 and R 5 H, halo, C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1-3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; R 4 and R 6 , H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0016] In some embodiments: n is an integer selected from 1 to 10; Each L 1 is C(=O), N(R N ), S, S(=O), S(=O)2, O, -C 1~3 Alkylene-O-, -OC 1~3 Alkylene-, -C 1~10 Alkylene-, C 2~6 Alkenylene, and C 2~6 independently selected from alkynylene; Each R N , H, C 1~3 Alkyl, and C 1~3 independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R 1 Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; Each R 2 , R 3 and R 5 H, halo, C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; R 4 and R 6 , H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0017] In some embodiments: n is an integer selected from 1 to 10; Each L 1 is C(=O), N(R N ), S, S(=O), S(=O)2, O, -C 1~3 Alkylene-O-, -OC 1~3 Alkylene-, -C 1~10 Alkylene-, C 2~6 Alkenylene, and C 2~6 independently selected from alkynylene; Each R N , H, C 1~3 Alkyl, and C 1~3 independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R 1 Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; Each R 2 , R 3 and R 5 H, halo, C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; R 4 and R 6 , H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0018] In some embodiments: n is an integer selected from 3 to 6; Each L 1 is C(=O), N(R N ), S, S(=O), S(=O)2, O, -C 1~3 Alkylene-O-, -OC 1~3 Alkylene-, -C 1~10 Alkylene-, C 2~6 Alkenylene, and C 2~6independently selected from alkynylene; Each R N , H, C 1~3 Alkyl, and C 1~3 independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R 1 Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; Each R 2 , R 3 and R 5 H, halo, C 1~3 Alkyl, C 1~4 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1~3 Alkylamino, di(C 1~3 alkyl)amino, carboxy, and C 1~3 independently selected from: alkoxycarbonyl; R 4 and R 6 , H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0019] In some embodiments, X is O.

[0020] In some embodiments, X is absent. When X is absent, the carbon atom of C=X becomes CH2.

[0021] In some embodiments, x is 1 or 2. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3 to 6. In some embodiments, x is 7 to 10.

[0022] In some embodiments, the compound of formula (I) has the formula:

[0023] [ka] or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, the compound of formula (I) has the formula:

[0025] [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, the compound of formula (I) has the formula:

[0027] [ka] or a pharma- ceutically acceptable salt thereof.

[0028] In some embodiments, the compound of formula (I) has the formula:

[0029] [ka] or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, n is an integer from 1 to 8. In some embodiments, n is an integer from 2 to 6. In some embodiments, n is an integer from 3 to 5. In some embodiments, n is an integer from 3 to 8.

[0031] In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0032] In some embodiments, each L 1 are C(=O), NH, O, and -C 1~10 alkylene-.

[0033] In some embodiments, each L 1 is C(=O), O, and -C 1~10 alkylene-.

[0034] In some embodiments, L 1 However, C(=O), N(R N ), S, S(=O), S(=O)2, or O, two groups are 1 For example, in some embodiments, L 1 does not contain an -OO- or -NO- moiety.

[0035] In some embodiments, the moiety -(L 1 ) n - is O, N(R N ), S, C(=O), C(=O)O, C(=O)N(R N ), N(R N )C(=O), N(R N )C(=O)O,N(R N )C(=O)N(R N ), OC(=O), OC(=O)O, OC(=O)N(R N ), S(O)2N(R N ), and N(R N )S(O)2, or combinations thereof.

[0036] In some embodiments, the moiety -(L 1 ) n- may be selected from any of the L groups listed in US Patent Application Serial No. 14 / 792,414 or US Patent Application Serial No. 14 / 707,930, the entireties of which are incorporated herein by reference.

[0037] In some embodiments, the compound of formula (I) has the formula:

[0038] [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 2 -C 1~10 It is alkylene.

[0039] In some embodiments, the compound of formula (I) has the formula:

[0040] [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 2 -C 1~10 It is alkylene.

[0041] In some embodiments, L 2 is butylene.

[0042] In some embodiments, L 2 is hexylene.

[0043] In some embodiments, L 2 is octylene.

[0044] In some embodiments, the compound of formula (I) is the following compound:

[0045] [ka] or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula (I) is

[0047] [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (I) is

[0049] [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the compound of formula (I) is

[0051] [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the compound of formula (I) is

[0053] [ka] or a pharma- ceutically acceptable salt thereof.

[0054] In some embodiments, the compound of formula (I) is

[0055] [ka] or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments, the compound of formula (I) is

[0057] [ka] or a pharma- ceutically acceptable salt thereof.

[0058] Pharmaceutically acceptable salts In some embodiments, the salt of a compound of formula (I) is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharma- ceutically acceptable acid addition salt.

[0059] In some embodiments, acids commonly used to form pharma- ceutically acceptable salts of compounds of formula (I) include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Such pharma- ceutically acceptable salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6 ... esters, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids, such as maleic acid.

[0060] In some embodiments, bases commonly used to form pharma- ceutically acceptable salts of the compounds of formula (I) include hydroxides of alkali metals including sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia; organic amines such as unsubstituted or hydroxyl-substituted mono-, di- or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds of formula (I), or pharma- ceutically acceptable salts thereof, are substantially isolated.

[0061] How to use In some embodiments, the disclosure provides a method for inhibiting tau tubulin kinase-1 (TTBK1), the method comprising contacting TTBK1 with an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the present disclosure provides a method for inhibiting tau tubulin kinase-1 (TTBK1) in a cell, the method comprising contacting the cell with an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the contacting is performed in vitro, ex vivo or in vivo.

[0063] In some embodiments, the disclosure provides a method for inhibiting tau tubulin kinase-1 (TTBK1) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0064] In some embodiments, the present disclosure provides a method for treating a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its pharma- ceutical acceptable salt, or a pharmaceutical composition comprising the same. In some embodiments, the neurodegenerative disease or disorder is selected from tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal lobar degeneration with tau pathology, Huntington's disease, and Parkinson's disease, and the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its pharma-ceutical acceptable salt, or a pharmaceutical composition comprising the same.

[0065] In some embodiments, the disclosure provides a method of treating a neurodegenerative disease or disorder in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, wherein the neurodegenerative disease or disorder is selected from tauopathies, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal lobar degeneration with tau pathology, Huntington's disease, and Parkinson's disease.

[0066] In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease. In some embodiments, the neurodegenerative disease or disorder is a tauopathy. In some embodiments, the neurodegenerative disease or disorder is frontotemporal dementia. In some embodiments, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative disease or disorder is progressive supranuclear palsy.

[0067] In some embodiments, the tauopathy is selected from primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), ganglioglioma and gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), argyrophilic grain disease (AGD), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, and Pick's disease. In some embodiments, the tauopathy is progressive supranuclear palsy. In some embodiments, the tauopathy is primary age-related tauopathy (PART). In some embodiments, the tauopathy is chronic traumatic encephalopathy (CTE). In some embodiments, the tauopathy is progressive supranuclear palsy (PSP). In some embodiments, the tauopathy is corticobasal degeneration (CBD). In some embodiments, the tauopathy is frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In some embodiments, the tauopathy is Lytico-bodig disease (Parkinson-dementia complex of Guam). In some embodiments, the tauopathy is ganglioglioma and gangliocytoma. In some embodiments, the tauopathy is meningioangiomatosis. In some embodiments, the tauopathy is postencephalitic parkinsonism. In some embodiments, the tauopathy is subacute sclerosing panencephalitis (SSPE). In some embodiments, the tauopathy is argyrophilic grain disease (AGD). In some embodiments, the tauopathy is lead encephalopathy. In some embodiments, the tauopathy is tuberous sclerosis. In some embodiments, the tauopathy is pantothenate kinase-associated neurodegeneration. In some embodiments, the tauopathy is lipofuscinosis. In some embodiments, the tauopathy is Pick's disease.

[0068] Pharmaceutical Compositions The application also provides a pharmaceutical composition comprising an effective amount of the disclosed compound (e.g., Formula (I)) disclosed herein, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one of the additional therapeutic agents described herein. The carrier(s) is "acceptable" in the sense of being compatible with the other ingredients of the formulation, and in the case of pharma- ceutical acceptable carriers, not deleterious to the recipient thereof in the amounts used in the medicament.

[0069] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0070] The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100%, with the remainder consisting of suitable pharmaceutically acceptable excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of any one of the compounds and therapeutic agents provided herein, with the remainder consisting of any pharmaceutically acceptable excipients described herein or any combination of these excipients.

[0071] Route of administration and dosage form Pharmaceutical compositions of the present application include those suitable for any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intrathecal, intrasynovial, intratesticular, intraarachnoid, intraductal, intratumor, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and intravaginal.

[0072] The compositions and preparations described herein can be conveniently present in unit dosage form, for example, in tablets, sustained release capsules, and in liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).These preparation methods include the step of associating the molecule to be administered with ingredients such as carriers, which constitute one or more accessory ingredients.In general, the composition is prepared by uniformly and intimately associating active ingredient with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0073] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is administered orally.The compositions of the present application suitable for oral administration can be expressed as individual units such as capsules, sachets, granules or tablets, each of which contains a predetermined amount (e.g., effective amount) of active ingredient; powder or granules; solution or suspension in aqueous liquid or non-aqueous liquid; oil-in-water liquid emulsion; water-in-oil liquid emulsion; filled in liposome; or bolus, etc.Soft gelatin capsules can be useful for containing such suspensions, which can advantageously increase the rate of compound absorption.In the case of tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, and silicic acid and starch. Other acceptable excipients may include: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clays; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspension is administered orally, active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners and / or flavorings and / or colorings can be added.Compositions suitable for oral administration include lozenges which comprise the ingredient in a flavored base, usually sucrose and acacia or tragacanth; and pastilles which comprise the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia.

[0074] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection or infusion solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injection solutions may be, for example, in the form of sterile injectable aqueous or oily suspensions. The suspensions may be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0075] The pharmaceutical composition of the present application can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present application with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and thus melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0076] The pharmaceutical compositions of the present application can be administered by nasal aerosol or inhalation.These compositions can be prepared according to techniques well known in the art of pharmaceutical formulations, and can be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.See, for example, U.S. Patent No. 6,803,031.Additional formulations and methods for intranasal administration can be found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0077] The topical composition of the present disclosure can be prepared and used in the form of aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly used in the art of topical administration, and / or cosmetic and dermatological preparations.The topical composition can be in emulsion form.Topical administration of the pharmaceutical composition of the present application is particularly useful when the desired treatment involves areas or organs that are easily accessible by topical application. In some embodiments, topical compositions comprise a combination of any one of the compounds and therapeutic agents disclosed herein and one or more additional ingredients, carriers, excipients or diluents, including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film formers / retentive agents, fragrances, leave-on exfoliants, formulas, preservatives, scrubbing agents, silicones, skin equalizing / repairing agents, lubricants, sunscreen actives, surfactants / detergents, cleaning agents, penetration enhancers, and thickeners.

[0078] The compounds and therapeutic agents of the present application can be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are illustrated in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. Coatings are typically biocompatible polymeric materials, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. Coatings can be optionally further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof, to impart controlled release properties to the composition. Coatings of invasive devices should be included within the definition of pharmaceutically acceptable carrier, adjuvant, or vehicle, as those terms are used herein.

[0079] According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or therapeutic agent, or a composition comprising a compound or therapeutic agent of the present application, wherein said compound or therapeutic agent is released from said device and is therapeutically active.

[0080] Dosage and Regimen In the pharmaceutical compositions of the present application, the compounds of the present disclosure (e.g., compounds of formula (I)) are present in an effective amount (e.g., a therapeutically effective amount). The effective dose can vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, excipient usage, the possibility of co-use with other therapeutic treatments, such as the use of other drugs, and the judgment of the treating physician.

[0081] In some embodiments, an effective amount of a compound of formula (I) can be, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; The effective dose of the compound of formula (I) may range from about 1 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 2 mg / kg; about 0.1 mg / kg to about 1 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, the effective amount of the compound of formula (I) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0082] The aforementioned dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day) or on a non-daily basis (e.g., every other day, every second day, every third day, once a week, twice a week, once every two weeks, once a month).

[0083] kit The present invention further includes pharmaceutical kits, useful in the treatment of disorders, diseases and conditions, for example, as mentioned herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present disclosure.Such kits can further include one or more of various conventional pharmaceutical kit components, such as a container with one or more pharma-ceutically acceptable carriers, additional containers, etc.Instructions indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing components, either as inserts or as labels, can also be included in the kit.The kits can optionally include additional therapeutic agents as described herein.

[0084] definition As used herein, the term "about" means plus or minus approximately 10% of the indicated value.

[0085] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0086] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution can be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by the valence of the atom.

[0087] Throughout the definition, "C n~m" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1~4 , C 1~6 etc.

[0088] As used herein, "C" used alone or in combination with other terms means n~m The term "alkyl" refers to a saturated hydrocarbon group that may be straight-chained or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0089] As used herein, "C" used alone or in combination with other terms means n~m The term "alkylene" refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1,-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methylpropane-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0090] As used herein, "C" used alone or in combination with other terms means n~mThe term "haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, where the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0091] As used herein, "C" used alone or in combination with other terms means n~m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0092] As used herein, "C n~m "Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0093] As used herein, the term "amino" refers to a group of formula -NH2.

[0094] As used herein, "C n~mThe term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

[0095] As used herein, "di(C n~m The term "-N(alkyl)amino" refers to a group of formula -N(alkyl)2, where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0096] As used herein, "C n~m The term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

[0097] As used herein, the term "carboxy" refers to the group -C(O)OH.

[0098] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0099] As used herein, the term "aryl", employed alone or in combination with other terms, refers to an aromatic hydrocarbon group which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has 6 to 10 carbon atoms. In some embodiments, an aryl group is phenyl or naphthyl. In some embodiments, the term "arylene" refers to a divalent aryl group.

[0100] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings) and spiro rings. The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted by one or two independently selected oxo or sulfido groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., typically with bonds) to the cycloalkyl ring, such as benzo or thienyl derivatives such as cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be attached through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups can be substituted with 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C 3~10 In some embodiments, the cycloalkyl can have the formula: 3~10 In some embodiments, the cycloalkyl is a monocyclic or bicyclic cycloalkyl. 3~7It is a monocyclic cycloalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the term "cycloalkylene" refers to a divalent cycloalkyl group.

[0101] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring having 5 ring atoms, where one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Illustrative 5-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A 6-membered heteroaryl ring is a heteroaryl having a ring with 6 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Illustrative 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. In some embodiments, the term "heteroarylene" refers to a divalent heteroaryl group.

[0102] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine, and the like. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally substituted by one or two independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). A heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains zero to three double bonds. In some embodiments, a heterocycloalkyl group contains zero to two double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., typically with bonds) to a cycloalkyl ring, such as benzo or thienyl derivatives, such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings can be attached through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the term "heterocycloalkylene" refers to a divalent heterocycloalkyl group.

[0103] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valence of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, while a pyridin-3-yl ring is attached at the 3-position.

[0104] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places in this specification.Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member when valence allows.For example, the term "pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0105] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that have aromatic character (i.e., have (4n+2) delocalized π (pi) electrons, where n is an integer).

[0106] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0107] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms, unless otherwise specified.

[0108] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like, may be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R)-configuration. In some embodiments, the compounds have the (S)-configuration.

[0109] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of adjacent double bonds and single bonds together with the concomitant migration of protons. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically fixed in one form by appropriate substitution.

[0110] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism, such as a mammal.

[0111] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or in vivo system. For example, "contacting" tau tubulin kinase-1 (TTBK1) with a compound of the present invention includes administering the compound of the present invention to an individual or patient, such as a human, having tau tubulin kinase-1 (TTBK1), as well as introducing the compound of the present invention into a sample containing, for example, a cell or purified preparation containing tau tubulin kinase-1 (TTBK1).

[0112] As used herein, the terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0113] As used herein, the phrases "effective amount" or "therapeutically effective amount" refer to that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, physician or other clinician.

[0114] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomology), or 2) ameliorating a disease; e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology). EXAMPLES

[0115] Chemical synthesis methods & analytical chemistry 1 H NMR spectra were recorded on a Bruker AV-III-400 or 500 MHz NMR spectrometer. Chemical shifts are reported in δ values ​​in ppm downfield from TMS as internal standard. 1 H NMR data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, b=broad, m=multiplet, quint=quintet), coupling constant (Hz), integration. 13C chemical shifts are reported in δ values ​​in ppm downfield from TMS as internal standard. Low-resolution mass spectra were obtained on a Waters Acquity Ultra Performance LC with electrospray ionization and SQ detector by injecting samples into a steady flow of 1 mM ammonium acetate in 20% water-acetonitrile at a rate of 0.2 mL / min. Purity of compounds was determined by analytical HPLC performed on an ELSD PDA multi and a Shimadzu Prominence-HPLC with a Gemini NX C-18 column (250 × 4.6 mm, 5μ) at a 1.0 mL / min flow rate using mobile phase (A) 0.1% formic acid in acetonitrile and mobile phase (B) 0.1% formic acid in water with the following gradient: B / A (0 min, 10%), (5 min, 90%), (6 min, 95%) and (10 min, 95%). Analytical thin-layer chromatography was performed on 250 μM silica gel F 254 Preparative thin-layer chromatography was performed on 1000 μM silica gel F 254 Flash column chromatography was performed using 230-400 mesh silica gel.

[0116] [Example 1] Methyl 2-bromo-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzoate (Ray06-01)

[0117] [ka] A solution of 6-chloro-7-deazapurine (78 mg, 0.49 mmol) and methyl 5-amino-2-bromobenzoate (120 mg, 0.52 mmol) in ethylene glycol was heated at 140° C. and stirred for 3 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with water (3×10 mL). The organic layer was dried over Na2SO4, concentrated, and recrystallized from CH2Cl2 to give the title compound (90 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (bs, 1H), 9.61 (s, 1H), 8.36-8.32 (m, 2H), 8.21 (dd, J = 2.8, 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 2.4, 3.2 Hz, 1H), 6.82 (dd, J = 1.6, 3.2 Hz, 1H), 3.89 (s, 3H). HPLC: t R = 6.12 minutes, 97.4%.

[0118] [Example 2]

[0119] [ka] Step 1. To a solution of 4-O-TBS-butyl-1-tosylate (1.30 mg, 4.6 mmol) and 4-nitrophenol (600 mg, 4.3 mmol) in dry dimethylformamide (DMF) (25 mL) was added K2CO3 (1.27 g, 9.2 mmol) and heated at 70 °C for 4 h. The reaction mixture was concentrated, diluted with water (2 mL) and brine (8 mL) and extracted with CHCl3 (3 x 30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was dissolved in dry tetrahydrofuran (THF) (10 mL), cooled and treated with 1 M tetra-n-butylammonium fluoride (TBAF) in THF (5 ml, 5 mmol). The resulting mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL) and washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give compound 2a. 4-(4-Nitrophenoxy)-1-butanol (compound 2a). 1H NMR (400 MHz, CDCl3) δ 8.23-8.17 (m, 2H), 6.97-6.92 (m, 2H), 4.10 (t, J = 6.4 Hz, 2H), 3.78-3.71 (m, 2H), 1.99-1.89 (m, 2H), 1.82-1.72 (m, 2H), 1.43-1.36 (m, 1H).

[0120] Step 2. To a solution of compound 2a (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 3a. 4-(4-aminophenoxy)-1-butanol (compound 3a). 1 H NMR (400 MHz, CDCl3) δ 6.77-6.71 (m, 2H), 6.67-6.62 (m, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3.42 (bs, 2H), 1.88-1.81 (m, 2H), 1.79-1.70 (m, 2H).

[0121] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 3a (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 4a. 4-(4-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-butanol (compound 4a) MS (ESI +) m / z 327.4 (M + H) + . 1 H NMR (500 MHz, DMSO-d6) δ 12.59 (bs, 1H), 10.83 (bs, 1H), 8.26 (s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.39 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.76 (bs, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 1.81-1.73 (m, 2H), 1.62-1.55 (m, 2H).

[0122] Step 4. To a solution of compound 4a (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-002. 4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)butyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-002). 1H NMR (400 MHz, DMSO-d6) δ 11.69 (bs, 1H), 11.11 (s, 1H), 9.17 (bs, 1H), 8.19 (s, 1H), 7.82-7.76 (m, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.51-7.40 (m, 2H), 7.20-7.16 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.67 (bs, 1H), 5.14-5.07 (m, 3H), 4.21 (t, J = 5.6 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.95-2.83 (m, 1H), 2.71-2.57 (m, 2H), 2.08-1.99 (m, 1H), 1.80-1.73 (m, 4H). HPLC: t R = 5.49 minutes, 98.7%.

[0123] [Example 3]

[0124] [ka] Step 1. To a solution of 4-nitrophenol (1 eq.) and 6-bromo-1-hexanol (1 eq.) in dry DMF (2.5 ml) was added K2CO3 (2 eq.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated. It was diluted with water (2 mL) and brine (8 mL) and extracted with CHCl3 (3×30 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give compound 2b. 6-(4-Nitrophenoxy)-1-hexanol (compound 2b). 1 H NMR (400 MHz, CDCl3) δ 8.20 (m, 2H), 6.94 (m, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 1.89-1.81 (m, 2H), 1.67-1.59 (m, 2H), 1.56-1.41 (m, 4H).

[0125] Step 2. To a solution of compound 2b (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 3b. 6-(4-Aminophenoxy)-1-hexanol (compound 3b). 1 H NMR (400 MHz, CDCl3) δ 6.76-6.71 (m, 2H), 6.66-6.61 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 1.80-1.71 (m, 2H), 1.64-1.54 (m, 2H), 1.52-1.41 (m, 4H).

[0126] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 3b (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 4b. 6-(4-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-hexanol (compound 4b). MS (ESI + ) m / z 327.4 (M + H) + . 1H NMR (400 MHz, DMSO-d6) δ 11.66 (bs, 1H), 9.13 (bs, 1H), 8.19 (s, 1H), 7.73-7.65 (m, 2H), 7.19-7.15 (m, 1H), 6.94-6.88 (m, 2H), 6.69-6.65 (m, 1H), 4.35 (t, J = 4.8 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.42-3.36 (m, 2H), 1.76-1.66 (m, 2H), 1.49-1.31 (m, 6H).

[0127] Step 4. To a solution of compound 4b (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-003. 6-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)hexyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-003). 1H NMR ((400 MHz, DMSO-d6) δ 11.67 (bs, 1H), 11.10 (s, 1H), 9.14 (bs, 1H), 8.19 (s, 1H), 7.79 (dd, J = 7.2, 8.4 Hz, 1H), 7.72-7.64 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.19-7.16 (m, 1H), 6.94-6.89 (m, 2H), 6.69-6.66 (m, 1H), 5.15-5.06 (m, 3H), 4.15 (t, J = 6.4 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.95-2.82 (m, 1H), 2.71-2.56 (m, 2H), 2.07-2.00 (m, 1H), 1.73-1.57 (m, 4H), 1.46-1.31 (m, 4H). HPLC: t R = 5.47 minutes, 96.9%.

[0128] [Example 4]

[0129] [ka] Step 1. To a solution of 4-nitrophenol (1 eq.) and 8-bromo-1-octanol (1 eq.) in dry DMF (2.5 ml) was added K2CO3 (2 eq.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated, diluted with water (2 mL) and brine (8 mL), and extracted with CHCl3 (3×30 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give compound 2c. 8-(4-Nitrophenoxy)-1-octanol (compound 2c). 1H NMR (400 MHz, CDCl3) δ 8.23-8.17 (m, 2H), 6.96-6.91 (m, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 1.88-1.78 (m, 2H), 1.62-1.56 (m, 2H), 1.52-1.44 (m, 2H), 1.42-1.34 (m, 6H).

[0130] Step 2. To a solution of compound 2c (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 3c. 8-(4-Aminophenoxy)-1-octanol (3c). 1 H NMR (500 MHz, CDCl3) δ 6.76-6.72 (m, 2H), 6.66-6.62 (m, 2H), 3.87 (t, J = 6.5 Hz, 2H), 3.64 (t, J = 6.5 Hz, 2H), 3.55-3.35 (bs, 2H), 1.78-1.69 (m, 2H), 1.61-1.51 (m, 2H), 1.49-1.40 (m, 2H), 1.40-1.30 (m, 4H).

[0131] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 3c (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 4c. 8-(4-[(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-octanol (compound 4c). 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (bs, 1H), 9.13 (bs, 1H), 8.19 (s, 1H), 7.72-7.67 (m, 2H), 7.19-7.16 (m, 1H), 6.93-6.89 (m, 2H), 6.69-6.66 (m, 1H), 4.35 (t, J = 4.8 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.41-3.35 (m, 2H), 1.75-1.64 (m, 2H), 1.44-1.38 (m, 4H), 1.36-1.24 (m, 6H).

[0132] Step 4. To a solution of compound 4c (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-004. 8-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)octyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-004). 1H NMR (400 MHz, DMSO-d6) δ 11.69 (bs, 1H), 11.10 (s, 1H), 9.16 (bs, 1H), 8.19 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.92 (d, J = 9.0 Hz, 2H), 6.66 (s, 1H), 5.14-5.06 (m, 3H), 4.13 (t, J = 6.5 Hz, 2H), 3.93 (t, J = 6.5 Hz, 2H), 2.93-2.84 (m, 1H), 2.65-2.55 (m, 2H), 2.06-2.01 (m, 1H), 1.73-1.65 (m, 2H), 1.62-1.54 (m, 2H), 1.43-1.34 (m, 2H), 1.32-1.22 (m, 6H). HPLC: t R = 5.81 points, 98.0%.

[0133] [Example 5]

[0134]

change

[0135] Step 2. To a solution of compound 7a (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 8a. 4-(3-aminophenoxy)-1-butanol (compound 8a). 1 H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 8.0 Hz, 1H), 6.34-6.26 (m, 2H), 6.24 (t, J = 2.4 Hz, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H), 1.90-1.82 (m, 2H), 1.79-1.71 (m, 2H).

[0136] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 8a (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 9a. 4-(4-[(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-butanol (compound 9a). 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (bs, 1H), 10.00 (bs, 1H), 8.30 (s, 1H), 7.43 (s, 1H), 7.34-7.25 (m, 3H), 6.81 (s, 1H), 6.74 (s, 1H), 3.99 (t, J = 6.4 Hz, 2H), 3.46 (t, J = 6.4 Hz, 2H), 1.81-1.72 (m, 2H), 1.61-1.53 ​​(m, 2H).

[0137] Step 4. To a solution of compound 9a (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-005. 4-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)butyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-005). 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (bs, 1H), 11.11 (s, 1H), 9.23 (bs, 1H), 8.28 (s, 1H), 7.78 (dd, J = 7.6, 8.8 Hz, 1H), 7.62 (t, J = 2.4 Hz, 1H), 7.51-7.39 (m, 3H), 7.26-7.19 (m, 2H), 6.79 (dd, J = 1.6, 3.2 Hz, 1H), 6.58 (dd, J = 2.0, 8.0 Hz, 1H), 5.14-5.07 (m, 3H), 4.22 (t, J = 6.4 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 2.94-2.84 (m, 1H), 2.64-2.55 (m, 2H), 2.07-1.99 (m, 1H), 1.83-1.75 (m, 4H). HPLC: t R = 5.49 minutes, 98.0%.

[0138] [Example 6]

[0139] [ka] Step 1. To a solution of 3-nitrophenol (1 eq.) and 6-bromo-1-hexanol (1 eq.) in dry DMF (2.5 ml) was added K2CO3 (2 eq.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated, diluted with water (2 mL) and brine (8 mL), and extracted with CHCl3 (3×30 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give compound 7b. 6-(3-nitrophenoxy)-1-hexanol (compound 7b). 1H NMR (400 MHz, CDCl3) δ 7.81 (ddd, J = 0.8, 2.4, 8.0 Hz, 1H), 7.71 (t, J = 2.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.21 (ddd, J = 0.8, 2.4, 8.4 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.67-1.58 (m, 2H), 1.56-1.41 (m, 4H).

[0140] Step 2. To a solution of compound 7b (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 8b. 6-(3-aminophenoxy)-1-hexanol (compound 8b). 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 8.0) 6.34-6.23 (m, 3H), 3.91 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 1.82-1.74 (m, 2H), 1.65-1.56 (m, 2H), 1.53-1.42 (m, 4H).

[0141] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 8b (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 9b. 6-(4-[(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-hexanol (compound 9b). 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (bs, 1H), 9.78 (bs, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 7.38-7.24 (m, 3H), 6.80 (s, 1H), 6.70 (d, J = 7.2 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 1.78-1.68 (m, 2H), 1.50-1.32 (m, 6H).

[0142] Step 4. To a solution of compound 9b (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-006. 6-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)hexyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-006). 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.10 (s, 1H), 9.26 (s, 1H), 8.28 (s, 1H), 7.78 (dd, J = 7.2, 8.4 Hz, 1H), 7.6 (t, J = 2.0 Hz, 1H), 7.50-7.39 (m, 3H), 7.25-7.18 (m, 2H), 6.81-6.77 (m, 1H), 6.59 (dd, J = 2.4, 8.4 Hz, 1H), 5.14-5.06 (m, 3H), 4.15 (t, J = 6.4 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 2.94-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.07-2.00 (m, 1H), 1.76-1.68 (m, 2H), 1.62-1.55 (m, 2H), 1.48-1.32 (m, 4H). HPLC:t R = 5.73 minutes, 97.6%.

[0143] [Example 7]

[0144] [ka] Step 1. To a solution of 3-nitrophenol (1 eq.) and 8-bromo-1-octanol (1 eq.) in dry DMF (2.5 ml) was added K2CO3 (2 eq.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated, diluted with water (2 mL) and brine (8 mL), and extracted with CHCl3 (3×30 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give compound 7c. 8-(3-nitrophenoxy)-1-octanol (compound 7c). 1H NMR (400 MHz, CDCl3) δ 7.81 (ddd, J = 0.8, 2.4, 8.0 Hz, 1H), 7.71 (t, J = 2.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.21 (ddd, J = 0.8, 2.4, 8.4 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.67-1.58 (m, 2H), 1.56-1.41 (m, 8H).

[0145] Step 2. To a solution of compound 7c (1 eq.) in 80% EtOH-water (5 mL) was added iron powder (6 eq.) and CaCl2 (0.6 eq.). The reaction mixture was refluxed for 2 h. The reaction mixture was cooled to ambient temperature and concentrated. The crude product was then diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give compound 8c. 8-(3-aminophenoxy)-1-octanol (compound 8c). 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 16.0 Hz, 1H), 6.34-6.23 (m, 3H), 3.90 (t, J = 6.8 Hz, 2H), 3.68-3.58 (m, 4H), 1.80-1.70 (m, 2H), 1.62-1.56 (m, 2H), 1.48-1.32 (m, 8H).

[0146] Step 3. A solution of 6-chloro-7-deazapurine (1 equiv.) and compound 8c (1 equiv.) in ethylene glycol (2 mL) was heated at 120° C. and stirred for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with 10% MeOH-CHCl3 (10×25 mL). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (MeOH-CHCl3) to give compound 9c. 8-(3-[(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino]phenoxy)-1-octanol (compound 9c). 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (bs, 1H), 9.89 (bs, 1H), 8.29 (s, 1H), 7.46 (s, 1H), 7.37-7.25 (m, 3H), 6.81 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 1.78-1.68 (m, 2H), 1.47-1.27 (m, 10H).

[0147] Step 4. To a solution of compound 9c (55 mg, 0.11 mmol), R5-2C (45 mg, 0.105 mmol) and HOBt (30 mg, 0.2 mmol) in dry DMF (1 mL) was added triethylamine (20 mg, 0.2 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (40 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, concentrated and purified by preparative TLC (8% EtOH in CHCl3) to give Ray06-007. 8-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy)octyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetate (Ray06-007). 1 H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.11 (s, 1H), 9.22 (s, 1H), 8.31 (d, J = 15.5 Hz, 1H), 7.81-7.76 (m, 1H), 7.64-7.61 (m, 1H), 7.50-7.39 (m, 3H), 7.25-7.18 (m, 2H), 6.80-6.78 (m, 1H), 6.58 (dd, J = 2.0, 7.5 Hz, 1H), 5.13-5.08 (m, 3H), 4.12 (t, J = 7.0 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 2.94-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.07-2.00 (m, 1H), 1.76-1.68 (m, 2H), 1.62-1.55 (m, 2H), 1.44-137 (m, 2H), 1.35-1.25 (m, 6H) . HPLC: t R = 6.15 minutes, 97.3%.

[0148] Example A Of the series of novel compositions designed, synthesized and tested, the TTBK1 degrader Ray06-006 showed the strongest dose-dependent effect on TTBK1 protein levels with IC50 of 0.05-0.2 μM. With respect to tau, a reduction in total tau was observed with a strong dose-dependent effect in the A152T tauopathy model. Moreover, there was a reduction in P-tau across all epitopes tested, whether TTBK1-dependent (AT8, S422) or not (S396). Analysis of P-tau / total tau in A152T suggests that the reduction in tau phosphorylation and in total tau levels is very similar, with the exception of S396 P-tau (non-TTBK1 site). For P301L neurons, the reduction in tau phosphorylation appears to be more pronounced than the effect on total tau. Overall, the results indicate that the reduction in P-tau occurs in parallel with the reduction in total tau, likely due to changes in tau oligomerization and degradation propensity. The results are shown in Figures 2, 3, and 6-12.

[0149] Example B. Human NPC lines and postmortem human brain samples Reprogramming of patient skin fibroblasts to iPSCs by a non-integrative method and subsequent conversion into cortical enriched neural progenitors was previously described (Silva MC, Cheng C, Mair W, Almeida S, Fong H, Biswas MHU, Zhang Z, Huang Y, Temple S, Coppola G, Geschwind DH, Karydas A, Miller BL, Kosik KS, Gao FB, Steen JA, Haggarty SJ. Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability. Stem Cell Reports. 2016 Sep 13;7(3):325-340; Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK, Lin YT, Ko T, Cho S, Penney J, Silva MC, Sheridan SD, Lucente D, Gusella JF, Dickerson BC, Haggarty SJ, Tsai LH. Inhibition of p25 / Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia. J Neurosci. 2017 Oct 11;37(41):9917-9924).The cell lines used in this work were as follows: NPC line FTD19-L5-RC6 (Silva et al., 2016) derived from a male individual with progressive supranuclear palsy (PSP) carrying the risk variant tau-A152T (c.1407G>A, rs143624519); NPC line MGH2046-RC1 (Seo et al., 2017; Silva et al., 2019) derived from an autosomal dominant mutation tau-P3 NPC control 1 or 8330-8-RC1 (Sheridan et al., 2011; Silva et al., 2016) were derived from healthy male individuals (tau wild type (WT)); NPC control 2 or MGH2069-RC1 (Seo et al., 2017; Silva et al., 2019) were derived from healthy female individuals (tau-WT). Postmortem human brain samples from healthy controls and A152T (PSP) and P301L (FTD) for comparison were generously provided by the University of California San Francisco (UCSF) Memory & Aging Center.

[0150] NPC culture, differentiation and compound treatment NPCs were cultured in 6-well (Fisher Scientific Corning) or 96-well flat-bottom (Fisher Scientific Corning) plates coated with polyornithine (20 μg / mL in water, Sigma) and laminin (5 μg / mL in PBS, Sigma), referred to as POL-coated plates. Culture medium was DMEM / F12-B27 [70% DMEM (Gibco), 30% Ham's F12 (Fisher Scientific Corning), 2% B27 (Gibco), 1% penicillin-streptomycin (Gibco)] supplemented with EGF (20 ng / mL, Sigma), FGF (20 ng / mL, Stemgent) and heparin (5 μg / mL, Sigma) for NPC proliferation. Cells were plated at 75,000 cells / cm for NPC differentiation over the course of several weeks (6 to 8 weeks, experiment dependent). 2Neurons were plated at an average density of 100 μL / well and growth factors were omitted from the medium which was changed twice per week (Silva et al., 2016). Compound treatment in 6-well plate format was performed in 2 mL medium volume by removing 1 mL of conditioned medium from the cultures and adding 1 mL of fresh medium premixed with compound at the appropriate 2X concentration, followed by incubation at 37°C for the indicated time. Compound treatment in 96-well plates was performed in 100 μL medium by adding compound directly to each well, followed by incubation at 37°C. As a control, neurons were also treated with vehicle alone, i.e., dimethyl sulfoxide (DMSO) at 0.1% v / v, which corresponds to the 0 μM degrader treatment in Figures 6-12. Compounds were kept as 10 mM stock concentrations and serial dilutions were prepared before each experiment in 10-fold dilutions so that the same volume (and % DMSO) was added per well of cells regardless of the final degrader concentration.

[0151] Western blot analysis NPCs were cultured at 75,000 cells / cm 2Neurons were differentiated in 6-well plates at an average density of 1000 x g. Neurons were washed in DPBS (Corning), detached into suspension by scraping, transferred to Eppendorf tubes, and spun down at 3,000 x g for 5 min. Cell pellets were lysed in RIPA buffer (Boston Bio-Products) supplemented with 2% SDS (Sigma), 1% Halt protease / phosphatase inhibitors (Thermo Fisher Scientific), 1:5000 Benzonase (Sigma), and 10 mM DTT (New England BioLabs) for 15 min at room temperature. Lysates were centrifuged at 20,000 x g for 20 min, and the supernatant was transferred to a new Eppendorf tube for analysis. For postmortem human brain lysates, tissue samples (approximately 20-30 mg chunks) were resuspended in 10X the volume of tissue weight with RIPA buffer (same composition as above) and thoroughly homogenized with a portable electric grinder (VWR) to promote tissue disintegration while keeping the tubes on dry ice. Samples were incubated at 4°C for 1 hour on an orbital shaker with constant agitation. Samples were then centrifuged at 26,000×g for 20 minutes at 4°C in a microcentrifuge, the supernatant transferred to a new ice-cold Eppendorf tube, and the pellet discarded. Protein concentration quantification was performed using the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific). For Western blots, 10 μg of total protein per well and in SDS blue loading buffer (New England Biolabs) were analyzed by SDS-PAGE. Alternatively, cell lysis was performed directly in 8X cell pellet volume with SDS sample loading buffer (New England Biolabs) and boiled for 15 min prior to SDS-PAGE. Electrophoresis was performed on a Novex NuPAGE SDS-PAGE Gel System (Invitrogen). Proteins were transferred from the gel onto a PVDF membrane (EMD Millipore) using standard procedures.Membranes were blocked in 5% BSA (Sigma) in Tris-buffered saline with Tween 20 (TBST, Boston Bio-Products) and incubated overnight in 5% BSA-TBST at 4°C with primary antibodies, followed by incubation with the corresponding HRP-linked secondary antibodies at a dilution of 1:4000 (Cell Signaling Technology). Antibodies used were: TTBK1 (Millipore ABN348), tau5 for total tau (Invitrogen AHB0042), tau1 for total non-phosphorylated tau (clone PC1C6 Millipore MAB3420), P-tau Ser396 (Invitrogen 44752G), P-tau Ser422 (GeneTex GTX86147), P-tau AT8 (Thermo Scientific MN1020) and β-actin (Sigma A1978). Blots were developed with SuperSignal West Pico Chemiluminescent Substrate (ThermoFisher) according to the manufacturer's instructions, exposed to autoradiographic film (LabScientific by ThermoFisher), and scanned on an Epson Perfection V800 Photo Scanner. Densitometry (average pixel intensity in arbitrary units, au) of protein bands was measured with the Adobe Photoshop 2021 (v.22.4.3) histogram function and normalized to the respective internal control (β-actin) bands. Calculations were performed in Microsoft Excel (v.16.52) and graphs were plotted in GraphPad Prism 9 (v.9.2.0).

[0152] Statistical information Graphed data represent the mean ± SD (standard deviation) or ± SEM (standard error of the mean) and were calculated using Microsoft Excel and GraphPad Prism. A P value <0.05 was considered the threshold for statistical significance. P value significance interval ( *) are provided in each figure legend along with the statistical tests performed for each experiment. N values ​​are indicated in the figure legend and refer to biological replicates (NPC differentiation culture independent setups and analyses at different times), whereas technical replicates refer to repeated analyses of the same sample. Derived statistics correspond to the analysis of the mean values ​​across biological replicates.

[0153] Other embodiments Although the present application has been described in conjunction with its detailed description, it is to be understood that the foregoing description is intended to be illustrative, and not limiting, of the scope of the present application, as defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (In the formula: n is an integer selected from 1 to 10; Each L １ is C(=O), N(R Ｎ ), S, S(=O), S(=O) ２ , O, (-C １～３ alkylene-O-) ｘ , (—O—C １～３ alkylene-) ｘ , -C １～１０ Alkylene-, C ２～６ Alkenylene, C ２～６ Alkynylene, C ３～１０ Cycloalkylene, C ６～１０ arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene, where each x is independently an integer from 1 to 10; and each C １～１０ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C ３～１０ Cycloalkylene, C ６～１０ Arylene, 5- to 14-membered heteroarylene, and 4- to 10-membered heterocycloalkylene are OH, NO ２ optionally substituted with 1, 2, or 3 substituents independently selected from , CN, halo, amino, and carboxy; Each R Ｎ is H, C １～３ Alkyl, and C １～３ independently selected from haloalkyl; X is O or X is absent; m is an integer from 0 to 4; Each R １ Ha, Halo, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, OH, NO ２ , CN, halo, amino, C １～３ Alkylamino, di(C １－３ alkyl)amino, carboxy, and C １～３ independently selected from: alkoxycarbonyl; Each R ２ , R ３ and R ５ is H, halo, C １～３ Alkyl, C １～４ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, OH, NO ２ , CN, halo, amino, C １～３ Alkylamino, di(C １～３ alkyl)amino, carboxy, and C １～３ independently selected from: alkoxycarbonyl; R ４ and R ６ is H, C １～３ Alkyl, and C １～３ haloalkyl).

2. The compound of claim 1 , wherein X is O.

3. 2. The compound of claim 1, wherein X is absent.

4. The compound of formula (I) is a compound of the formula: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) has the formula: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) has the formula: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) has the formula: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, wherein n is an integer from 3 to 8.

9. 9. The compound of claim 8, wherein n is 6.

10. Each L １ is C(=O), NH, O, and -C １～１０ The compound of claim 1 , wherein each of the groups is independently selected from alkylene-.

11. Each L １ is C(=O), O, and -C １～１０ The compound of claim 1 , wherein each of the groups is independently selected from alkylene-.

12. The compound of formula (I) has the formula: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof. (In the formula: L ２ is -C １～１０ alkylene-).

13. The compound of formula (I) has the formula: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof. (In the formula: L ２ is -C １～１０ alkylene-).

14. L ２ The compound of claim 12, wherein is butylene.

15. L ２ The compound of claim 12, wherein is hexylene.

16. L ２ The compound of claim 12, wherein is octylene.

17. The compound of claim 13, wherein L 2 is butylene.

18. The compound of claim 13, wherein L 2 is hexylene.

19. The compound of claim 13, wherein L 2 is octylene.

20. The compound of formula (I) may be the following compound: 【Chemistry 8】 10. The compound of claim 1, selected from any one of:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. 1. A pharmaceutical product for use in a method for treating a neurodegenerative disease or disorder selected from tauopathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal lobar degeneration with tau pathology, Huntington's disease, and Parkinson's disease, comprising: The pharmaceutical product comprises a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21; The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

23. 23. The pharmaceutical product of claim 22, wherein the tauopathy is selected from primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Guam's Parkinson-dementia complex), ganglioglioma and gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), argyrophilic grain disease (AGD), lead encephalopathy, tuberous sclerosis complex, pantothenate kinase-associated neurodegeneration, and lipofuscinosis, and Pick's disease.

24. 23. The pharmaceutical product of claim 22, wherein the neurodegenerative disease or disorder is Alzheimer's disease.

25. 23. The pharmaceutical product of claim 22, wherein the neurodegenerative disease or disorder is frontotemporal dementia.

26. The pharmaceutical agent of claim 23, wherein the tauopathy is progressive supranuclear palsy.

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