Small molecule drugs for treating diseases associated with oligomerization of TDP-43, alpha-synuclein, huntingtin protein, and tau protein, and related methods

Abstract

The present invention provides small molecule drugs and pharmaceutical compositions for the treatment and prevention of certain types of oligomerization-related diseases in a subject. More specifically, the drugs and compositions inhibit or prevent the formation of oligomers formed from tau protein, TDP-43, huntingtin protein, and / or α-synuclein. Furthermore, a method for inhibiting or disrupting the oligomerization of TDP-43, α-synuclein, huntingtin protein, and / or tau protein in a subject is provided. The method comprises administering a therapeutically effective amount of a pharmaceutical composition to the subject in need thereof.

Description

[Technical Field]

[0001] This invention was made with government support under NSF SBIR Phase I Award #1143484 entitled "Identifying Drug Leads Via 3D Pharmacophore Space Analysis."

[0002] FIELD OF THE INVENTION The present invention provides small molecule drugs and pharmaceutical compositions for treating and preventing certain types of oligomer formation-related diseases in subjects, such as typical neurodegenerative diseases such as Alzheimer's disease. More specifically, the drugs and compositions suppress or prevent the formation of oligomers formed from tau protein, TDP-43, α-synuclein, and / or huntingtin protein. [Background technology]

[0003] Compounds and compositions that interact with tau protein, TDP-43, α-synuclein, huntingtin protein, and related oligomers have been reported. U.S. Patent No. 10,220,011, entitled "TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases," is said to have the following summary claim: "Provided herein are antigen-binding constructs, e.g., antibodies, that bind to the RRM-1 domain of TDP-43. The antigen-binding constructs can block the interaction of TDP-43 with NF-κB in cells. Also provided herein are methods of using the antigen-binding constructs in the treatment of diseases associated with TPD-43 proteinopathies, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Lewy body disease, and motor neuron disease."

[0004] U.S. Patent No. 10,301,381, entitled "Anti-α-Synuclein Binding Molecules," is said to make the following summary claim: "In a related method, anti-human α-synuclein-specific binding molecules, e.g., antibodies or antigen-binding fragments, variants, or derivatives, are provided. Also provided are anti-human α-synuclein binding molecules that bind to specific epitopes at the N-terminus and C-terminus of human α-synuclein. The binding molecules described herein can be used in medicaments for immunotherapy and diagnosis targeting α-synuclein, and in diagnostic compositions, respectively."

[0005] U.S. Patent No. 9,175,094, entitled "Monoclonal Antibodies," is said to make the following summary claim: "The present invention relates to methods and compositions for therapeutic and diagnostic use in the treatment of diseases and disorders caused by amyloid or amyloid-like proteins, including amyloidoses, a group of disorders and disorders associated with amyloid proteins, such as Alzheimer's disease. The present invention provides novel methods and compositions comprising highly specific and effective antibodies capable of specifically recognizing and binding specific epitopes from a range of β-amyloid proteins. The antibodies made possible by the teachings of the present invention are particularly useful for treating diseases and disorders caused by or associated with amyloid or amyloid-like proteins, including amyloidoses, e.g., neurological disorders such as Alzheimer's Disease (AD), and the group of diseases and disorders associated with the formation of amyloid plaques, including secondary amyloidosis and age-related amyloidosis." Summary of the Invention [Problem to be solved by the invention]

[0006] Despite various reports, there remains a need for new compounds, compositions and methods for treating diseases associated with the oligomerization of tau protein, TDP-43, α-synuclein and huntingtin protein. [Means for solving the problem]

[0007] Summary of the Invention In one aspect, the present invention provides a method for inhibiting oligomerization or disrupting oligomers of TDP-43, alpha-synuclein, tau protein, and / or huntingtin protein in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of AC0101, AC0102, AC0103, AC0104, AC0105, AC0106, AC0107, AC0201, AC0202, AC0203, and AC0204.

[0008] In another aspect, administration of the pharmaceutical composition results in improved or enhanced movement in a subject with reduced movement, hi another embodiment, the subject has been diagnosed with or is at risk for developing ALS.

[0009] In other embodiments, the compound administered to inhibit or disrupt oligomerization of TDP-43, alpha-synuclein, tau protein, and / or huntingtin protein in a subject is selected from the group consisting of N-[4-({[2-(3-chlorophenyl)ethyl]amino}methyl)-phenyl]acetamide (AC0101), (2,3-dihydroxy-1,4-benzodioxin-6-ylmethyl)({4[(dimethylamino)-methyl]phenyl}methyl)amine (AC0102), 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2-phenylacetamide (AC0103), 3), 3-[({[4-(morpholin-4-ylmethyl)phenyl)methyl}amino)-methyl]benzonitrile (AC0104), 4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (AC0105), 4-{1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1,2,3,6 tetrahydropyridin-4-yl}phenol (AC0106), 4-[({[3-(pyrrolidin-1-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile (AC0107), AC0201, AC0202, AC0203, and AC0204.

[0010] In another aspect, the present invention provides a method for inhibiting or disrupting oligomerization of TDP-43, α-synuclein, tau protein, and / or huntingtin protein in a subject, comprising using the following compounds shown in Figures 9-29: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 149, 200, 201, 202, 203, 204, 205, 206, 207, 208, 210, 211, 212, 213, 214, 215, 216, 217, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 2 administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of 50, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, and 224. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows the occurrence of TDP-43307-319 oligomers. [Figure 2] Figure 2 shows the experimental setup for inhibitor analysis. [Figure 3] Figure 3 shows the co-incubation study with AC0107. [Figure 4] Figure 4 shows further results from the co-incubation study with AC0107. [Figure 5] Figure 5 shows the recovery study with AC0107. [Figure 6] Figure 6 shows an overview of inhibitors. [Figure 7] Figure 7 shows the TDP-43 (307-319) recovery test using AC0201. [Figure 8] FIG. 8 shows AC0101 to AC0107, which are specific compounds of the present invention. [Figure 9]FIG. 9 shows specific compounds according to the invention for treating ALS or a related disorder. [Figure 10] FIG. 10 shows specific compounds according to the present invention for treating ALS or a related disorder. [Figure 11] FIG. 11 shows certain compounds according to the present invention for treating ALS or a related disorder. [Figure 12] FIG. 12 shows specific compounds according to the present invention for treating ALS or a related disorder. [Figure 13] FIG. 13 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 14] FIG. 14 shows specific compounds according to the present invention for treating ALS or a related disorder. [Figure 15] FIG. 15 shows certain compounds according to the present invention for treating ALS or a related disorder. [Figure 16] FIG. 16 shows specific compounds according to the invention for treating ALS or a related disorder. [Figure 17] FIG. 17 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 18] FIG. 18 shows specific compounds according to the present invention for treating ALS or a related disorder. [Figure 19] FIG. 19 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 20] FIG. 20 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 21] FIG. 21 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 22] FIG. 22 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 23] FIG. 23 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 24]FIG. 24 shows specific compounds according to the invention for treating ALS or a related disorder. [Figure 25] FIG. 25 shows certain compounds according to the present invention for treating ALS or a related disorder. [Figure 26] Figure 26 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 27] FIG. 27 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 28] Figure 28 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 29] FIG. 29 shows certain compounds according to the invention for treating ALS or a related disorder. [Figure 30] Figure 30 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 31] FIG. 31 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 32] FIG. 32 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 33] Figure 33 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 34] FIG. 34 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 35] FIG. 35 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 36] FIG. 36 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 37] FIG. 37 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 38] FIG. 38 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 39] FIG. 39 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 40] FIG. 40 shows a synthetic scheme for making certain compounds according to the present invention. [Figure 41] Figure 41 shows Benzaldo 1, fluorophenyl, aminofluorophenyl, dimethoxy, verapamil and dobutamine. [Figure 42] Figure 42 shows the percentage increase in cytoplasmic TDP-43 granules quantified for various concentrations of compounds AC0101, AC0102, AC0103, AC0104, AC0105, AC0106, AC0107, AC0201, AC0202, AC0203, and AC0204. Data points represent the mean ± SD for each condition for each experiment performed in triplicate. Images were acquired using a 20x objective lens. Nine photographs were taken for each well. Results were normalized by sodium arsenite and vehicle, considering sodium arsenite and vehicle as 100% and 0%, respectively. [Figure 43] Figure 43 shows compounds AC0201, AC0202, AC0203 and AC0204. [Figure 44] Figure 44 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 45] Figure 45 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 46] Figure 46 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 47] Figure 47 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 48] Figure 48 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 49] Figure 49 shows further compounds according to the invention for treating ALS or a related disorder. [Figure 50] Figure 50 shows further compounds according to the invention for treating ALS or a related disorder. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description of the Invention Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that attacks nerve cells in the brain and spinal cord. It is the most common motor neuron disease. Currently, there is no cure for ALS, and the average life expectancy of people with the disease is 2 to 5 years. ALS exists in two forms: sporadic and familial. Sporadic ALS is the most common form of ALS in the United States, accounting for approximately 90% to 95% of all cases. Familial ALS is inherited and accounts for 5 to 10% of cases in the United States. Symptoms of ALS include difficulty walking or performing normal daily activities, stumbling and falling, weakness in the legs, feet, or ankles, weakness or clumsiness in the hands, feet, or ankles, slurred speech or difficulty swallowing, muscle spasms or twitching in the arms, shoulders, or tongue, and difficulty holding the head up and maintaining good posture. It often begins in the hands, feet, or limbs and spreads to other parts of the body. As the disease progresses, muscle strength gradually weakens and nerve cells are destroyed, eventually affecting chewing, swallowing, speaking and breathing.

[0013] "Frontotemporal dementia" is a term used to describe a diverse group of disorders that primarily affect the frontal and temporal lobes of the brain. In frontotemporal dementia, portions of the frontal and temporal lobes shrink or atrophy. Symptoms of the disease include behavioral changes, speech, language, and movement disorders. Examples of behavioral changes include increasingly inappropriate behavior, loss of empathy and ability to get along with others, lack of judgment and inhibition, lethargy, repetitive compulsive behaviors, poor personal hygiene, changes in diet, primarily overeating, oral exploration, and pica, and lack of awareness of changes in thought or behavior. Examples of speech and language disorders include primary progressive aphasia, semantic dementia, and progressive agrammatic aphasia. Examples of movement disorders include tremors, rigidity, muscle spasms, incoordination, difficulty swallowing, and muscle weakness.

[0014] "Chronic traumatic encephalopathy (CTE)" is the term used for brain degeneration possibly caused by repeated head injuries. Symptoms of the disease include difficulty thinking (cognitive impairment), impulsive behavior, depression or apathy, short-term memory loss, difficulty planning and completing tasks (executive function), emotional lability, substance abuse, and suicidal thoughts or behaviors.

[0015] "Progressive supranuclear palsy," or Steele-Richardson-Olszewski syndrome, is a brain disorder caused by the deterioration of brain cells that control movement and thought. Symptoms of the disease include problems with balance when walking, difficulty looking properly, stiff and clumsy movements, falls, problems speaking and swallowing, sensitivity to light, sleep disturbances, loss of interest in pleasurable activities, impulsive behavior, sometimes including crying or laughing for no apparent reason, difficulty with memory, reasoning, problem-solving, and decision-making, depression and anxiety, and expressions of surprise or fear due to rigid facial muscles.

[0016] "Corticobasal degeneration" is a term used to describe the shrinkage of certain brain areas, such as the cerebral cortex and basal ganglia, and the degeneration and death of nerve cells. This makes movement on one or both sides of the body increasingly difficult. Example symptoms include poor coordination, stiffness, difficulty thinking (cognition), and speech or language problems.

[0017] "Parkinson's disease" is a progressive disorder of the nervous system. The disease affects movement. Examples of symptoms include tremors, slow movements (bradykinesia), muscle rigidity, impaired posture and balance, loss of motor coordination, changes in speech and writing. Complications associated with Parkinson's disease include difficulty thinking, depression and emotional changes, swallowing problems, chewing and feeding problems, insomnia and sleep disorders, bladder problems, and constipation.

[0018] "Huntington's disease" is the term used for a genetic disorder that causes progressive degeneration of nerve cells in the brain. This can significantly affect a person's functional abilities, resulting in motor, cognitive, and psychiatric disorders. Examples of symptoms associated with movement disorders include involuntary jerking or writhing movements (chorea), muscle disorders such as muscle stiffness or muscle contractures (dystonia), slow or abnormal eye movements, problems with walking, posture, or balance, and difficulties with the physical accomplishments of speaking or swallowing. Examples of symptoms associated with cognitive disorders include difficulty organizing, prioritizing, or concentrating on tasks; inflexibility in thinking or tending to get caught up in actions or activities (perseveration); lack of impulse control that can lead to emotional outbursts, mindless behavior, and sexual promiscuity; lack of awareness of one's own actions and abilities; slow thought processing; and difficulty learning new information. Examples of symptoms associated with mental disorders include irritable, sad or lethargic feelings, social withdrawal, insomnia, fatigue and loss of energy, frequent thoughts of death or dying or suicide, obsessive-compulsive disorder, mania, and bipolar disorder.

[0019] Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a type of dementia. The symptoms of LATE are similar to those of Alzheimer's disease. However, LATE is caused by the deposition of TDP-43 in the brain, rather than beta-amyloid.

[0020] Alpha-synuclein is a protein that is abundant in the human brain and also present in certain other body tissues (e.g., heart, muscle, and intestine). This protein has a tendency to accumulate near the tips of nerve cells (i.e., neurons) in association with synaptic vesicles that initiate neurotransmitter release. In certain pathological conditions (e.g., Parkinson's disease), alpha-synuclein misfolds and forms toxic aggregates.

[0021] Tau proteins are proteins that stabilize microtubules. They are abundant in neurons. Diseases such as Alzheimer's and Parkinson's are associated with defective and aggregated tau proteins.

[0022] TDP-43 is a transcriptional repressor that also regulates alternative splicing of the CFTR gene. Hyperphosphorylated, ubiquitinated, truncated forms of TDP-43 are associated with ubiquitin-positive, tau-negative, and α-synuclein-negative frontotemporal dementia and amyotrophic lateral sclerosis.

[0023] Huntingtin's protein is a protein highly expressed in neurons and testis, which increases the expression of brain-derived neurotrophic factor and is primarily associated with vesicles and microtubules.

[0024] The present invention relates to small molecule compounds that treat or prevent ALS, LATE, Huntington's disease, Parkinson's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases by suppressing, inhibiting or disrupting oligomers of TDP-43, alpha-synuclein, tau protein and huntingtin protein.

[0025] The terms "oligomeric" or "oligomer" refer to a protein complex of a finite number of monomeric subunits. In the context of the present invention, oligomers are referred to as trimers, low-n-mers, hexamers, and 12-mers, as well as large-n-multimers composed of TDP-43 peptide, α-synuclein, tau protein, and / or huntingtin protein.

[0026] The terms "patient" or "subject" refer to animals, including mammals, humans, and non-human mammals. In certain embodiments, the patient is an animal, particularly an animal selected from mammalian species, including rats, rabbits, bovines, ovines, porcines, canines, felines, murines, equines, and primates, particularly humans. In preferred embodiments, the patient or subject is a human.

[0027] "Treating" or "treatment of" a disease includes (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in a patient who may be exposed to or predisposed to the disease but who has not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; (3) palliating the disease, i.e., reducing the disease or its clinical symptoms; or (4) reducing the clinical symptoms of the disease.

[0028] The terms "suffering" or "in need thereof" in relation to the term "treatment" refer to a patient or individual who has been diagnosed with or is predisposed to a disease. A patient may also be "at risk of suffering" from a disease. The patient may not yet have the characteristic disease symptoms but is known to be predisposed to a disease due to a family history of genetic predisposition, or may have been diagnosed with a disease or disorder and is predisposed to developing the disease being treated.

[0029] In therapeutic applications, pharmaceutical compositions containing one or more compounds described herein are administered to patients suspected of or already suffering from ALS, LATE, Huntington's disease, Parkinson's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia, and / or related motor neuron diseases, in an amount sufficient to cure or at least partially arrest disease symptoms (biochemical, histological, and / or behavioral), including complications and intermediate pathological phenotypes in disease development. In prophylactic applications, pharmaceutical compositions containing one or more compounds described herein are administered to patients susceptible to or otherwise at risk of developing ALS, LATE, Huntington's disease, Parkinson's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia, and / or related motor neuron diseases. wherein the compound is administered in an amount sufficient to eliminate or reduce the risk, reduce the severity of, or delay the onset of, the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifesting during the development of the disease.

[0030] The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient being treated, all of which are within the skill of the attending clinician. A therapeutically effective amount of one or more compounds described herein is believed to alter or prevent the accumulation of oligomers of TDP-43, α-synuclein, tau protein, and / or huntingtin protein in a patient compared to no treatment. Accordingly, movement disorders are reduced or prevented.

[0031] In some methods, administering a compound ameliorates or eliminates muscle weakness in patients who have not yet developed characteristic ALS symptoms. In certain embodiments, a therapeutically effective amount is meant to refer to the amount of one or more compounds described herein administered or provided to a patient that is most likely to result in a desired response to treatment. In other methods, administering a compound ameliorates or eliminates muscle weakness, behavioral changes, speech and language disorders, and / or movement disorders in patients with frontotemporal dementia. In other methods, administering a compound ameliorates or eliminates cognitive impairment, impulsive behavior, depression, or apathy in patients with CTE. In other methods, administering a compound ameliorates or eliminates balance problems, inability to orient, and movement problems in patients with progressive supranuclear palsy. In other methods, administering a compound ameliorates or eliminates incoordination, stiffness, cognitive difficulties, and speech or language disorders in patients with corticobasal degeneration. In another method, administration of the compound ameliorates or eliminates tremors, slow movements, rigid muscles, impaired posture and balance, loss of motility, changes in speech and writing in patients with Parkinson's disease. In another method, administration of the compound ameliorates or eliminates movement disorders, cognitive impairments, and psychiatric disorders in patients with Huntington's disease. In another method, administration of the compound ameliorates or eliminates dementia-related symptoms in patients with LATE.

[0032] Embodiments of the present invention also include pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof (typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) is preferred). Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0033] For oral administration, pharmaceutically acceptable preparations may contain carriers.Carriers include, but are not limited to, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, and flavoring agents.For injection preparations, carriers may include buffers, preservatives, analgesics, solubilizers, isotonicity agents, and stabilizers.For topical administration preparations, carriers may include bases, excipients, lubricants, and preservatives.

[0034] The disclosed compositions may be combined with the aforementioned pharmaceutically acceptable carriers and formulated into various dosage forms. For example, for oral administration, the pharmaceutical compositions may be formulated into tablets, lozenges, capsules, elixirs, suspensions, syrups, or wafers. For injection preparations, the pharmaceutical compositions may be formulated in ampoules as single-dose dosage forms or in multi-dose containers. The pharmaceutical compositions may also be formulated into solutions, suspensions, tablets, pills, capsules, and long-acting preparations.

[0035] Examples of suitable carriers, excipients, and diluents for pharmaceutical formulations include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.In addition, pharmaceutical formulations may further include fillers, anticoagulants, lubricants, moisturizers, fragrances, and disinfectants.

[0036] For treating the above-mentioned disorders, the effective amount of the compositions of the present invention may vary depending on various factors, including the means of administration, the physiological condition of the patient, whether the patient is human or animal, other administered medications, and whether the treatment is prophylactic or therapeutic. Typically, the patient is a human. However, in certain embodiments, the patient is an animal, particularly an animal selected from mammalian species, including canines, felines, murines, equines, and primates.

[0037] The compounds can be administered multiple times, with the interval between single doses being daily, weekly, monthly, or yearly. The intervals can also be irregular, as indicated by measuring blood levels of TDP-43 protein, α-synuclein, tau protein, huntingtin protein, or related oligomers in the patient. Alternatively, one or more compounds of the present invention can be administered as a sustained-release formulation, requiring less frequent administration. The dosage and frequency may vary depending on the half-life of the compounds of the present invention. In therapeutic applications, relatively high dosages at relatively short intervals may be required until disease progression is reduced or halted, and preferably until the patient shows partial or complete improvement in disease symptoms. Thereafter, the patient may be administered a prophylactic regimen.

[0038] For the compounds described herein, administration of the pharmaceutical compositions may be carried out via a variety of routes, including, but not limited to, oral, topical, pulmonary, rectal, subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intraarticular injection, etc. The most typical route of administration is oral, although other routes may be effective as well.

[0039] One or more compounds described herein may be administered, optionally in combination with other biological or chemical agents that are at least partially effective in treating diseases associated with TDP-43 oligomers, α-synuclein oligomers, huntingtin protein oligomers, or tau protein oligomers. Examples of such agents include, but are not limited to, antibodies against TDP-43, as described in The Journal of Clinical Investigation, published January 22, 2019, at https: / / www.jci.org / articles / view / 123931.

[0040] The compounds described herein may be administered to a patient in an amount sufficient to inhibit and / or modulate TDP-43, α-synuclein, huntingtin protein, or tau protein oligomerization in the patient. A skilled clinician will be able to readily ascertain an appropriate amount of the compounds described herein to effectively inhibit, modulate, and / or regulate TDP-43, α-synuclein, huntingtin protein, or tau protein oligomerization in the patient. Contemplated amounts of the compounds described herein include, for example, about 0.05 to 2000 mg / m of one compound or one or more compounds. 2 / day, including but not limited to:

[0041] As mentioned above, the compounds described herein may be administered, for example, but not limited to, orally, topically, pulmonary, rectally, subcutaneously, intradermally, intranasally, intracranially, intramuscularly, intraocularly, or intraarterially. The carrier or excipient or excipient mixture can be, for example, but not limited to, a solvent or dispersion medium, including various polar or nonpolar solvents, suitable mixtures thereof, or oils. As used herein, "carrier" or "excipient" refers to a pharmaceutically acceptable carrier or excipient, including any and all solvents, dispersants or dispersion media, coatings, antimicrobial agents, isotonic, hypotonic, or hypertonic agents, absorption-modifying agents, and the like. The use of such substances or agents for pharmaceutically active substances is well known in the art. Furthermore, other or additional active ingredients can be incorporated into the final composition.

[0042] Diseases that may be treated by the methods described herein include ALS, Alzheimer's disease, LATE, Huntington's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases.

[0043] When used as a drug, the compounds of the present invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by various routes, including oral, topical, pulmonary, rectal, subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intra-articular injection. These compounds are effective as both injectable and oral compositions. Such compositions are prepared by methods well known in the pharmaceutical arts and contain at least one active compound.

[0044] The present invention also includes pharmaceutical compositions containing, as an active ingredient, one or more compounds described herein in association with a pharmaceutically acceptable carrier. In preparing compositions according to this invention, the active ingredient is typically mixed with or diluted by an excipient, or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper, or other container. The excipient used is typically one suitable for administration to a patient. When serving as a diluent, the excipient may be a solid, semi-solid, or liquid material that acts as a solvent, carrier, or medium for the active ingredient. Thus, compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid vehicles), ointments containing up to 10% by weight of the active compound, soft or hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0045] When preparing a formulation, it may be necessary to mill the active compound to obtain a suitable particle size before combining with other ingredients.If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh.If the active compound is substantially soluble in water, the particle size is usually adjusted by milling, for example, to 40 mesh, to provide a substantially uniform distribution in the formulation.

[0046] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricating agents such as mica, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present invention can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by methods known in the art.

[0047] The administration of therapeutic agents via intravenous formulations is widely known in the pharmaceutical industry. Intravenous formulations must possess certain properties beyond being a soluble composition of the therapeutic agent. For example, the formulation must promote the overall stability of the active ingredient and must be cost-effective to manufacture. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation.

[0048] Other auxiliary additives that may be included in formulations of the compounds of the present invention include solvents such as ethanol, glycerol, and propylene glycol; stabilizers such as ethylenediaminetetraacetic acid (EDTA) and citric acid; antimicrobial preservatives such as benzyl alcohol, methylparaben, and propylparaben; buffers such as citric acid / sodium citrate, potassium bitartrate, sodium bitartrate, acetic acid / sodium acetate, maleic acid / sodium maleate, sodium bithalate, phosphoric acid / potassium dihydrogen phosphate, and phosphoric acid / disodium dihydrogen phosphate; and tonicity adjusters such as sodium chloride, mannitol, and dextrose.

[0049] The presence of a buffer may be necessary to maintain the aqueous pH in the range of about 4 to about 8, more preferably in the range of about 4 to about 6. Buffer systems are generally mixtures of weak acids and their soluble salts, e.g., sodium citrate / citric acid, or monocationic or dicationic salts of dibasic acids, e.g., potassium bitartrate, sodium bitartrate, potassium phosphate / dihydrogen phosphate, and phosphate / disodium hydrogen phosphate.

[0050] The amount of buffer system used is determined by (1) the desired pH and (2) the amount of drug. Typically, the amount of buffer used is in a buffer:drug molar ratio (the number of moles of buffer taken as the total number of moles of buffer components, e.g., sodium citrate and citric acid) of 0.5:1 to 50:1 to maintain a pH within the range of 4 to 8, and is generally used in a molar ratio of 1:1 to 10:1 (combined) buffer to drug present.

[0051] One useful buffer in the present invention is a sodium citrate / citric acid buffer ranging from 5-50 mg sodium citrate per mL to 1-15 mg citric acid per mL. ,set It is sufficient to maintain the aqueous pH of the composition between 4 and 6.

[0052] A buffering agent may be present to prevent precipitation of the drug through the formation of soluble metal complexes with dissolved metal ions, e.g., Ca, Mg, Fe, Al, Ba, that may leach from the glass container or rubber stopper or that are present in ordinary tap water. This agent may act as a competitive complexing agent with the drug, resulting in soluble metal complexes that result in the presence of undesirable particles.

[0053] Furthermore, when administering intravenous formulations, the presence of sodium chloride, for example, in an amount of about 1-8 mg / mL, may be required to adjust the osmolality to that of human blood to avoid swelling or shrinkage of red blood cells, which can cause undesirable side effects such as nausea or diarrhea and, in some cases, related blood disorders. Generally, the osmolality of the formulation matches that of human blood, which ranges from 282 to 288 mOsm / kg, and is typically 285 mOsm / kg, which is equivalent to the osmolality of a 0.9% solution of sodium chloride.

[0054] Intravenous formulations can be administered by direct intravenous injection or bolus injection, or can be added to a suitable infusion fluid, such as 0.9% sodium chloride injection or other compatible infusion fluid, and administered by infusion.

[0055] The compositions can be formulated in oral unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unitary patient dosages, each containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0056] The total effective amount of the compositions disclosed herein may be administered to a patient in a single dose, or may be administered over an extended period of time in multiple doses according to a divided treatment protocol. The content of the active ingredient in the pharmaceutical compositions disclosed herein may be varied depending on the severity of the disease. Preferably, the total daily dose of the compounds disclosed herein may be about 0.0001 to 500 mg per kg of patient body weight. However, the effective amount of the compound is determined by taking into account various factors, including the patient's age, body weight, health condition, sex, severity of the disease, diet, and excretion rate, as well as the route of administration and frequency of treatment. In light of these factors, those skilled in the art can easily determine the effective amount of the pharmaceutical compositions disclosed herein appropriate for a particular use. The pharmaceutical compositions disclosed herein are not particularly limited in terms of dosage form, route of administration, or mode of administration, as long as they exhibit the appropriate effect. Furthermore, the pharmaceutical compositions may be administered alone or in combination with or simultaneously with other pharmaceutical preparations that exhibit prophylactic or therapeutic efficacy.

[0057] In one embodiment, a single dose of the composition may be administered daily, semiweekly, weekly, biweekly, or monthly. The treatment period may be 1 week, 2 weeks, 1 month, 2 months, 4 months, 6 months, 8 months, 1 year, or longer. The initial dose may be greater than the sustained dose. In one embodiment, the weekly dose ranges are at least 0.10 mg, at least 0.50 mg, at least 1.0 mg, at least 5.0 mg, at least 10.0 mg, at least 50.0 mg, at least 100.0 mg, at least 500.0 mg, at least 1.0 g, at least 5.0 g, or at least 10.0 g. In one embodiment, the weekly dosage may be at most 0.5 mg, at most 2.5 mg, at most 5.0 mg, at most 25.0 mg, at most 50.0 mg, at most 250.0 mg, at most 500.0 mg, at most 2.50 g, at most 5.0 g, at most 25.0 g, or at most 50.0 g. In certain aspects, the weekly dosage may range from 1.0 mg to 50.0 g, 10.0 mg to 25.0 g, or 100 mg to 5.0 g.

[0058] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, from 0.05 to about 2000 mg of the active ingredient of the present invention.

[0059] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a shell over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for the enteric layer or coating. Such materials include a number of polymeric acids and mixtures of polymeric acids with, for example, shellac, cetyl alcohol, and cellulose acetate.

[0060] The novel compositions of the present invention may incorporate liquid forms for oral or injectable administration, including aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0061] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of an inert gas. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to an anesthesia machine mask tent or intermittent positive pressure breathing mechanism. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0062] Compositions for ALS, Alzheimer's disease, LATE, Huntington's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases.

[0063] "Acyl" refers to a ketone substituent, C(O)R, where R is alkyl or substituted alkyl, aryl or substituted aryl, as defined herein.

[0064] "Alkenyl" refers to an unsaturated "alkyl" group containing a double bond.

[0065] "Alkoxy" refers to the group -OR, where R is alkyl, or a substituted analog thereof. Suitable alkoxy groups include, for example, methoxy, ethoxy, t-butoxy, and the like.

[0066] "Alkyl" refers to a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon group generally having about 1 to 30 carbon atoms, preferably 4 to 20 carbon atoms, and more preferably 6 to 18 carbon atoms. Alkyl groups having 1 to 6 carbon atoms are referred to as "lower alkyl." Branched structures have branching motifs similar to i-propyl, t-butyl, i-butyl, 2-ethylpropyl, etc. As used herein, the term includes "substituted alkyls" and "cyclic alkyl." The term (C1-C8) alkyl refers to an alkyl having 1 to 8 carbon atoms.

[0067] "Alkynyl" refers to an unsaturated "alkyl" group containing a triple bond.

[0068] "Amino" refers to -NRR', where R and R' are independently H, alkyl, aryl, or substituted analogs thereof. "Amino" includes "alkylamino," which refers to secondary or tertiary amines, and "acylamino," which refers to the group RC(O)NR'.

[0069] "Aryl" refers to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings linked by a covalent bond or to a common group such as a diazo, methylene, or ethylene moiety. The common linking group may also be a carbonyl, as in benzophenone. The aromatic rings include phenyl, naphthyl, biphenyl, diphenylmethyl, and benzophenone, among others. The term "aryl" includes "arylalkyl" and "substituted aryl."

[0070] "Arylalkyl" refers to a moiety of "aryl", where the aryl group is attached to another group by an alkyl group, as defined herein.

[0071] "Aryloxy" refers to an aromatic group bonded directly to another group through an oxygen atom. The term includes "substituted aryloxy" moieties in which the aromatic group is substituted as described above for "substituted aryl." Typical aryloxy moieties include phenoxy, substituted phenoxy, benzyloxy, phenethyloxy, and the like.

[0072] "Aryloxyalkyl" refers to an aromatic group, as defined herein, attached to an alkyl group via an oxygen atom. The term "aryloxyalkyl" includes "substituted aryloxyalkyl" moieties in which the aromatic group is substituted as described for "substituted aryl."

[0073] "Electron withdrawing group" refers to an atom or group that attracts electron density from neighboring atoms to itself through resonance or inductive effects. This includes groups such as, for example, -NO, -CN, -C(O)H, -C(O)R where "R" is an alkyl group, -COR where "R" is an alkyl group, and -COH.

[0074] "Halogen" refers to fluorine, bromine, chlorine, and iodine atoms.

[0075] "Heteroaryl" refers to an aromatic ring in which one or more carbon atoms of the aromatic ring are replaced by a heteroatom, such as nitrogen, oxygen, or sulfur. Heteroaryl refers to a structure that may be a single aromatic ring, multiple aromatic rings, or one or more aromatic rings bonded to one or more non-aromatic rings. In structures with multiple rings, the rings may be bonded together, covalently bonded, or bonded to a common group, such as a diazo, methylene, or ethylene moiety. This common linking group may also be a carbonyl, such as in phenylpyridyl ketone. As used herein, rings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, and the like, or benzo-fused analogs of these rings, are defined by the term "heteroaryl."

[0076] "Heteroarylalkyl" refers to a species of "heteroaryl" in which the heteroaryl group is attached to another group by an alkyl group, as defined herein.

[0077] "Heterocyclic" refers to a monovalent, saturated or unsaturated, non-aromatic group having a single ring or multiple condensed rings of 1 to 12 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen within the ring. Examples of such heterocyclic rings include tetrahydrofuran, morpholine, piperidine, and pyrrolidine.

[0078] "Heterocyclic alkyl" refers to a subset of "heterocycles" in which the heterocyclic group is attached to another group by an alkyl group, as defined herein.

[0079] "Hydroxy" refers to the group --OH.

[0080] "Mercapto" refers to a moiety of the general structure -SR, where R is H, alkyl, aryl, or heterocycle, as described herein.

[0081] "Saturated cyclic hydrocarbon" refers to groups such as cyclopropyl, cyclobutyl, cyclopentyl, and the like, as well as substituted analogs of these structures. These cyclic hydrocarbons can be single ring structures or multiple ring structures.

[0082] "Substituted alkenyl" refers to an alkenyl group which has one or more substituents, such as lower alkyl, aryl, acyl, halogen (e.g., alkylhalo), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamide, acyloxy, aryloxy, "Alkenyl" refers to groups such as aryloxyalkyl, mercapto, thia, aza, oxo, saturated and unsaturated cyclic hydrocarbons, heterocycles, and the like. These groups may be attached to any carbon or substituent of the alkenyl moiety. Furthermore, these groups may be pendent from or integral to the alkenyl chain.

[0083] "Substituted alkyl" refers to an "alkyl" that includes one or more substituents, such as lower alkyl, aryl, acyl, halogen (e.g., alkylhalo), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamido, acyloxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo, saturated and unsaturated cyclic hydrocarbons, heterocycles, and the like. These groups may be attached to any carbon or substituent of the alkyl moiety. Furthermore, these groups may be pendent from or integral to the alkyl chain.

[0084] "Substituted alkynyl" refers to an "alkynyl" containing one or more substituents, such as lower alkyl, aryl, acyl, halogen (e.g., alkylhalo), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamido, acyloxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo, saturated and unsaturated cyclic hydrocarbon, heterocyclic, and the like. These groups may be bonded to any carbon or substituent of the alkynyl moiety. Furthermore, these groups may be pendent from or integral to the alkynyl chain.

[0085] "Substituted aryl" refers to an "aryl" containing one or more functional groups, such as lower alkyl, acyl, halogen, alkylhalo (e.g., CF), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, phenoxy, mercapto, and saturated and unsaturated cyclic hydrocarbons covalently bonded or fused to an aromatic ring that is bonded to a common group, such as a diazo moiety, or a methylene or ethylene moiety. This linking group may also be a carbonyl, such as in cyclohexyl phenyl ketone. The term "substituted aryl" includes "substituted arylalkyl."

[0086] "Substituted arylalkyl" refers to a subset of "substituted aryl" groups in which the substituted aryl group is attached to another group by an alkyl group, as defined herein.

[0087] "Substituted heteroaryl" refers to a heteroaryl in which the heteroaryl nucleus is substituted with one or more functional groups, such as lower alkyl, acyl, halogen, alkylhalo (e.g., CF), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc. Thus, for example, substituted analogs of aromatic heterocycles such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, etc., or benzo-fused analogs of these rings are defined by the term "substituted heteroaryl."

[0088] "Substituted heteroarylalkyl" refers to a subset of "substituted heteroaryl" groups in which a heteroaryl group is linked to another group by an alkyl group, as defined herein.

[0089] "Substituted heterocyclic" refers to some "heterocyclic" rings in which the heterocyclic nucleus is substituted with one or more substituents, such as lower alkyl, acyl, halogen, alkylhalo (e.g., CF), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, and the like.

[0090] "Unsaturated cyclic hydrocarbon" refers to a monovalent non-aromatic group having at least one double bond, such as, for example, cyclopentene, cyclohexene, and their substituted analogs. These cyclic hydrocarbons can be single ring structures or multiple ring structures.

[0091] 9-29 show specific compounds according to the present invention for treating ALS, LATE, Huntington's disease, Parkinson's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia, and / or related motor neuron diseases. Where a cation is shown (e.g., compounds 102 and 106), a negatively charged, pharmaceutically acceptable counterion (e.g., AcO) is implied.

[0092] Referring to FIG. 9, compound 100, the substituents R1, R3 to R6, R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0093] Referring to FIG. 9, compound 102, the substituents R1 to R6, R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0094] Referring to FIG. 9, compound 104, the substituents R3 to R6, R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0095] Referring to FIG. 10, compound 106, the substituents R3 to R6, R 20 , R 22 , R 24 , R 25 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0096] Referring to FIG. 10, compound 108, the substituents R3 to R6, R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0097] Referring to FIG. 10, compound 110, the substituents R3 to R6, R 20 , R 22 , R 24 , R 26 ~R 28 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0098] Referring to Figure 11, compound 112, the substituent R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0099] Referring to Figure 11, compound 114, the substituent R 20 , R 22 , R 24 , R 26 ~R 28 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0100] Referring to Figure 11, compound 116, the substituent R 22 , R 26are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0101] Referring to Figure 12, compound 118, the substituent R 22 , R 26 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0102] Referring to FIG. 12, compound 120, the substituents R1, R3 to R8, R 20 ~R 29are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0103] Referring to FIG. 12, compound 122, the substituents R1 to R8, R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0104] Referring to FIG. 13, compound 124, the substituents R3 to R8, R 20 , R 22 , R 24 , R 25 ~R 29are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0105] Referring to FIG. 13, compound 126, the substituents R3 to R8, R 20 , R 22 , R 24 , R 25 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0106] Referring to FIG. 13, compound 128, the substituents R3 to R8, R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0107] Referring to Figure 14, compound 130, the substituent R 20 , R 22 , R 24 , R 26 ~R 28 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0108] Referring to Figure 14, compound 132, the substituent R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0109] Referring to Figure 14, compound 134, the substituent R 22 , R 26 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0110] Referring to Figure 15, compound 136, the substituent R 22 , R 26are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0111] Referring to FIG. 15, compound 138, the substituents R1, R3 to R 10 , R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0112] Referring to FIG. 15, compound 140, the substituents R1 to R 10 , R 20 ~R 29are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0113] Referring to FIG. 16, compound 142, the substituents R3 to R 10 , R 20 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0114] Referring to FIG. 16, compound 144, the substituents R3 to R 10 , R 20 ~R 29are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0115] Referring to FIG. 16, compound 146, the substituents R3 to R 10 , R 20 、 R 22 , R 24 , R 25 ~R 29 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0116] Referring to FIG. 17, compound 148, the substituents R3 to R 10 , R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0117] Referring to Figure 17, compound 150, the substituent R 20 , R 22 , R 24 , R 26 ~R 28 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0118] Referring to Figure 17, compound 152, the substituent R 20 , R 22 , R 24 , R 26 ~R 28are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0119] Referring to Figure 18, compound 154, the substituent R 22 , R 26 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0120] Referring to Figure 18, compound 156, the substituent R 22 , R 26are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0121] Referring to Figure 18, compound 158, the substituent R 40 , R 42 ~R 48 , R 50 ~R 54 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0122] Referring to Figure 19, compound 160, the substituent R 40 ~R 48 , R 50 ~R 54are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0123] Referring to Figure 19, compound 162, the substituent R 40 , R 44 ~R 46 , R 50 ~R 54 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0124] Referring to Figure 19, compound 164, the substituent R 40 , R 41 , R 44 ~R 46 , R 50 ~R 54are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0125] Referring to Figure 20, compound 166, the substituent R 40 , R 44 , R 50 ~R 54 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0126] Referring to Figure 20, compound 168, the substituent R 40 , R 41 ,R 44 , R 50 ~R 54are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0127] Referring to Figure 20, compound 170, the substituent R 40 , R 50 ~R 54 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0128] Referring to Figure 21, compound 172, the substituent R 40 , R 41 , R 50 ~R 54are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0129] Referring to Figure 21, compound 174, the substituent R 40 , R 51 ~R 53 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0130] Referring to Figure 21, compound 176, the substituent R 40 , R 41 , R 51 ~R 53are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0131] Referring to Figure 22, compound 178, the substituent R 40 , R 52 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0132] Referring to Figure 22, compound 180, the substituent R 40 , R 41 , R 52are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0133] Referring to Figure 22, compound 182, the substituent R 60 , R 62 ~R 69 , R 80 ~R 84 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0134] Referring to Figure 23, compound 184, the substituent R 60 , R 61 , R 62 ~R 69 , R 80 ~R 84are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0135] Referring to Figure 23, compound 186, the substituent R 60 , R 64 ~R 67 , R 80 ~R 84 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0136] Referring to Figure 23, compound 188, the substituent R 60 , R 61 , R 64 ~R 67 , R 80 ~R 84are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0137] Referring to Figure 24, compound 190, the substituent R 60 , R 81 ~R 83 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0138] Referring to Figure 24, compound 192, the substituent R 60 , R 61 , R 81 ~R 83are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0139] Referring to Figure 24, compound 194, the substituent R 60 , R 82 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0140] Referring to Figure 25, compound 196, the substituent R 60 , R 61 , R 82are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0141] Referring to Figure 25, compound 198, the substituent R 60 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0142] Referring to Figure 25, compound 200, the substituent R 60 , R 61are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0143] Referring to Figure 26, compound 202, the substituent R 91 , R 93 ~R 96 , R 100 ~R 108 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0144] Referring to Figure 26, compound 204, the substituent R 91 ~R 96 , R 100 ~R 108are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0145] Referring to Figure 26, compound 206, the substituent R 111 , R 113 ~R 116 , R 120 ~R 127 , R 129 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0146] Referring to Figure 27, compound 208, the substituent R 111 ~R 116 , R 120 ~R 127 , R 129are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0147] Referring to Figure 27, compound 210, the substituent R 131 , R 133 ~R 136 , R 140 ~R 146 , R 148 , R 149 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0148] Referring to Figure 27, compound 212, the substituent R 131 ~R 136 , R 140 ~R 146 , R 148 , R 149are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0149] Referring to Figure 28, compound 214, the substituent R 151 , R 153 ~R 156 , R 163 ~R 167 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different). "X" is O, S, or NR, where R is hydrogen or alkyl.

[0150] Referring to Figure 28, compound 216, the substituent R 151 ~R 156 , R 163 ~R 167are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different). "X" is O, S, or NR, where R is hydrogen or alkyl.

[0151] Referring to Figure 28, compound 218, the substituent R 171 , R 173 ~R 176 , R 180 ~R 186 , R 188 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different). "X" is O, S, or NR, where R is hydrogen or alkyl.

[0152] Referring to Figure 29, compound 220, the substituent R 171 ~R 176 , R 180 ~R 186 , R 188are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different). "X" is O, S, or NR, where R is hydrogen or alkyl.

[0153] Referring to Figure 29, compound 222, the substituent R 191 , R 193 ~R 196 , R 200 ~R 206 , R 209 are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0154] Referring to Figure 29, compound 224, the substituent R 191 ~R 196 , R 200 ~R 206 , R 209are independently selected from the group consisting of hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon (e.g., all can be the same or all can be different).

[0155] Other non-limiting examples of compounds according to the present invention for treating ALS, LATE, Huntington's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases include N-[4-({[2-(3-chlorophenyl)ethyl]amino}methyl)-phenyl]acetamide (AC0101), (2,3-dihydroxy-1,4-benzodioxin-6-ylmethyl)({4[(dimethylamino)-methyl]phenyl}methyl)amine (AC0102), 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2-phenylacetamide (AC0103), These include cetoamide (AC0103), 3-[({[4-(morpholin-4-ylmethyl)phenyl)methyl}amino)-methyl]benzonitrile (AC0104), 4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (AC0105), 4-{1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1,2,3,6 tetrahydropyridin-4-yl}phenol (AC0106), 4-[({[3-(pyrrolidin-1-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile (AC0107), AC0201, AC0202, AC0203, and AC0204.

[0156] Specific Embodiments

[0157] A compound having the following structure: [ka] where R 40 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 42 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 43 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 44is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 45 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 46 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 47is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 48 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 50 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 51is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 52 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 53 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 54is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon.

[0158] R 40 is hydrogen, alkyl or acyl.

[0159] R 42 , R 43 , R 47 and R 48 are independently hydrogen or alkyl.

[0160] R 44 ~R 46 is hydrogen or alkyl.

[0161] R 50 ~R 54 is hydrogen, alkyl or halogen.

[0162] Methods of treating or preventing ALS, LATE, Huntington's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases using the compounds described above.

[0163] A method of inhibiting or preventing the formation of oligomers of TDP-43, alpha-synuclein, huntingtin protein and / or tau protein using the aforementioned compounds.

[0164] A compound having the following structure: [ka] where R 60 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 62 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 63 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 64is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 65 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 66 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 67is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 68 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 69 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 80is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 81 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 82 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 83is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon; R 84 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, an electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocycle, or unsaturated cyclic hydrocarbon.

[0165] R 60 is hydrogen, alkyl or acyl.

[0166] R 62 , R 63 , R 68 and R 69 are independently hydrogen or alkyl.

[0167] R 64 , R 65 , R 66 and R 67 are independently hydrogen or alkyl.

[0168] R 80 ~R 84 are independently hydrogen, alkyl or halogen.

[0169] The aforementioned compounds can be used to treat ALS, LATE, Huntington's disease, Parkinson's disease, Alzheimer's disease, Methods for treating or preventing corticobasal degeneration, progressive supranuclear palsy, CTE, frontotemporal dementia and / or related motor neuron diseases.

[0170] A method of inhibiting or preventing the formation of oligomers of TDP-43, alpha-synuclein, huntingtin protein and / or tau protein using the aforementioned compounds.

[0171] 1. A method of inhibiting oligomer formation or disrupting oligomers of TDP-43, alpha-synuclein, huntingtin protein, and / or tau protein in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221 4, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzaldo 1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0172]

[0023] A method of treating or preventing ALS in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176 , 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzald1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0173]

[0023] A method of treating or preventing LATE in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176 , 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzald1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0174] 1. A method of treating Huntington's disease in a subject, comprising administering to a subject a compound selected from the group consisting of: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176 , 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzald1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0175] 1. A method of treating or preventing Parkinson's disease in a subject, comprising administering to a subject a compound selected from the group consisting of: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 2 76, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzaldo 1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl to said subject in need thereof.

[0176] 1. A method of treating or preventing corticobasal degeneration in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzaldo 1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0177] 1. A method of treating or preventing progressive supranuclear palsy in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 226, 228, 230, 231, 232, 233, 234, 235, 236, 23 76, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzaldo 1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl to said subject in need thereof.

[0178]

[0023] A method of treating or preventing CTE in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176 , 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzald1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl.

[0179] 1. A method of treating or preventing frontotemporal dementia in a subject, comprising administering to a subject the following compounds: 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 226, 228, 230, 231, 232, 233, 234, 235, 236, 238, 24 76, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, benzaldo 1, fluorophenyl, aminofluorophenyl, and dimethoxyphenyl to said subject in need thereof. [Example]

[0180] [Table 1]

[0181] Three different assays were performed on the activity of compounds AC0101-AC0107 and AC0201-AC0204. The first was a computational assay. The second was a cell-based assay targeting the inhibition of TDP43 granule formation in cells after arsenite treatment. The third was a cell-based assay targeting the inhibition of TDP43 granule formation in the presence of arsenite. 307-319 IM-MS was utilized to monitor the formation of oligomers.

[0182] Experimental Section Calculation Methods Molecules AC0101-AC0107, AC0201-AC0204, and their derivatives have been discovered and evaluated for their activity against proteins through computational methods. Essentially, a machine learning model was trained using a set of positive and negative results and used to predict the activity of molecules from a selected subspace. This computational activity can then be subjected to further analysis, such as IM-MS. Mechanistically, proteins that are intrinsically disordered and prone to aggregation (e.g., tau, TDP-43, α-synuclein) are widely believed to adopt prion-like properties. Prion-like proteins act as templates for propagation from donor cells to recipient cells, thereby compromising the endogenous protein form and allowing the toxic oligomeric / aggregated state to spread from cell to cell. This feature is exploited in the design of molecules that affect many proteins.

[0183] Experimental Section Cell Analysis

[0184] Introduction Amyotrophic lateral sclerosis (ALS) is one of the most common degenerative diseases of the motor neuron system. TDP-43-associated pathology appears to be the predominant pathology across sporadic ALS subtypes. We have developed a novel fluorescent cell-based assay for high-concept screening that allows for quantification of pathological TDP43 granules. In this study, we used this model to screen the effects of three compounds, using riluzole as a positive control. The TDP-43U2OS cell line contains U2OS cells stably expressing tGFP-tagged human TDP-43. This cell line was designed to test compounds and analyze their function in regulating TDP43 granule formation after cytotoxic stress induction. This cell line was generated at Innoprot. It is a stable cell line that expresses the LacRI repressor protein and the TDP43-turboGFP protein. This cell line was generated using the pCMVLacRI-Hygro (hygromycin-resistant) plasmid and the pPuro-TDP43tGFP (puromycin-resistant) plasmid. The cell line was generated by transfection of these plasmids using Lipofectamine LTX reagent, followed by dilution of the transfected cells to critical dilution. Negative controls exhibit a diffuse nuclear distribution of fluorescence, but after sodium arsenite treatment, the phenotype changes to a cytoplasmic vesicular pattern corresponding to stress granules, followed by a focal nuclear granular pattern. The objective of this study was to analyze 11 compounds at different doses.

[0185] the purpose The aim of these experiments was to screen the protective effects of 11 compounds and a reference compound (arimoclomol) against cellular oxidative stress induced by sodium arsenite (such as arsenite salts). μ M, 5 μ M, 2 μ M and 1 μEach compound was tested at 100 M, as well as appropriate controls (solvent, arsenite and control). The following compounds were tested: 101, 102, 103, 104, 105, 106, 107, 201, 202, 203 and 204.

[0186] Abbreviation Abbreviations are: nm (nanometer), nM (nanomolar), mM (millimolar), SD (standard deviation), DMEM (Dulbecco's modified Eagle's medium), Opti-MEM (Opti-Minimal Essential Medium), FBS (fetal bovine serum), DMSO (dimethyl sulfoxide).

[0187] Materials and Methods U2OS cells (CLS, reference number 300364), DMEM-F12 (Sigma-Aldrich D6421, batch RNBG7141), Opti-MEM (Thermo-Fisher scientific 31985070, batch 1932076), FBS (Sigma-Aldrich F2442, batch BCBW6329), IPTG (Sigma-Aldrich I 5502, batch 077M4016V), flat-bottom black 96-well plate (Becton Dickinson 353219, batch E1804340), arimoclomol (Sequoia, batch 067897776), sodium arsenite solution (Sigma Aldrich 35000 Fluka, batch HC85455377), and Thermofisher Cell Insight High-Content Bioimager CX7.

[0188] Compound dissolution Each compound was prepared in Optimem. Made At the final dilution, DMSO was added to obtain a final DMSO concentration of 0.1%, the same as the reference compound (arimoclomol). All compounds were tested at a final concentration of 0.1% DMSO (vehicle).

[0189] method On day 1 (Thursday), thaw the recombinant TDP43-tGFP-U2OS cell line (2 × 10 cells per T75). 6 After 24 hours, on Day 2 (Friday), cells were maintained at 37°C in DMEM-F12 supplemented with 10% FBS in a humidified 5% CO2 atmosphere. On Day 5 (Monday), cells were plated in 96-well plates coated with 10,000 cells (±2,000) per well. Cells were maintained at 37°C for 24 hours in DMEM-F12 medium supplemented with 10% FBS in a humidified 5% CO2 atmosphere. On Day 6 (Tuesday), cells were incubated with test compound and 1 mM IPTG in triplicate for 24 hours. On Day 7 (Wednesday), medium was changed and cells were incubated at 250°C for 120 minutes. μ The formation of TDP-43 aggregates was quantified in both the cytoplasm and the cell nucleus after treatment with 100 μM sodium arsenite. After fixation of the cells with formaldehyde (3.7 wt %, 20 min), the formation of TDP-43 granules was quantified. μNuclei were stained with 100µg / ml TDP43 (Tetrahydrofuran) and fluorescence was measured using a Thermofisher Cell Insight High-Content Bioimager. Filters used to detect DAPI were 380 / 10nm and 460 / 10nm for excitation and emission, respectively, and filters to detect TDP43 granules were 488 / 20nm and 520 / 20nm, respectively. Images were acquired for each well, capturing nine images using a 20x objective. Cell quantification was performed by delineating a region of interest (ROI) for the nucleus (stained with DAPI). After quantification, triplicate data were averaged. Granule quantification was also performed using Thermofisher Celomics Scan Viewer 6.1.1. Using the spot detection application in Cell Software, two regions of interest (nucleus and cytoplasm) were delineated. Using this software, the number of granules per nucleus was quantified, and the average number of granules per cytoplasm for each well was calculated. The triplicate data were then averaged. Both Excel 2003 and Sigmaplot 9.0 were used for data management.

[0190] result Cells were incubated with compounds for 24 hours before induction of oxidative stress by sodium arsenite. The number of nuclear and cytoplasmic granules was then quantified using Thermofisher Celomics Scan Viewer 6.1.1 and the Cell Software spot detection application. The ability of compounds to inhibit cytotoxic stress mediated by sodium arsenite treatment was examined in dose-response experiments. The compound concentrations used were suggested by the sponsor.

[0191] The 11 compounds tested were AC0101-AC0107 and AC0201-AC0204. Compounds AC0101, AC0102, and AC0103 were positive in inhibiting TDP43 granule formation in cells after arsenite treatment. Compound AC0101 showed dose-dependent inhibition of stress granules, and 5 μ M and 10 μ The maximum reductions were 62.47% in the nucleus and 43.96% in the cytosol, respectively. Compound AC0102 showed dose-dependent inhibition of stress granules, and at 10 μ The maximum was 27.70% in the nucleus and 36.89% in the cytosol at 10 M. Compound AC0103 showed a dose-dependent inhibition of stress granules, μ The maximum activity in the cytosol was 47.20% for M. As shown in Figure 42, AC0104 and AC0105 also had slight activity.

[0192] Experimental section IM-MS analysis

[0193] Materials and Methods Peptide synthesis and purification. TDP-43 307-319 WT peptide 307 [MGGGMNF GAFSIN] 319 was synthesized using standard 9-fluorenylmethoxycarbonyl (Fmoc) chemistry using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate / hydroxybenzotriazole (HBTU / HOBT) manual solid-phase peptide synthesis. The peptide was amidated using Fmoc-Rink Amide resin (AnaSpec). The peptide was cleaved from the resin at 295 K for 2 h using 94% TFA, 5% triisopropylsilane, and 1% phenol. The crude peptide was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) on a semi-preparative C18 column (Phenomenex) using a gradient of water [0.1% (v / v) TFA] and acetonitrile [0.1% (v / v) TFA]. Because this peptide is insoluble in water and acetonitrile, it was dissolved in 6 M guanidine hydrochloride (GdnHCl) prior to injection. The purity of the peptide was determined to be >93% by analytical RP-HPLC. The molecular weight of the peptide was confirmed by ESI mass spectrometry.

[0194] The compounds are [AC0107], p-{[({[m-(1-pyrrolidinyl)methyl]phenyl}methyl)-amino]-methyl}benzonitrile, [AC0105], p-{[({[p-(1-pyrrolidinyl)methyl]phenyl}methyl)-amino]methyl}benzonitrile, [AC0102], (2,3-dihydro-1,4-benzodioxin-6-yl)[({[p-(dimethylamino)methyl]-phenyl}methyl)amino]methane, [AC0201], 3-[1-(benzylamino)-2-methylpropyl]benzaldehyde, and [AC0202].

[0195] Ion-Mobility Mass Spectroscopy (IM-MS) Using IM-MS, the activity of TDP-43 in the presence of molecules AC0107, AC0105, AC0102, and AC0201 was investigated. 307-319 The oligomerization of different [n] was monitored based on measuring the arrival time distribution (ATD). z+ (n = number of oligomers) containing a specific type of [m] z+ The ability of IM-MS to separate (m = mass, z = charge) gives the distribution of oligomers. Samples were prepared as described above and incubated at room temperature under quiescent conditions.

[0196] result TDP43 307-319 The WT peptide was dissolved in 10 mM ammonium acetate (pH 7.4) with 2% HFIP to a final peptide concentration of 100 μ The sample was incubated at room temperature under static conditions for 4 hours to allow the generation of higher order oligomers. z+ =[1] 1+ or [1] 2+ Two major mass / charge (m / z) peaks were always present in the mass spectra corresponding to the charge states [1]. 2+ shows a single structure in ATD, while [1] 1+shows oligomers ranging from dimers to octamers. Mass spectra at 15 minutes showed well-resolved peaks, but after 4 hours of incubation at room temperature, the signal-to-noise ratio (S / N) decreased and a raised baseline appeared, indicating aggregation. [1] 1+ The peak ATD showed a predominant monomer and some dimers. After 4 hours of incubation at room temperature, the distribution shifted to higher-order oligomers. Experimental collision cross sections (CCS) showed little change, consistent with no conformational changes throughout the incubation period. Upon confirming the presence of higher-order oligomers, inhibitors (either [AC0107], [AC0105], [AC0102], [AC0201], or [AC0202]) were added to the peptide (100 μ M): Inhibitor (100 μ M) = 1:1 molar ratio. Subsequent time points were taken to monitor the remodeling properties of the inhibitors.

[0197] Mass spectra after the addition of [AC0107] showed no complex formation between this molecule and the WT peptide, suggesting that the interaction between this molecule and the peptide was very short-lived and fairly weak. An increase in signal-to-noise ratio and a decrease in baseline were also observed, indicating [1] 1+The strong decrease in peaks suggested a decrease in the degree of aggregation. Similar results were obtained for [AC0105], [AC0102], [AC0201], and [AC0202]. Treatment of aggregated WT peptide with [AC0107] initially demonstrated an increase in the number of higher-order oligomers. After 3 hours, the majority of the oligomers redistributed to monomers and dimers. This initial increase in the number of higher-order oligomers may be due to larger species that began to degrade into species readily observable by IM-MS (but cannot be detected by IM-MS). Addition of the inhibitor [AC0105] to aggregated WT peptide rapidly degraded the higher-order oligomers to monomers and dimers. This redistribution of lower-order oligomers was maintained for 1 week after this single treatment. Drug [AC0102] acted at a slower rate than the other inhibitors. After the initial addition of [AC0102], a transition to higher oligomers occurred (similar to the results for [AC0107]). After 1 hour, remnants of higher oligomers were present. Later time points showed a distribution consisting primarily of monomers and dimers, similar to that of the other two inhibitors.

[0198] The second-generation molecule [AC0201] quickly reverted the majority of the distribution to monomers, dimers, and trimers. Between 3 and 24 hours, the spectrum was dominated by monomers and dimers. One week after this single treatment, a predominant monomer peak was observed, demonstrating that [AC0201] successfully redistributed the oligomers back to monomers and prevented the reformation of higher-order oligomers. Recovery experiments using different concentrations of molecule [AC0201] were performed to determine the lower limit of drug efficacy. WT peptide concentrations were increased to 100 μg / mL. μ M, and [AC0201] 50 μ M(2:1), 25 μ M(4:1), and 10 μExperiments were performed at a molar ratio of 10:1. Results showed that molar ratios of 2:1 and 4:1 were effective in redistributing and maintaining low-order oligomers. At a 10:1 ratio, it took a long time to degrade the oligomers to mostly monomers, but even at this concentration [AC0201] was a very effective inhibitor.

[0199] Molecules [AC0107], [AC0105], and [AC0102] were all able to remodel the resulting higher-order oligomers and prevent the reformation of these toxic related species. [AC0201] showed the fastest and most efficient redistribution of all molecules, and was shown to be effective at a relative concentration ratio of 10:1.

Claims

1. 1. A pharmaceutical composition for inhibiting the formation of TDP-43 oligomers or disrupting TDP-43 oligomers in a subject, said pharmaceutical composition comprising a compound of the following structure: 【Chemical 1】 Here, R １ is hydrogen, acyl, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ３ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ４ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ５ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ６ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２０ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２１ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２２ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２３ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２４ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２５ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２６ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２７ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２８ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２９ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; The pharmaceutical composition, wherein R in each of said -CO 2 R is independently alkyl.

2. R １ The pharmaceutical composition of claim 1 , wherein is hydrogen, alkyl, or acyl.

3. R ３ ~R ６ 3. The pharmaceutical composition of claim 1 or claim 2, wherein is independently hydrogen or alkyl.

4. R ２０ ~R ２４ 4. The pharmaceutical composition of claim 1, wherein each of R, ...

5. R ２５ ~R ２９ 5. The pharmaceutical composition of claim 1, wherein is independently hydrogen, alkyl, or halogen.

6. 1. A pharmaceutical composition for inhibiting the formation of TDP-43 oligomers or disrupting TDP-43 oligomers in a subject, said pharmaceutical composition comprising a compound of the following structure: 【Chemistry 2】 Here, R １ is hydrogen, acyl, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ３ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ４ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ５ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ６ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ７ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ８ is hydrogen, alkenyl, alkyl, alkynyl, halogen, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２０ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２１ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２２ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２３ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２４ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２５ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２６ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２７ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２８ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ２９ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; The pharmaceutical composition, wherein R in each of said -CO 2 R is independently alkyl.

7. R １ The pharmaceutical composition of claim 6, wherein is hydrogen, alkyl, or acyl.

8. R ３ ~R ６ 8. The pharmaceutical composition of claim 6 or claim 7, wherein is independently hydrogen or alkyl.

9. R ２０ ~R ２４ 9. The pharmaceutical composition of any one of claims 6 to 8, wherein is independently hydrogen, alkyl, or halogen.

10. R ２５ ~R ２９ 10. The pharmaceutical composition of any one of claims 6 to 9, wherein is independently hydrogen, alkyl, or halogen.

11. 1. A pharmaceutical composition for inhibiting the formation of TDP-43 oligomers or disrupting TDP-43 oligomers in a subject, said pharmaceutical composition comprising a compound of the following structure: 【Chemistry 3】 Here, R ６０ is a substituted alkyl; R ６２ is hydrogen, alkyl or halogen, R ６３ is hydrogen, alkyl or halogen, R ６４ is hydrogen, alkyl or halogen, R ６５ is hydrogen, alkyl or halogen, R ６６ is hydrogen, alkyl or halogen, R ６７ is hydrogen, alkyl or halogen, R ６８ is hydrogen, alkyl or halogen, R ６９ is hydrogen, alkyl or halogen, R ８０ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ８１ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ８２ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ８３ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; R ８４ is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, —NO 2 , —CN, —C(O)H, —CO 2 R, —CO 2 H, halogen, hydroxy, substituted alkenyl, substituted alkyl, or substituted alkynyl; The pharmaceutical composition, wherein R in each of said -CO 2 R is independently alkyl.

12. R ６０ The pharmaceutical composition of claim 11, wherein is N,N-dimethyl-2-phenylacetamide.

13. R ６２ ~R ６９ 13. The pharmaceutical composition of claim 11 or claim 12, wherein is hydrogen.

14. R ８０ ~R ８４ are independently hydrogen or hydroxy, and R ８０ ~R ８４ 14. The pharmaceutical composition of claim 11, wherein at least one of is hydroxy.

15. The pharmaceutical composition of claim 11, wherein the compound is 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2-phenylacetamide.

16. 1. A pharmaceutical composition for inhibiting the formation of TDP-43 oligomers or disrupting TDP-43 oligomers in a subject, said pharmaceutical composition comprising: N-[4-({[2-(3-chlorophenyl)ethyl]amino}methyl)-phenyl]acetamide, (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)({4-[(dimethylamino)methyl]phenyl}methyl)amine, 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2-phenylacetamide, 3-[({[4-(morpholin-4-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile, 4-[({[4-(pyrrolidin-1-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile, 4-{1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl}phenol, 4-[({[3-(pyrrolidin-1-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile, and A compound represented by one of the following chemical structural formulas: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 A pharmaceutical composition comprising a compound selected from the group consisting of:

17. 17. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition results in improved or enhanced activity in a subject with reduced activity.

18. 17. The pharmaceutical composition of any one of claims 1 to 16, administered to a subject diagnosed with ALS.

19. 17. The pharmaceutical composition of any one of claims 1 to 16, administered to a subject at risk of developing ALS.

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