Inhibitors of taok

Abstract

Disclosed herein are compounds, and salts thereof, which inhibit Thousand-and-one kinase (TAOK). Also disclosed are pharmaceutical formulations and methods of treatment for diseases associated with TAOK.

Description

INHIBITORS OF TAOK

[0001] This application claims the benefit of priority of United States provisional application no. 63 / 674,067, filed July 22, 2024, the contents of which are incorporated by reference as if written herein in their entirety.

[0002] Deposition of pathogenic tau is a driver of neurotoxicity in Alzheimer’s disease (AD) and other tauopathies. A pathway connecting toxic tau to neuronal death has been identified, in which pathological tau relocates from the axon to the perinuclear region, overstabilizes filamentous actin near the nuclear pore and deforms nucleoskeletal architecture. Disruption of the nucleoskeleton causes the nuclear envelope to invaginate and heterochromatin to decondense, promoting expression of genes and repetitive elements that are normally silenced and activating the cell cycle, which drives cell death in post-mitotic neurons. Interrupting this process at any number of steps attenuates neuronal loss.

[0003] The thousand-and-one amino acid kinases (TAOK) are members of the Mitogen Activated Protein kinase kinase kinase (MAP3K) family, linking extracellular stimuli to downstream signaling. TAOK2, the major mammalian homologue of Tao in the brain, is linked to impaired neuronal health and tau pathology in AD and was implicated as a putative risk gene linked to increased risk of AD. Intriguingly, TAOK2 regulates RhoA-mediated F- actin stability and the Hippo pathway effector YAP / TAZ-driven cell cycle activation, both of which play critical roles in tau-induced neurotoxicity. Therefore, inhibitors of TAOKs are expected to be useful as drugs to treat neurodegenerative disorders such as AD and primary tauopathies. Currently, there are no TAOK inhibitors approved for clinical use and only minimal examples in the literature.

[0004] There is a need for compounds that target TAOK and methods for the treatment of TAOK-mediated diseases. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0005] Provided is a compound of Formula Ior a salt or tautomer thereof, wherein:A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with one or more R2;B is an arylene or heteroarylene, either of which may be optionally substituted with one or more R3;E is a 5- to 7-membered cycloalkylene or heterocycloalkylene, either of which may be optionally substituted with one or more R4;W is chosen from CR5and N;X is chosen from CR6and N;Y is chosen from CR7and N;Z is chosen from CR8and N;R1, R2, R3, and R4are independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino;R5, R6, R7, and R8are independently chosen from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino; and m is chosen from 0, 1, 2, or 3.

[0006] Also provided is a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0007] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0008] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of TAOK, comprising the administration of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0009] Also provided are methods of inhibiting at least one TAOK function comprising the step of contacting TAOK with a compound as described herein, or a pharmaceutically acceptable salt thereof. The cell phenotype, cell proliferation, activity of TAOK, change in biochemical output produced by active TAOK, expression of TAOK, or binding of TAOK with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0010] Also provided are methods of treatment of a TAOK-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.[Oi l] Also provided is a method of inhibition of TAOK comprising contacting TAOK with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0012] Also provided is a method of modulation of an TAOK-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0013] These and other aspects of the invention will be apparent upon reference to the following detailed description.DETAILED DESCRIPTION

[0014] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0016] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in anembodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0017] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0018] When ranges of values are disclosed, and the notation “from m ... to n2” or “between m . . . and m” is used, where and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0019] The term “alkoxy”, and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.

[0020] The term “alkyl,” as used herein, refers to a straight-chain or branched-chain saturated, hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, alkyl will comprise from 1 to 10 carbon atoms. In some embodiments, alkyl will comprise from 1 to 8 carbon atoms. The term “alkylene” refers to a bivalent alkyl group.

[0021] The terms “amido,” “carbamoyl,” and “carbonylamino,” as used herein, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa.

[0022] The term “amino,” as used herein, refers to -NRR , wherein R and R are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl. Additionally, R and R’ may combine with the amino nitrogen atom to form heterocycloalkyl. In some embodiments, R and R’ are both hydrogen. In some embodiments, amino is -NH2.

[0023] The term “aryl,” as used herein, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term “arylene” refers to a bivalent aryl group.

[0024] The term “carbonyl,” as used herein, refers to -C(O)R, wherein R is chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl.

[0025] The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0026] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, refers to a saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. In some embodiments, cycloalkyl will comprise from 5 to 7 carbon atoms. In some embodiments, cycloalkyl will comprise a spirocyclic ring system. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, as well as the multicyclic (multi centered) saturated type. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0027] The term “halo,” or “halogen,” as used herein, refers to fluorine, chlorine, bromine, or iodine.

[0028] The term “haloalkyl,” as used herein, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalky 1 radicals. A monohaloalky 1 radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.

[0029] The term “haloalkoxy,” as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0030] The term “heteroaryl,” as used herein, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S. In some embodiments, heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings wherein heteroaryl rings are fused with other heteroaryl rings wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. The term “heteroarylene” refers to a bivalent heteroaryl group.

[0031] The term “heterocycloalkoxy,” as used herein, refers to a heterocycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0032] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bridged;saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclic heterocyclic group containing at least one heteroatom as a ring member wherein each heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.

[0033] In some embodiments, heterocycloalkyl will comprise a spirocyclic ring system. In some embodiments, heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl or heteroaryl group, as defined herein, or an additional heterocycle group. The term “heterocycloalkylene” refers to a bivalent heterocycloalkyl group.|034] The term “sulfonyl,” as used herein, refers to a -S(O)2-, -S(O)2R, or -S(O)2R- group, wherein R is chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl.

[0035] Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds, and pharmaceutically acceptable salts thereof, can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds, and pharmaceutically acceptable salts thereof, disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0036] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0037] As used herein, “administering to a patient” refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0038] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0039] The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co- administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0040] The phrase “therapeutically effective” is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint. The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0041] As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating, or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term“treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0042] The term “patient” is synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0043] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of steps or features unless specifically stated otherwise.|044] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0045] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0046] Provided is a compound of Formula I,or a salt or tautomer thereof, wherein:A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with one or more R2;B is an arylene or heteroarylene, either of which may be optionally substituted with one or more R3;E is a 5- to 7-membered cycloalkyl or heterocycloalkyl, either of which may be optionally substituted with one or more R4;W is chosen from CRSand N;X is chosen from CR6and N;Y is chosen from CR7and N;Z is chosen from CR8and N;R1, R2, R3, and R4are independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino;R5, R6, R7, and R8are independently chosen from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino; and m is chosen from 0, 1, 2, or 3.

[0047] In some embodiments, B is arylene.

[0048] In some embodiments, B is phenylene.

[0049] In some embodiments, E is a 5-membered cycloalkylene optionally substituted by one R4.

[0050] In some embodiments, W is CH.

[0051] In some embodiments, Z is N.

[0052] In some embodiments, m is 0.

[0053] In some embodiments, the compound has structural Formula II:or a salt or tautomer thereof, whereinA is heteroaryl optionally substituted by one, two, or three R2;X is chosen from CH and N;Y is chosen from CH and N; each occurrence of R2is independently chosen from halo and haloalkoxy;R4is hydroxyl; and n is 0, 1, or 2.

[0054] In some embodiments, A is chosen from pyridyl, pyrazinyl and pyrazolyl, any of which may be optionally substituted by one R2.

[0055] In some embodiments, R2is chosen from chloro and trifluoromethoxy.

[0056] In some embodiments, A is chosen from 4-chloro-pyrazol-l-yl, 4- trifluoromethoxy-pyridin-2-yl, and pyrazin-2-yl.

[0057] In some embodiments, X is CH.

[0058] In some embodiments, X is N.

[0059] In some embodiments, Y is CH.

[0060] In some embodiments, n is 0.|0611 In some embodiments, the compound has a structural formula of

[0062] The compounds disclosed herein can exist as pharmaceutically acceptable salts.The present disclosure includes compounds listed herein in the form of salts, including acidaddition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0063] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0064] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxicquaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, M / V-dimethylaniline. A-methylpiperidine, jV-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, A,A-dibenzylphenethylamine, 1 -ephenamine, and / V'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0065] While it may be possible for the compounds, and pharmaceutically acceptable salts thereof, of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation.

[0066] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0067] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.

[0068] Compounds, or pharmaceutically acceptable salts thereof, may be administered at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 5 mg to 2 g / day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0069] The compounds, or pharmaceutically acceptable salts thereof, can be administered in various modes. In some embodiments, the pharmaceutical formulation is formulated for oral administration.

[0070] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceuticallyacceptable salt thereof, is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof, may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0071] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein, or a pharmaceutically acceptable salt thereof) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0072] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of TAOK, comprising the administration of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0073] Also provided are methods of inhibiting at least one TAOK function comprising the step of contacting TAOK with a compound as described herein, or a pharmaceutically acceptable salt thereof. The cell phenotype, cell proliferation, activity of TAOK, change in biochemical output produced by active TAOK, expression of TAOK, or binding of TAOK with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0074] Also provided are methods of treatment of a TAOK-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0075] Also provided is a method of inhibition of TAOK comprising contacting TAOK with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0076] Also provided is a method of modulation of a TAOK-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the TAOK is chosen from TAOK1, TAOK2, and TAOK3.

[0078] In some embodiments, the TAOK-mediated disease is a neurodegenerative disease.

[0079] In some embodiments, the neurodegenerative disease is Alzheimer's disease, a primary tauopathy, or a syndrome associated with an underlying primary tauopathy.

[0080] In some embodiments, the primary tauopathy is progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), primary age-related tauopathy (PART), or aging- related tau astrogliopathy (ARTAG).

[0081] In some embodiments, the syndrome associated with an underlying primary tauopathy is Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA), pure akinesia with gait freezing (PAGF), behavioral variant frontotemporal dementia (bvFTD), Parkinsonian syndrome, late onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), amnestic syndrome of the hippocampal type, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), chemotherapy-induced cognitive impairment, or radiation therapy-induced cognitive impairment.

[0082] In some embodiments, the TAOK-mediated disease is cancer cachexia or cancer cachexia-associated muscle atrophy.

[0083] Further embodiments include the embodiments disclosed in the following Schemes and Examples, which are not to be construed as limiting in any way.

[0084] In the Examples below and throughout the disclosure, the following abbreviations may be used: RT = Room Temperature; SM = Starting Material; MeCN or ACN = acetonitrile; CDI = l,l’-carbonyldiimidazole; DCE = dichloroethane; DCM = dichloromethane; DIEA or DIPEA = N,N-Diisopropylethylamine; DMF = dimethylformamide; DMSO = dimethylsulfoxide; EtsN or TEA = triethylamine; EtOAc = ethyl acetate; EtOH = ethanol; H2O = water; MeCN = acetonitrile; MeOH = methanol; n- BuLi = n-butyl lithium; NMP = A-methyl-2-pyrrolidone; PE = petroleum ether; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; HATU = 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; NCS = N-chlorosuccinimide;1H-NMR = Proton Nuclear magneticResonance; LCMS = Liquid chromatography-mass spectrometry; TLC = thin layer chromatography; and HPLC = High Performance Liquid Chromatography. Other abbreviations may be used and will be familiar in context to those of skill in the art.SCHEMESFormula I

[0085] Referring to Scheme I, Step 1, to a solution of a compound of Formula 101 in an organic solvent, such as dioxane, is added a compound of formula 102 (Q = halogen) and a base, such as triethylamine. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred from 2-4 h. The product, a compound of Formula 103, is isolated and purified using methods known in the art.

[0086] Referring to Scheme I, Step 2, to a solution of the compound of Formula 103 in a polar solvent, such as methanol, is added a catalyst, such as palladium on carbon. The mixture is stirred, optionally at ambient temperature, under hydrogen gas. In some embodiments, the mixture is stirred for 2-4 h. The product, a compound of Formula 104, is isolated and purified using methods known in the art.

[0087] Referring to Scheme I, Step 3, to a solution of a compound of Formula 104 in a polar aprotic solvent, such as dimethylformamide, is added a non-nucleophilic base, such as DIPEA, a coupling agent, such as HATU, and a compound of Formula 105. The mixture isstirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 16-24 h. The product, a compound of Formula I, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.EXAMPLE 1N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyridin-3-yI)-4-(pyr azin-2- yl)benzamideStep 1: (lR,2R)-l-((3-nitropyridin-2-yI)amino)-2,3-dihydro-lH-inden-2-ol

[0088] To a solution of (lR,2R)-l-amino-2,3-dihydro-lH-inden-2-ol (1000 mg, 6.71 mmol) in 1,4-dioxane (50 mL) was added 2-chloro-3-nitropyridine (1067 mg, 6.71 mmol) and TEA (1355 mg, 13.42 mmol). After stirred for 2 h at 100°C, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried over Na2SC>4, filtered, concentrated, and purified by silica gel chromatography (PE: EtOAc = 0- 10%) to afford (lR,2R)-l-((3-nitropyridin-2-yl)amino)-2,3-dihydro-lH-inden-2-ol (800 mg, 44%) as a yellow solid. MS (ES+): C14H13N3O3, requires: 271, found: 272 [M+l]+.Step 2: (lR,2R)-l-((3-aminopyridin-2-yl)amino)-2,3-dihydro-lH-inden-2-oI

[0089] To a solution of (lR,2R)-l-((3-nitropyridin-2-yl)amino)-2,3-dihydro- lH-inden-2- ol (800 mg, 2.95 mmol) in MeOH (10 ml) was added 10% Pd / C (80 mg). The resulting mixture was stirred at room temperature under H2 (1 atm) for 2 h. Then the reaction mixture was filtered and concentrated. Then the residual solid was purified by silica gel chromatography (PE: EtOAc = 0-50%) to afford (lR,2R)-l-((3-aminopyridin-2-yl)amino)-2 -dihydro- lH-inden-2-ol (700 mg, 98%) as a yellow solid. MS (ES+): C14H15N3O, requires: 241, found: 242 [M+l]+.Step 3: N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyridin-3-yl)-4- (pyrazin-2-yI)benzamide

[0090] To a solution of (lR,2R)-l-((3-aminopyridin-2-yl)amino)-2,3-dihydro-lH-inden- 2-ol (800 mg, 3.32 mmol) in DMF (50 ml) was added 4-(pyrazin-2-yl)benzoic acid (995 mg, 4.98 mmol), HATU (1600 mg, 4.21 mmol) and DIPEA (1284 mg, 9.96 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (NH4HCO3) to afford N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro- lH-inden-l-yl)amino)pyridin-3-yl)-4-(pyrazin-2-yl)benzamide (460 mg, 33% yield) as white solid. MS (ES+): C25H21N5O2, requires: 423, found: 424 [M+H]+;]H NMR (400 MHz, DMSO-dfi) 5 9.75 (s, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.82 - 8.73 (m, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.28 (d, 7 = 8.4 Hz, 2H), 8.12 (d, 7 = 8.4 Hz, 2H), 7.98 (dd, 7 = 4.9, 1.6 Hz, 1H), 7.63 (d, 7 = 6.3 Hz, 1H), 7.26 - 7.11 (m, 4H), 6.70 (dd, 7 = 7.5, 4.9 Hz, 1H), 6.51 (d, 7 = 7.8 Hz, 1H), 5.45 (dd, 7= 9.3, 6.0 Hz, 2H), 4.42 - 4.30 (m, 1H), 3.16 (dd, 7 = 15.5, 7.2 Hz, 1H), 2.75 (dd, 7 = 15.4, 7.6 Hz, 1H).4-(4-chloro-lH-pyrazol-l-yl)-N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yI)amino)pyridin-3-yl)benzamideStep 1: 4-(4-chloro-lH-pyrazol-l-yl)benzoic acid|091 ] To a solution of 4-(lH-pyrazol-l-yl)benzoic acid (10 g, 53 mmol) in dioxane (150 mL) was added NCS (10.6 g, 79 mmol). After stirred at 100°C for 16 h, the mixture was poured into water (300 mL). The solid was filtered and washed with water to give 4-(4- chloro-lH-pyrazol-l-yl)benzoic acid (10 g, 84.7%) as a white solid. MS (ES+): C10H7CIN2O2, requires:222, found: 223 [M+H]+.Step 2: 4-(4-chloro-lH-pyrazol-l-yl)-N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)amino)pyridin-3-yl)benzamide

[0092] To a solution of 4-(4-chloro-lH-pyrazol-l-yl)benzoic acid (3.13 g, 14 mmol) in DMF (60 mL) were added HATU (5.36 g, 14 mmol), (lR,2R)-l-((3-aminopyridin-2- yl)amino)-2,3-dihydro-lH-inden-2-o (1.7 g,7 mmol) and DIPEA (3 ml) and the resulting mixture was stirred at RT for 16 hours. Then the mixture was purified by Prep-HPLC (NH4HCO3) to afford 4-(4-chloro-lH-pyrazoLl-yl)-N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro- lH-inden-l-yl)amino)pyridin-3-yl)benzamide (1031 mg, 33.0%) as a white solid. MS (ES+): C24H20CIN5O2, requires: 445, found: 446 [M+H]+.1H NMR (400 MHz, DMSO-d6) 59.70 (s, 1H), 8.94 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.99 - 7.95 (m, 4H), 7.60 (dd, 7 = 7.2, 1.2 Hz, 1H), 7.20 - 7.14 (m, 4H), 6.69 (dd, J = 7.6, 4.8 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 5.48 - 5.43 (m, 2H), 4.39 - 4.32 (m,lH), 3.16 (dd, 7= 16.0, 7.6 Hz, 1H), 2.75 (dd, 7= 15.6, 7.6 Hz, 1H).EXAMPLE 3N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-4-(pyrazin- 2-yl)benzamideStep 1: (lR,2R)-l-((5-ainino-6-chIoropyriinidin-4-yI)amino)-2,3-dihydro-lH-inden-2-ol

[0093] A mixture of 4,6-dichloropyrimidin-5-amine (164 mg, 1.00 mmol), (1R,2R)-1- amino-2,3-dihydro-lH-inden-2-ol (149 mg, 1.00 mmol) and DIPEA (388 mg, 3.00 mmol) in NMP (2 mL) was heated at 150°C for 4h. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered off and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give (lR,2R)-l-((5-amino-6- chloropyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol (170 mg, 61.4%) as a brown solid. MS (ES+) C13H13CIN4O requires: 276, found: 277[M+H]+.Step 2: (lR,2R)-l-((5-aminopyrimidin-4-yl)amino)-2,3-dihydro-lH-inden-2-ol

[0094] To a solution of (lR,2R)-l-((5-amino-6-chloropyrimidin-4-yl)amino)-2,3- dihydro-lH-inden-2-ol (170 mg, 0.61 mmol) in acetic acid (10 mL) was added 10% Pd / C (30 mg). After hydrogenated (1 atm) at RT for 16 h, the mixture was filtered and concentrated. The residue was diluted with saturated NaHCOs solution and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water and brine, dried over Na2SO4,filtered, and concentrated to give (lR,2R)-l-((5-aminopyrimidin-4-yl)amino)-2,3-dihydro- lH-inden-2-ol (140 mg, 94.7%) as a light yellow solid. MS (ES+) C13H14N4O, requires: 242, found: 243[M+H]+.Step 3: N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-4- (pyrazin-2-yl)benzamide

[0095] To a mixture of (lR,2R)-l-((5-aminopyrimidin-4-yl)amino)-2,3-dihydro-lH- inden-2-ol (60 mg, 0.25 mmol) and 4-(pyrazin-2-yl)benzoic acid (61mg, 0.30 mmol) in DMF (4 mL) was added DIPEA (97 mg, 0.75 mmol) and HATU (152 mg, 0.40 mmol). After being stirred for 16 h at RT, the mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered off and concentrated. The residue was purified by prep-HPLC (NH4HCO3) to give the target (12 mg, 11.3%) as a white solid. MS (ES+) C24H20N6O2 requires: 424, found: 425 [M+H]+;1H NMR (400 MHz, DMSO-d6) 5 9.82 (s, 1H), 9.36 (d, J = 2.0 Hz, 1H), 8.77 (dd, J = 2.4, 1.6 Hz 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.22 (s, 1H), 8.14 (d, 7 = 8.4 Hz, 2H), 7.49 (d, 7 = 8.4 Hz, 1H), 7.20 - 7.10 (m, 4H), 5.62 (t, 7 = 8.0 Hz, 1H), 5.31 (d, 7 = 6.0 Hz, 1H), 4.46 - 4.41(m, 1H), 3.14 (dd, 7 = 15.6, 7.2 Hz, 1H), 2.75 (dd, 7 = 15.6, 8.0 Hz, 1H).EXAMPLE 4N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-4-(4-(trifluoromethoxy)pyridin-2-yl)benzamideStep 1: Tert-butyl 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoate

[0096] To a solution of 2-chloro-4-(trifluoromethoxy)pyridine (4.0 g, 20.25 mmol) and 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (5.4 g, 24.30 mmol) in dioxane (100 mL) and H2O (30 mL) were added K3PO4 (12.9 g, 60.75 mmol) and cataCXium-A-Pd- G3 (444 mg, 0.61 mmol) under N2. The reaction mixture was heated at 100°C for 3 h and diluted with H2O (100 mL) and extracted with EtOAc (50mL x 3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (30% PE in EtOAc) to give tertbutyl 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoate (6.0 g, 87.1%) as a white solid. MS (ES+) C17H16F3NO3 requires: 339, found: 340[M+H]+.Step 2: 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoic acid hydrochloride

[0097] A solution of tert-butyl 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoate (6.0 g, 17.68 mmol) in 4M HCl / dioxane (60 mL) was stirred for 16 h at RT. The solution was concentrated to give 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoic acid hydrochloride (5.6 g, 100%) as a white solid. MS (ES+) C13H9CIF3NO3 requires: 283, found: 284[M+H]+.Step 3: N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yI)amino)pyrimidin-5-yl)-4- (4-(trifluoromethoxy)pyridin-2-yl)benzamide

[0098] To a mixture of (lR,2R)-l-((5-aminopyrimidin-4-yl)amino)-2,3-dihydro-lH- inden-2-ol (2.6 g, 10.7 mmol) and 4-(4-(trifluoromethoxy)pyridin-2-yl)benzoic acid hydrochloride (3.76 g, 11.77 mmol) in DMF (50 mL) at 0°C was added DIPEA (5.53 g, 42.8 mmol) and HATU (6.10 g, 16.05 mmol). The mixture was stirred for 16 h at RT. The mixture was diluted with H2O (200 mL) and filtered to give a solid. The solid was dissolved in THF (100 mL) / H2O (20 mL) / MeOH (10 mL) and LiOH H2O (1.35 g, 32.10 mmol) was added. The mixture was stirred for 4 h and then concentrated. The residue was washed with H2O (50 mL) and DCM (50 mL) and then purified by silica gel chromatography (5% MeOH in DCM) to give N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-4-(4- (trifhioromethoxy)pyridin-2-yl)benzamide (2.69 g, 49.5%) as a white solid. MS (ES+) C26H20F3N5O3 requires:507, found: 508[M+H]+; 'H NMR (400 MHz, DMSO) 8 9.81 (s, 1H), 8.82 (d, 7 = 5.2 Hz, 1H), 8.41 (s, 1H), 8.30 (d, 7 = 8.4 Hz, 2H), 8.20 (s, 1H), 8.10 (d, 7 = 8.4 Hz, 2H), 8.09 - 8.07 (m, 1H), 7.50 - 7.47 (m, 2H), 7.20 - 7.10 (m, 4H), 5.62 (t, 7 = 8.0 Hz, 1H), 5.31 (d, 7 = 6.0 Hz, 1H), 4.48 - 4.42 (m, 1H), 3.15 (dd, 7 = 15.6, 7.6 Hz, 1H), 2.74 (dd, 7 = 15.2, 8.0 Hz, 1H).

[0099] The activity of the compounds in Examples 1-4 as TAOK inhibitors is illustrated in the following assays. The compounds described herein can be tested for efficacy in the treatment or prevention of symptoms or indications of TAOK-mediated diseases using techniques well known to those in the art.Biological Activity Assays

[0100] Binding constants for compounds against TAOK were determined by the following protocol for a KINOMEscan® assay. A fusion protein of a full-length construct of human TAOK and the DNA binding domain of NF-KB was expressed in transiently transfected HEK293 cells. From these HEK 293 cells, extracts were prepared in M-PER extraction buffer (Pierce) in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) per manufacturers’ instructions. The TAOK fusion protein was labeled with a chimeric double-stranded DNA tag containing the NF-KB binding site fused to an amplicon for qPCR readout, which was added directly to the expression extract. Streptavidin-coated magnetic beads were treated with a biotinylated small molecule ligand for 30 minutes at room temperature to generate affinity resins in the binding assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.

[0101] The binding reaction was assembled by combining 15.75 pL of DNA-tagged kinase extract, 3.75 pL liganded affinity beads, and 0.18 pL test compound (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 pg / ml sonicated salmon sperm DNA)]. Extracts were used directly in binding assays without any enzyme purification steps at a >10,000-fold overall stock dilution (final DNA tagged enzyme concentration <0.1 nM). Extracts were loaded with DNA-tag and diluted into the binding reaction in a two-step process. Extracts were first diluted 1:100 in lx binding buffer (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 pg / ml sonicated salmon sperm DNA) containing 10 nM DNA-tag. This dilution was equilibrated at room temperature for 15 minutes and then subsequently diluted 1 :100 in lx binding buffer. Test compounds were prepared as 1 l lx stocks in 100% DMSO.

[0102] Binding constants (KD) were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for KD measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. Each was a final volume of 0.02 mL. Assays were incubated with shaking for 1 hour at room temperature. The beads were pelleted and washed with buffer (lx PBS, 0.05% Tween 20) to remove displaced kinase and test compound. The washed beads were re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. qPCR reactions were assembled by adding 2.5 pL of kinase eluate to 7.5 pL of qPCR mastermix containing 0.15 pM amplicon primers and 0.15 pM amplicon probe. The qPCR protocol consisted of a 10-minute hot start at 95 °C, followed by 35 cycles of 95°C for 15 seconds, 60 °C for 1 minute. Binding constants were calculated with a standard dose-response curve using the Hill equation:

[0103] The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.Table 1. TAOK 1 / 2 / 3 activity

[0104] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.

[0105] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.

Claims

CLAIMSWhat is claimed is:1 . A compound of structural Formula I:or a salt or tautomer thereof, wherein:A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with one or more R2;B is arylene or heteroarylene, either of which may be optionally substituted with one or more R3;E is a 5- to 7-membered cycloalkyl or heterocycloalkyl, either of which may be optionally substituted with one or more R4;W is chosen from CR5and N;X is chosen from CR6and N;Y is chosen from CR7and N;Z is chosen from CR8and N ;R1, R2, R3, and R4are independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino;R5, R6, R7, and R8are independently chosen from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino; and m is chosen from 0, 1, 2, or 3.

2. The compound of claim 1 , or a salt or tautomer thereof, wherein B is arylene.

3. The compound of claim 2, or a salt or tautomer thereof, wherein B is phenylene.

4. The compound of any one of the preceding claims, or a salt or tautomer thereof, whereinE is a 5-membered cycloalkyl optionally substituted by one R4.

5. The compound of any one of the preceding claims, or a salt or tautomer thereof, wherein W is CH.

6. The compound of any one of the preceding claims, or a salt or tautomer thereof, wherein Z is N.

7. The compound of any one of the preceding claims, or a salt or tautomer thereof, wherein m is 0.

8. The compound of claim 1 , or a salt or tautomer thereof, having a structural Formula II:or a salt or tautomer thereof, whereinA is heteroaryl optionally substituted by one, two, or three R2;X is chosen from CH and N;Y is chosen from CH and N; each occurrence of R2is independently chosen from halo and haloalkoxy;R4is hydroxyl; and n is 0, 1, or 2.

9. The compound of any one of the previous claims, or a salt or tautomer thereof, wherein A is chosen from pyridyl, pyrazinyl and pyrazolyl, any of which may be optionally substituted by one R2.

10. The compound of claim 9, or a salt or tautomer thereof, wherein R2is chosen from chloro and trifluoromethoxy.

11. The compound of claim 9, or a salt or tautomer thereof, wherein A is chosen from 4- chloro-pyrazol- 1 -yl, 4-trifluoromethoxy-pyridin-2-yl, and pyrazin-2-yl.

12. The compound of any one of the previous claims, or a salt or tautomer thereof, wherein X is CH.

13. The compound of any one of claims 1 to 11 , or a salt or tautomer thereof, wherein X is N.

14. The compound of any one of the previous claims, or a salt or tautomer thereof, wherein Y is CH.

15. The compound of any one of claims 8 to 14, or a salt or tautomer thereof, wherein n is 0.

16. The compound of claim 1, or a salt or tautomer thereof, having a structural formula of17. A pharmaceutical formulation comprising a compound as recited in any one of claims 1 to 16, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

18. The pharmaceutical formulation as recited in claim 17, formulated for oral administration.

19. The pharmaceutical formulation as recited in claim 17 or 18, additionally comprising another therapeutic agent.

20. A method of inhibition of a Thousand-and-one kinase (TAOK), comprising contacting the TAOK with a compound as recited in any one of claims 1 to 16, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of claims 17 to 19.

21. A method of treatment of a TAOK-mediated disease, comprising the administration of a therapeutically effective amount of a compound as recited in any one of claims 1 to 16, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of claims 17 to 19.

22. The method as recited in claim 20 or 21 , wherein the TAOK is chosen from TAOK1 , TAOK2, and TAOK3.

23. The method as recited in claim 21, wherein the TAOK-mediated disease is a neurodegenerative disease.

24. The method as recited in claim 23, wherein the neurodegenerative disease is Alzheimer's disease, a primary tauopathy, or a syndrome associated with an underlying primary tauopathy.

25. The method as recited in claim 24, wherein the primary tauopathy is progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), primary age-related tauopathy (PART), or aging-related tau astrogliopathy (ART AG).

26. The method as recited in claim 24, wherein the syndrome associated with an underlying primary tauopathy is Richardson syndrome (RS), corticobasal syndrome (CBS), nonfluent agrammatic primary progressive aphasia (nfaPPA), pure akinesia with gait freezing (PAGF), behavioral variant frontotemporal dementia (bvFTD), Parkinsonian syndrome, late onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), amnestic syndrome of the hippocampal type, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), chemotherapy- induced cognitive impairment, or radiation therapy-induced cognitive impairment.

27. The method as recited in claim 21, wherein the TAOK-mediated disease is cancer cachexia or cancer cachexia-associated muscle atrophy.

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