WO2026024466A1 - Inhibiteurs de taok - Google Patents

Inhibiteurs de taok

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Publication number
WO2026024466A1
WO2026024466A1 PCT/US2025/037059 US2025037059W WO2026024466A1 WO 2026024466 A1 WO2026024466 A1 WO 2026024466A1 US 2025037059 W US2025037059 W US 2025037059W WO 2026024466 A1 WO2026024466 A1 WO 2026024466A1
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Prior art keywords
compound
tautomer
salt
chosen
recited
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Inventor
Michael J. Soth
Kang Le
Jiacheng Ma
William J. Ray
Christopher L. Carroll
Suyambu Kesava Vijayan RAMASWAMY
Bess FROST
Farzeneh ATRIAN
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms
    • C07C13/465—Indenes; Completely or partially hydrogenated indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Deposition of pathogenic tau is a driver of neurotoxicity in Alzheimer’s disease (AD) and other tauopathies.
  • AD Alzheimer’s disease
  • 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.
  • TAOK The thousand-and-one amino acid kinases
  • MA3K Mitogen Activated Protein kinase kinase kinase family
  • 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.
  • 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.
  • TAOK inhibitors are no TAOK inhibitors approved for clinical use and only minimal examples in the literature.
  • A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with one or more R 2 ;
  • B is an arylene or heteroarylene, either of which may be optionally substituted with one or more R 3 ;
  • E is a 5- to 7-membered cycloalkylene or heterocycloalkylene, either of which may be optionally substituted with one or more R 4 ;
  • W is chosen from CR 5 and N;
  • X is chosen from CR 6 and N;
  • Y is chosen from CR 7 and N;
  • Z is chosen from CR 8 and N;
  • R 1 , R 2 , R 3 , and R 4 are independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino;
  • R 5 , R 6 , R 7 , and R 8 are 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.
  • a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • 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.
  • alkoxy and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.
  • alkyl 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.
  • alkylene refers to a bivalent alkyl group.
  • amino refers to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa.
  • amino 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.
  • aryl means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • arylene refers to a bivalent aryl group.
  • carbonyl refers to -C(O)R, wherein R is chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl.
  • cycloalkoxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • cycloalkyl 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.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • halo refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl 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.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • heteroaryl 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.
  • heteroaryl will comprise from 1 to 4 heteroatoms as ring members.
  • heteroaryl will comprise from 1 to 2 heteroatoms as ring members.
  • heteroaryl will comprise from 5 to 7 atoms.
  • heteroarylene refers to a bivalent heteroaryl group.
  • heterocycloalkoxy refers to a heterocycloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • 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.
  • 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.
  • heterocycloalkylene refers to a bivalent heterocycloalkyl group.
  • sulfonyl 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.
  • 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.
  • 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,
  • E
  • Z
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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.
  • 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.
  • A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with one or more R 2 ;
  • B is an arylene or heteroarylene, either of which may be optionally substituted with one or more R 3 ;
  • E is a 5- to 7-membered cycloalkyl or heterocycloalkyl, either of which may be optionally substituted with one or more R 4 ;
  • W is chosen from CR S and N;
  • X is chosen from CR 6 and N;
  • Y is chosen from CR 7 and N;
  • Z is chosen from CR 8 and N;
  • R 1 , R 2 , R 3 , and R 4 are independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, halo, hydroxyl, amino, sulfonyl, carbonyl, and carbonylamino;
  • R 5 , R 6 , R 7 , and R 8 are 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.
  • B is arylene
  • B is phenylene
  • E is a 5-membered cycloalkylene optionally substituted by one R 4 .
  • W is CH.
  • Z is N.
  • m is 0.
  • the compound has structural Formula II: or a salt or tautomer thereof, wherein A is heteroaryl optionally substituted by one, two, or three R 2 ;
  • X is chosen from CH and N;
  • Y is chosen from CH and N; each occurrence of R 2 is independently chosen from halo and haloalkoxy;
  • R 4 is hydroxyl; and n is 0, 1, or 2.
  • A is chosen from pyridyl, pyrazinyl and pyrazolyl, any of which may be optionally substituted by one R 2 .
  • R 2 is chosen from chloro and trifluoromethoxy.
  • A is chosen from 4-chloro-pyrazol-l-yl, 4- trifluoromethoxy-pyridin-2-yl, and pyrazin-2-yl.
  • X is CH.
  • X is N.
  • Y is CH.
  • n 0.
  • the compound has a structural formula of
  • the present disclosure includes compounds listed herein in the form of salts, including acid addition 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.
  • Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).
  • salts or zwitterionic forms of the compounds disclosed herein represent 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-phenyl
  • 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.
  • 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.
  • 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 nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, M/V-dimethylaniline.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • 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.
  • active ingredient a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof (“active ingredient”)
  • active ingredient a pharmaceutically acceptable salt thereof
  • 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.
  • Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.
  • 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.
  • the compounds, or pharmaceutically acceptable salts thereof can be administered in various modes.
  • the pharmaceutical formulation is formulated for oral administration.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceutically acceptable salt thereof, is hypertension.
  • 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).
  • 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.
  • another therapeutic agent which also includes a therapeutic regimen
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • the multiple therapeutic agents 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.
  • 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.
  • 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.
  • a method of inhibition of TAOK comprising contacting TAOK with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the TAOK is chosen from TAOK1, TAOK2, and TAOK3.
  • the TAOK-mediated disease is a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease, a primary tauopathy, or a syndrome associated with an underlying primary tauopathy.
  • 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).
  • PSP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • PiD Pick’s disease
  • GTT globular glial tauopathy
  • AGD argyrophilic grain disease
  • PART primary age-related tauopathy
  • ARTAG aging- related tau astrogliopathy
  • 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.
  • RS Richardson syndrome
  • CBS corticobasal syndrome
  • nfaPPA non-fluent agrammatic primary progressive aphasia
  • PAGF gait freezing
  • bvFTD behavioral variant frontotemporal dementia
  • Parkinsonian syndrome late onset cerebellar ataxia
  • the TAOK-mediated disease is cancer cachexia or cancer cachexia-associated muscle atrophy.
  • 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 tetrahydr
  • Q halogen
  • 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.
  • 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.
  • 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.
  • 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.
  • a non-nucleophilic base such as DIPEA
  • a coupling agent such as HATU
  • a compound of Formula 105 is added to a solution of a compound of Formula 104 in a polar aprotic solvent, such as dimethylformamide.
  • a non-nucleophilic base such as DIPEA
  • a coupling agent such as HATU
  • 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.
  • Step 1 (lR,2R)-l-((3-nitropyridin-2-yI)amino)-2,3-dihydro-lH-inden-2-ol
  • Step 2 (lR,2R)-l-((3-aminopyridin-2-yl)amino)-2,3-dihydro-lH-inden-2-oI
  • Step 3 N-(2-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyridin-3-yl)-4- (pyrazin-2-yI)benzamide
  • 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
  • Step 1 (lR,2R)-l-((5-ainino-6-chIoropyriinidin-4-yI)amino)-2,3-dihydro-lH-inden-2-ol
  • 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).
  • Step 3 N-(4-(((lR,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-4- (pyrazin-2-yl)benzamide
  • 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
  • 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.
  • 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.
  • Binding constants 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.
  • buffer lx PBS, 0.05% Tween 20
  • elution buffer lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand
  • 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 master mix 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:

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Abstract

L'invention concerne des composés, et des sels de ceux-ci, qui inhibent la Thousand-and-one kinase (TAOK). L'invention concerne également des formulations pharmaceutiques et des méthodes de traitement de maladies associées à TAOK.
PCT/US2025/037059 2024-07-22 2025-07-10 Inhibiteurs de taok Pending WO2026024466A1 (fr)

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US63/674,067 2024-07-22

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