Small molecule drugs for the treatment of diseases associated with Aβ42 oligomerization and related methods

Abstract

To provide small molecule drugs and pharmaceutical compositions for the treatment and prevention of diseases related to the formation of Aβ42 oligomers in a subject.SOLUTION: A compound used for reducing the formation of Aβ42 oligomers or disrupting Aβ42 oligomers has a structure in the figure, where: R60 is substituted alkyl; R62 to R69 are hydrogen; R80 to R84 are hydrogen or hydroxy. Preferably, the compound is 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2 phenylacetamide.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This invention was funded by NSF SBIR Phase I Award #1 143484 under the program "Identifying Drug Leads Via 3 The project was supported by the government and titled "D Pharmacophore Space Analysis."

[0002] The present invention provides a method for treating and preventing diseases associated with the formation of Aβ42 oligomers in a subject. The present invention provides small molecule drugs, as well as pharmaceutical compositions. [Background technology]

[0003] AD is a serious disease characterized by progressive memory loss, behavioral changes, cognitive loss, and neurodegeneration. It is the most common form of dementia, affecting more than 5.4 million people in the United States alone. With the aging of the population, these numbers are expected to increase dramatically unless effective treatments are developed. In fact, if current trends continue, the number of patients in the United States is expected to increase by 2050. The number is estimated to be 16 million, with annual losses exceeding $1 trillion.

[0004] Unfortunately, currently available anti-AD drugs are, at best, of very limited utility. Even more problematic is the lack of discipline in conducting clinical trials of new drugs under development. Two notable examples are the use of “Aβ immunization” strategies for encephalitis. The clinical trial had to be stopped. In the Phase I trial (Bapineuzma), two studies were conducted: one for cognitive function and one for functional function. The primary endpoint was also not clinical benefit. Some argue that the failure was due to the lack of early drug administration (Reiman et al, J. A Ilzheimers Dis., 26 Suppl 3:321-329 (2011)), antibody-based strategies also have poor BBB penetration. The lack of disease-modifying properties (e.g., amyloid beta (Aβ)) has also been a concern. Drug candidates with tau and tau targeting have been investigated, but clinical trials have continued to fail. (Giacobini and Gold, Nature Reviews Neurology (2013)).

[0005] Despite the above failures, the "amyloid hypothesis" remains This is a central and potentially curative perspective for Alzheimer's disease. Genentech, the NIH, and the Banner Alzheimer's Institute recently reported that presenilin mutations Pre-AD clusters are genetically predestined to develop early AD as a result of To evaluate the ability of crenezumab (a humanized monoclonal antibody against Aβ) against the The rationale is that the antibody-mediated The goal is to reduce Aβ levels.

[0006] Another important part of the collective effort to develop effective anti-Alzheimer's drugs A factor is that the research community has focused on the wrong form of Aβ for many years. (Though so far unsuccessful). The Aβ42 fibrils and plaques that doctors have seen under microscopes for nearly 100 years are neurotoxic species. This has been thought to be the reason for many of the failures in clinical trials (small molecules, tramivir, etc.). Rosete, PBT1, PBT2, and ELND005 (scyllo-Inositol), and immunotherapy, Bapineuzu With reference to Figure 1, the focus of these approaches is The state of Aβ fibrils and β sheets is shown on the right. However, currently, the actual toxic substances The primary target of Aβ42 is recognized to be early soluble Aβ42 oligomers (Benilova et al., Nat. Neurosci., 15(3):349- 357 (2012); Busche et al., Nat. Neurosci., 18(12): 1 725-1727 (2015); Dahlgren et al, Journal of Biological Chemistry 277(35):32046-3 2053 (2002); Hayden and Teplow, Alzheimers Res Ther. 5(6):60 (2013)).

[0007] Several advances have been made in characterizing the different oligomeric stages of the Aβ amyloid cascade. and immunologically distinct classes of oligomers, EPR and thioflavin Furthermore, gamma bodies (Perchiacca et al., Proceedings of f the National Academy of Sciences 109(1):84- 89 (2012)) l, Journal of Biological Chemistry 285(9):6071-6079 (2010)) has been developed, This utilizes a novel grafted fragment method to differentially recognize soluble oligomers. While these and other methods are powerful and informative, they do not provide a clearer picture of the distribution of soluble oligomeric states. It is not possible to determine the structure of these states or to identify them. Screening for potential inhibitors (e.g., Meng et al, Biochemistry 49(37): 8127-8 133 (2010)) has been conducted, but the analytical method is indirect and, moreover, Aβ fibril formation (these Although it is now known that the fibers are not proximal toxic agents, It is most commonly used as a sei. Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, the present invention provides a method for disrupting Aβ oligomer formation (especially the dodecamer form of Aβ42) and Therapeutic small molecule agents useful for the treatment of Alzheimer's disease are provided. [Means for solving the problem]

[0009] In one aspect, the present invention provides a method for reducing or disrupting the formation of Aβ42 oligomers in a subject. This method comprises the steps of AC0101, AC0102, AC0103, and AC01 a compound selected from the group consisting of AC0104, AC0105, AC0106 and AC0107 The method includes administering a therapeutically effective amount of a pharmaceutical composition comprising the compound to a subject in need thereof.

[0010] In another embodiment, the Aβ42 oligomer is a dodecamer, hexamer, or higher order oligomer. oligomers, and Aβ42 dodecamers, hexamers, or higher oligomers The formation or amount of is reduced.

[0011] In another aspect, administration of the pharmaceutical composition improves cognitive function in a subject with cognitive impairment. In another embodiment, the subject is a genetically altered individual diagnosed with AD. predisposed to AD, carry the gene for early-onset familial AD, or develop AD There is a risk.

[0012] In another aspect, administration of the pharmaceutical composition improves vision in a subject with macular degeneration or glaucoma. This results in improved power or slowed vision degeneration.

[0013] In another embodiment, the compound is N-[4-({[2-(3-chlorophenyl)ethyl]amino] (2,3-Dihydro-1,4-phenyl)acetamide (A0101); (benzodioxin-6-ylmethyl)({4[(dimethylamino)methyl]phenyl}methyl 2-[4-(4-hydroxyphenyl)piperazine-1-yl]amine (A0102); 3-[({[4-( Morpholin-4-ylmethyl)phenyl]methyl}amino)methyl]benzonitrile (A 0104);4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzyl benzonitrile (AC0105); 4-{1-[(5-methyl-1,2-oxazole-3 -yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl}phenol (A0 106); or 4-[({[3-(pyrrolidin-1-ylmethyl)phenyl]methyl} amino)methyl]benzonitrile.

[0014] In another aspect, the present invention provides a method for reducing or disrupting the formation of Aβ42 oligomers in a subject. The method provides a method for the preparation of the following compounds: 100, 102, 104, 106, 108, 11 0, 112, 114, 116, 118, 122, 124, 126, 128, 130, 13 2, 134, 136, 138, 140, 144, 146, 148, 150, 152, 15 4, 156, 158, 160, 162, 164, 166, 168, 170, 172, 17 4, 176, 178, 180, 182, 184, 186, 188, 190, 192, 19 4, 196, 198, 198, 200, 202, 204, 206, 208, 210, 21 2, 214, 216, 220, 222, 224 (these 9-29) to a subject in need thereof. The method includes administering the compound to a subject. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 illustrates the amyloid hypothesis, including the assembly states and transitions of Aβ42 oligomers. The states are monomer, dimer, tetramer, hexamer, dodecamer, and higher-order structures. The dodecamer is the largest oligomer observed, is metastable, and ultimately seeds protofibril formation. [Figure 2] FIG. 2 shows the mass spectrum of wild-type Aβ42. [Figure 3] Figure 3 shows the arrival time distribution (ADT) of wild-type Aβ42. [Figure 4] Figure 4 shows a typical ADT of the monomeric charge state of wild-type Aβ42. [Figure 5] Figure 5 shows the ADT of wild-type Aβ42 plus 1:10 4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (A0107) (Day 1). [Figure 6] FIG. 6 shows the mass spectrum and ADT of wild-type Aβ42 plus 1:10 4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (A0107) (Day 2, 26 hours and 27 hours). [Figure 7]FIG. 7 shows the ADT of wild-type Aβ42 plus 1:10 4-({[3-(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (A0107) (Day 2, 29 hours and 30 hours). [Figure 8] FIG. 8 shows certain compounds A0101-A0107 of the present invention. [Figure 9] FIG. 9 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 10] FIG. 10 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 11] FIG. 11 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 12] FIG. 12 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 13] FIG. 13 shows certain compounds according to the invention for the treatment of AD or related disorders. [Figure 14] FIG. 14 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 15] FIG. 15 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 16] FIG. 16 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 17] FIG. 17 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 18] FIG. 18 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 19] FIG. 19 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 20] FIG. 20 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 21] FIG. 21 shows certain compounds according to the invention for the treatment of AD or related disorders. [Figure 22]FIG. 22 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 23] FIG. 23 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 24] FIG. 24 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 25] FIG. 25 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 26] FIG. 26 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 27] FIG. 27 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 28] FIG. 28 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 29] FIG. 29 shows certain compounds according to the present invention for the treatment of AD or related disorders. [Figure 30] FIG. 30 shows further compounds according to the invention for the treatment of AD or a related disorder. [Figure 31] FIG. 31 shows further compounds according to the invention for the treatment of AD or a related disorder. [Figure 32] FIG. 32 shows further compounds according to the invention for the treatment of AD or related disorders. [Figure 33] FIG. 33 shows further compounds according to the invention for the treatment of AD or related disorders. [Figure 34] FIG. 34 shows further compounds according to the invention for the treatment of AD or a related disorder. [Figure 35] FIG. 35 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 36] FIG. 36 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 37] FIG. 37 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 38]FIG. 38 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 39] FIG. 39 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 40] FIG. 40 shows a synthetic scheme for preparing certain compounds according to the present invention. [Figure 41] Figure 41. [Figure 42] FIG. 42 shows the mass spectrum and ATD of Benzald-1. [Figure 43] FIG. 43 shows the mass spectrum and ATD of Benzald-1. [Figure 44] FIG. 44 shows the mass spectrum and ATD of fluorophenyl. [Figure 45] FIG. 45 shows the mass spectrum and ATD of fluorophenyl. [Figure 46] FIG. 46 shows the mass spectrum and ATD of aminofluorophenyl. [Figure 47] FIG. 47 shows the mass spectrum and ATD of aminofluorophenyl. [Figure 48] FIG. 48 shows the mass spectrum and ATD of dimethoxy. [Figure 49] FIG. 49 shows the mass spectrum and ATD of dimethoxy. [Figure 50] Figure 50 shows the mass spectrum and ATD of verapamil. [Figure 51] FIG. 51 shows the mass spectrum and ATD of verapamil. [Figure 52] FIG. 52 shows the mass spectrum and ATD of dobutamine. [Figure 53] FIG. 53 shows the mass spectrum and ATD of dobutamine. [Figure 54] FIG. 54 shows the mass spectrum and ATD of cinacalcet. [Figure 55] FIG. 55 shows the mass spectrum and ATD of cinacalcet. [Figure 56] FIG. 56 shows the mass spectrum and ATD of cinacalcet. DETAILED DESCRIPTION OF THE INVENTION

[0016] Alzheimer's disease (AD) is the most commonly diagnosed neurodegenerative disease in people aged 65 and over. However, 4% to 5% of cases are autosomal dominant mutations that often manifest before age 65. It is an early-onset familial form of AD. AD impairs cognitive function and is accompanied by related symptoms. The most common early symptom is short-term memory loss. As the disease progresses, symptoms may include speech impairment, Symptoms include disorientation, mood swings, loss of motivation, difficulty with self-care, and behavioral disorders. As the disease progresses, patients often withdraw from their families and society. The rate of progression varies, but life expectancy after diagnosis is 3 to 9 years.

[0017] Alzheimer's disease can develop early or late. These include family history and genetic or biochemical markers. Genetic markers for this disease include mutations in the APP gene (especially the mutation at position 717). The mutations at positions 670 and 671 were Ha These include the rudy mutation and the Swedish mutation. Risk markers include mutations in the presenilin genes, PS1 and PS2, and ApoE. 4. If you have a family history of Alzheimer's disease, hypercholesterolemia, or atherosclerosis Individuals currently suffering from Alzheimer's disease have the characteristic dementia and the risk factors mentioned above. Furthermore, to identify patients with Alzheimer's disease, Many diagnostic tests are available. These include CSF tau and Aβ1-42 level Individuals with Alzheimer's disease also need to be assessed according to the ADRDA criteria or this It can be diagnosed by the methods disclosed herein.

[0018] In asymptomatic patients, treatment can be initiated at any age (e.g., 10, 20, or 30 years). However, treatment is usually not recommended until patients reach 40, 50, 60, or 70 years of age. There is no need to start. Treatment usually involves multiple doses over a period of time.

[0019] Alzheimer's disease is characterized by the formation of senile plaques. The plaques are composed of amyloid beta (Aβ) and Aβ consists of small peptides about 42 amino acids long called amyloid β. It is a fragment of the amyloid precursor protein (APP). Recent studies have shown that it is involved in the amyloid assembly cascade. Soluble Aβ42 oligomers (especially hexamers and dodecamers) formed at the onset of These results suggest that ATP (higher order states such as oligomers) is a neurotoxic agent in AD. (Bernstein et al., Nature Chemistry l(4):326-331 (2009); Bernstein et al., Journal of the American Chemical Society 127(7):2075-2084 (2005); Cheng, et al, Journal of Biological Chemistry 282(33):23818-2382 (2007); Lesne, et ai, Nature, 440(7082):352-357 (2006)).

[0020] Therefore, the present invention provides a method for treating or preventing Alzheimer's disease in patients with cognitive decline. and / or enhance cognitive function, reducing or disrupting Aβ42 oligomer formation. Concerning child compounds.

[0021] The term "cognitive function" refers to the intellectual processes by which we perceive, understand, and Cognitive functions include perception, recognition, conception, sensation, thinking, reasoning, The present invention also aims to improve cognitive function by reducing cognitive decline. Inhibition, treatment, or prevention are also contemplated.

[0022] Cognitive decline can be caused by many conditions. The term "condition" is used generically and refers to conditions that are at least partially caused by Aβ42 oligomers. In the context of the present invention, a disease refers to any condition mediated by insoluble amyloidogenic compounds. fibrils, senile plaques, neurofibrillary tangles, and / or amyloid beta 1-42 Protein overexpression Examples include Alzheimer's disease, Down's syndrome, mild cognitive impairment, and stroke. These include, but are not limited to, dementia associated with focal ischemia, and neurodegeneration. Eligible patients include those who are currently symptomatic as well as those at risk for disease but who are not yet symptomatic. Therefore, the compounds described herein may be used to reduce any risk to the patient. It can be administered prophylactically to the general population without the need for evaluation.

[0023] The term "cognitive decline" or "cognitive impairment" refers to memory loss, mental decline ( This refers to mental slowing, intellectual decline, and / or amnesia. Memory loss can be immediate or delayed. Mental retardation can be characterized as difficulty or failure to recall previously learned tasks. Difficulty processing or completing tasks quickly or processing new information quickly Intellectual decline refers to the loss of information or information previously possessed or used by an individual. Amnesia is the extreme loss of cognitive abilities that results in partial loss of past experiences. Partial or complete inability to recall, impaired ability to speak or write, or Cognitive decline can be caused by many diseases, detailed below. It is possible.

[0024] Methods for assessing cognitive function include, but are not limited to, standardized Instruments, e.g., Folstein Mini-Mental State Examination Modified Mini-Mental State Examination ination; Middlesex Elderly Assessment of Mental Status Short Portable Mental Status Questionnaire Alzheimer's Disease Assessment Scale e); Clock Drawing Test; Clinical Dementia Rating Scale Neuropsychiatric Inventory, or similarly designed Using the above tests, a skilled clinician can assess the cognitive function of a patient after treatment. Furthermore, the level of cognitive decline or enhancement may be assessed. Although not a medical professional, family members, friends, formal caregivers such as nurses, and those who have previously spoken to the patient Informal observation and interaction with patients (including individuals with in-depth knowledge) also may improve cognitive function. It can be used to evaluate.

[0025] Mechanical measurements of neurons and neuronal tissue to assess cognitive function include: including but not limited to, computed tomography (CT), computerized axial tomography (CAT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), positron emission tomography (PET) PET: Single Photon Emission Computed Tomography (SPECT), Diffuse Light Imaging ( DOI, Diffuse Optical Tomography (DOT), or any similarly designed device The device may be used.

[0026] The term "oligomeric" or "oligomer" refers to a finite number of units. In the context of the present invention, oligomers refer to protein complexes consisting of dimeric subunits. is a trimer, oligomer, hexamer, dodecamer (12-mer), and multimer of Aβ 1-4 It consists of two peptides.

[0027] The term "patient" or "subject" refers to an animal, including mammals, humans, and non-human mammals. In certain embodiments, the patient is an animal, particularly a rat, rabbit, cow, sheep, or broiler. mammalian species, including cat, dog ... In a preferred embodiment, the patient or subject is a human.

[0028] "Treatment" or "treatment of disease" means (1) preventing the disease, i.e., preventing exposure to the disease; may have or be predisposed to the disease but have not yet experienced symptoms of the disease or (2) to prevent the development of clinical symptoms of the disease in patients who do not present with symptoms of the disease; inhibiting, i.e., preventing or reducing the manifestation of a disease or its clinical symptoms; (3 ) alleviating the disease, i.e., reducing the disease or its clinical symptoms; or (4) alleviating the clinical symptoms of the disease.

[0029] In connection with the term "treatment," the term "suffering" or "in need thereof" is used. The term "patient or patient who has been diagnosed with or is predisposed to a disease" refers to a patient or A patient is also an individual who is "at a risk of suffering" from a disease. This patient has not yet developed characteristic disease pathology, but Family history, genetic predisposition to develop a disease, or family history, genetic predisposition, or predisposition It is understood that he has been diagnosed with a disease that causes

[0030] In addition to Alzheimer's disease, other conditions include, but are not limited to, Down's syndrome, stroke Other diseases, including mild to moderate cognitive impairment, macular degeneration, and glaucoma, are associated with Aβ 1-42 Regarding the formation of As with Alzheimer's disease, the mechanisms of these diseases are parallel. As a result, treatment of patients with or at risk of developing these diseases is becoming increasingly difficult. It is believed to be possible.

[0031] For therapeutic use, pharmaceutical compositions containing one or more of the compounds described herein can be administered in the presence of The compound is administered to a patient suspected of or already suffering from AD or a related disorder. The substance is a substance that is capable of detecting the symptoms (biochemical, histological, and / or behavioral) of a disease (including the development of the disease) at least in amounts sufficient to cure the disease (including complications and intermediate pathological phenotypes) In prophylactic applications, the compounds described herein are administered in an amount sufficient to partially prevent or at least partially prevent the development of a disease. Pharmaceutical compositions containing one or more of the compounds described herein may be used to treat AD or a related disorder. Otherwise, the compound is administered to a patient at risk, where the compound eliminates or The therapeutic agent is administered in an amount sufficient to reduce, lessen the severity of, or delay the onset of the disease. This includes biochemical, histological and / or behavioral manifestations of the disease, complications, and the progression of the disease. This includes intermediate pathological phenotypes that appear in

[0032] The "therapeutically effective amount" will depend on the compound, the disease and its severity, and the age, weight, and other characteristics of the patient to be treated. These may vary depending on factors such as the type of treatment, the amount of medication, and other factors, all of which are within the skill of the attending physician. A therapeutically effective amount of one or more of the compounds administered reduces the amount of steroid hormone in the brain of a patient compared to the absence of treatment. It is intended to alter or prevent the accumulation of Aβ oligomers. The impairment of memory formation following administration of the compound is reduced or prevented.

[0033] In some methods, administration of the compound is effective in treating a patient who has not yet developed characteristic Alzheimer's disease. In certain embodiments, the therapeutically effective amount is , one or more of the compounds described herein that are most likely to result in a desired response to treatment. is intended to refer to the amount of compound administered or delivered to a patient.

[0034] Embodiments of the present invention also include pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a salt in which the parent compound is reacted with an existing acid or Derivatives of the disclosed compounds are modified by converting the base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of basic groups such as amines. salts of inorganic or organic acids of groups, alkali or organic salts of acidic groups such as carboxylic acids, etc. Pharmaceutically acceptable salts of the present invention include, for example, salts formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound. They can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base. or an acid in water or an organic solvent or a mixture thereof. The solvent is generally ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Non-aqueous media such as nitrile (ACN) are preferred. A list of suitable salts can be found in "Remington's s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418" ​​and "Journal of Pharmaceutical Science, 66, 2 (1977)" No. 6,239,999, each of which is incorporated herein by reference in its entirety.

[0035] For oral administration, pharmaceutically acceptable formulations include carriers, including but not limited to, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, and For injectable formulations, the carrier may contain a buffer, a preservative, an analgesic, For formulations for topical administration, the carrier may include: It may contain a base, excipient, lubricant, and preservative.

[0036] The disclosed compositions can be formulated into various dosage forms in combination with the aforementioned pharmaceutically acceptable carriers. For example, for oral administration, the pharmaceutical composition may be in the form of tablets, lozenges, capsules, It can be formulated into an elixir, suspension, syrup or wafer. The pharmaceutical compositions may be formulated in single dose form or in multi-dose containers in ampoules. Pharmaceutical compositions can also be formulated into solutions, suspensions, tablets, pills, capsules, and long-acting formulations. It can be done.

[0037] 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, gum arabic, alginate, gelatin , calcium phosphate, calcium phosphate, calcium silicate, cellulose, methylcellulose cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoic acid, proline These include hydroxybenzoic acid, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical formulation may further comprise fillers, anticoagulants, lubricants, humectants, flavorings, and preservatives. It can be seen.

[0038] The effective dose of the composition of the present invention for treating the above-mentioned diseases depends on the means of administration, the physiological condition of the patient, the condition, whether the patient is human or animal, other medications being administered, and whether the treatment is prophylactic or therapeutic The patient is usually a human, but the specific In embodiments, patients are animals, particularly mammals, including dogs, cats, mice, horses, and primates. The animal is selected from the species.

[0039] The compound can be administered multiple times, where the interval between single doses is daily, weekly, monthly, etc. In addition, the patient's blood Aβ 1-42 Protein or oligomer concentration The spacing may also be irregular, as indicated by measuring the degree. One or more of the compounds of the present invention may be administered as a sustained release formulation, in which case the frequency of administration may be adjusted. The dosage and frequency of administration depend on the half-life of the compound of the present invention. In therapeutic applications, the treatment is continued until the progression of the disease is reduced or terminated, and preferably or relatively high doses at relatively short intervals until the patient shows partial or complete improvement in the symptoms of the disease. A dose may be required, after which the patient may be placed on a prophylactic regimen.

[0040] The routes of administration of pharmaceutical compositions of the compounds described herein include oral, topical, pulmonary, rectal, and dermal. injections, including but not limited to subcutaneous, intradermal, intranasal, intracranial, intramuscular, intraocular, or intra-articular injections. This can be done via a variety of routes, the most typical being oral, although other routes are possible as well. It is effective in

[0041] One or more of the compounds described herein may inhibit Aβ 1-42 In the treatment of related diseases Optionally administered in combination with other biological or chemical agents that are at least partially effective. Examples of such agents include, but are not limited to, those described in International Application No. WO2003 / 200409. 53673, WO2006 / 014478, U.S. Patent No. 2,489,195, U.S. Patent No. No. 2007-0048312 and U.S. Patent Application No. 11 / 571,532. Aβ 1-42 Targeting antibodies, which are incorporated herein by reference.

[0042] The compounds described herein are useful for inhibiting and / or modulating Aβ oligomers in patients. A skilled clinician will determine the appropriate amount of the compounds described herein. and effectively inhibit, modulate, and / or inhibit the formation of Aβ oligomers in patients. The contemplated amounts of the compounds described herein are not intended to be limiting. However, for example, about 0.05 to 2000 mg / m 2 / day one compound or two or more compounds Includes compounds.

[0043] As noted above, the compounds described herein can be administered, for example, orally, topically, pulmonary, rectally, subcutaneously, or intradermally. The administration may be by any of the following routes: intravenous, intranasal, intracranial, intramuscular, intraocular, or intra-arterial, but is not limited to these routes. The carrier or excipient or excipient mixture may be, for example, a variety of polar or non-polar solvents, The solvent or dispersion medium may be, but is not limited to, a suitable mixture of As used herein, the term "carrier" or "excipient" refers to a pharmaceutically acceptable carrier or excipient. means any and all solvents, dispersants or media, coatings, antimicrobial agents, isotonic agents / hypotonicity agents / hypertonicity agents, absorption modifiers, etc. For such substances and pharmaceutically active substances The use of these agents is well known in the art. In addition, other or supplementary active ingredients may be added to the final It can be incorporated into the composition.

[0044] Diseases that may be treated by the methods described herein include Alzheimer's disease, Down's syndrome, Symptoms, stroke, mild cognitive impairment, focal ischemia associated with dementia, neurodegeneration, macular degeneration and green Includes internal disorders.

[0045] When employed as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. These compounds are administered orally, topically, pulmonary, rectally, subcutaneously, intradermally, intranasally, intracranially, intramuscularly, and intraocularly. These compounds can be administered by a variety of routes, including intraarticular or intravenous injection. Such compositions are effective as both a single composition and an oral composition. and comprising at least one active compound.

[0046] The present invention also provides a method for treating a rheumatoid arthritis, as described herein, in association with a pharmaceutically acceptable carrier, as an active ingredient. In preparing the compositions of the present invention, the active ingredient is a pharmaceutical composition containing one or more of the compounds. The ingredients are usually mixed with or diluted by excipients or packaged in capsules, sachets, or other containers. The excipients used are typically: In general, it is an excipient suitable for administration to a patient. When an excipient is used as a diluent, It may be a solid, semi-solid, or liquid substance and acts as a vehicle, carrier, or medium for the active ingredient. The composition may therefore be in the form of a tablet, pill, powder, lozenge, sachet, or oak leaf. Salves, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids) or in a liquid medium), for example ointments, softeners and emulsions containing up to 10% by weight of the active compound. It may be in the form of hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0047] When preparing a formulation, the active compound is milled to the appropriate particle size before mixing with other ingredients. When the active compound is substantially insoluble, it is usually necessary to provide Milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble The particle size is typically adjusted, e.g., by milling, to provide a substantially uniform distribution in the formulation. It is adjusted to about 40 mesh.

[0048] Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannose, and the like. Nititol, starch, gum arabic, calcium phosphate, alginate, tragacanth, Gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water , syrup, and methylcellulose. The agent may further contain a lubricant (talc, stearyl alcohol, etc.). Magnesium phosphate, and mineral oil, etc.), wetting agent, emulsifying and suspending agent, preservative (methyl benzoate, The compositions of the present invention may contain sweeteners and flavoring agents (e.g., benzoyl and propyl hydroxybenzoates). The product may be formulated to provide rapid and sustained release of the active ingredient after administration to a patient by methods known in the art. The active ingredient may be formulated to provide sustained or delayed release.

[0049] The administration of therapeutic agents via intravenous formulations is well known in the pharmaceutical industry. Not only should the composition be one in which the therapeutic agent is soluble, but it should also possess certain properties. For example, The formulation should promote the overall stability of the active ingredient(s) and the manufacture of the formulation All of these factors ultimately affect the overall value of intravenous formulations. Determine the overall success and usefulness of the

[0050] Other auxiliary additives that may be included in pharmaceutical formulations of the compounds of the invention are as follows: Solvents: ethanol, glycerol, propylene glycol; Stabilizers: EDTA (ethylenediaminetetraacetic acid), citric acid; Antimicrobial preservatives: benzyl alcohol, methylparaben, propylparaben; Buffers: Citric acid / sodium citrate, potassium bitartrate, sodium bitartrate , acetic acid / sodium acetate, maleic acid / sodium maleate, sodium hydrogen phthalate , phosphoric acid / potassium dihydrogen phosphate, phosphoric acid / disodium hydrogen phosphate; and Tonicity adjusters: sodium chloride, mannitol, dextrose.

[0051] The presence of a buffer solution provides an aqueous pH in the range of about 4 to about 8, more preferably in the range of about 4 to about 6. Buffer systems generally consist of a mixture of a weak acid and its soluble salt, e.g. For example, sodium citrate / citric acid; or mono- or dications of dibasic acids. Salts, e.g., potassium bitartrate; sodium bitartrate; phosphate / potassium dihydrogen phosphate and phosphoric acid / disodium hydrogen phosphate.

[0052] The amount of buffer system used depends on (1) the desired pH and (2) the amount of drug. The amount of buffer used is generally determined by the ratio of the buffer to the drug to maintain a pH in the range of 4-8. The molar ratio of the buffer solution is 0.5:1 to 50:1. It is considered to be the total moles of the acid buffer components, including ammonium and citric acid. A molar ratio of buffer (combined) to drug of 1:1 to 10:1 is used.

[0053] One buffer useful in the present invention is a solution of 100% ethanol sufficient to maintain an aqueous pH of 4-6 of the composition. , 5-50 mg per ml of sodium citrate and 1-15 mg per ml of citric acid mL range of sodium citrate / citric acid.

[0054] Buffers also contain dissolved metal ions (e.g., Ca, Mg, Fe, Al, Ba, soluble metals (which may leach from glass containers or rubber stoppers or be present in ordinary tap water) A buffer may be present to prevent precipitation of the drug by forming a complex. Acts as a competitive complexing agent, resulting in soluble metal complexes and eliminating the presence of undesirable particulates It can be achieved.

[0055] Furthermore, to adjust the tonicity to the same value as human blood, a drug in an amount of about 1 to 8 mg / ml, e.g. For example, the presence of sodium chloride may contribute to swelling or shrinkage of red blood cells (as occurs with intravenous administration). more unwanted side effects such as nausea or diarrhea, and possibly related blood disorders. Generally, the tonicity of the formulation should be consistent with that of human blood. The range is 282 to 288 mOsm / kg, and is generally 285 mOsm / kg. This is equivalent to the osmotic pressure of a 0.9% solution of sodium chloride.

[0056] Intravenous formulations can be administered by direct intravenous injection, intravenous bolus, or should be added to an appropriate infusion fluid such as 0.9% sodium chloride injection or other compatible infusion fluid. It can be administered by injection.

[0057] The composition can be formulated in an oral unit dosage form. The term "unit dosage form" means physically discrete units suitable as dosages for a patient, each unit containing an appropriate medical Contains a predetermined amount of active substance, together with pharmaceutical excipients, calculated to produce a desired therapeutic effect .

[0058] The total effective amount of the compositions disclosed herein may be administered to a patient in a single dose, and The compound may also be administered over time in multiple doses according to a divided treatment protocol. In the pharmaceutical compositions disclosed in the specification, the content of the active ingredient varies depending on the severity of the disease. Preferably, the total daily dose of the compounds disclosed herein is about 1 / 2 of the patient's body weight. However, the effective amount of the compound is about 0.0001 to 500 mg per kg. The age, weight, health condition, sex, disease of the patient, as well as the route of administration of the pharmaceutical composition and frequency of treatment. This is determined by taking into account various factors, including the severity of the condition, diet, and secretion rate. Those skilled in the art will readily be able to determine an effective dosage appropriate for a particular use of the pharmaceutical compositions disclosed herein. The pharmaceutical composition disclosed herein can be used in a variety of ways, as long as it shows appropriate effects. The formulation, route of administration, and mode of administration are not particularly limited. Alone, in combination with, or simultaneously with other pharmaceutical preparations that exhibit prophylactic or therapeutic efficacy It can also be administered.

[0059] In one embodiment, the dose of the composition is administered daily, semi-weekly, weekly, biweekly, or monthly. The duration of treatment can be 1 week, 2 weeks, 1 month, 2 months, 4 months, 6 months, 8 months, The initial dose may be greater than the sustained dose. In embodiments, the weekly dose is at least 0.10 mg, at least 0.50 mg, at least At least 1.0 mg, at least 5.0 mg, at least 10.0 mg, at least 50.0 mg mg, at least 100.0 mg, at least 500.0 mg, at least 1.0 g, small In one embodiment, the weekly dose is at least 5.0 g, or at least 10.0 g. are up to 0.5 mg, up to 2.5 mg, up to 5.0 mg, up to 25.0 mg, and up to 50. 0mg, maximum 250.0mg, maximum 500.0mg, maximum 2.50g, maximum 5.0g, maximum In certain embodiments, the weekly dose may be 1.0 mg to 50.0g, 10.0mg to 25.0g, or 100mg to 5.0g obtain.

[0060] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients and the composition of the present invention is Solid preformulation compositions containing a homogeneous mixture of the compounds are formed. A pharmaceutical composition is homogeneous when it is formulated into equally effective units such as tablets, pills, and capsules. the active ingredient is dispersed evenly throughout the composition so as to be readily subdivided into dosage forms; This solid preformulation is then added to a pharmaceutical composition containing, for example, 0.05 to about 2000 mg of active ingredient. It may be subdivided into unit dosage forms of the type described above containing the ingredient.

[0061] Tablets or pills may be coated or otherwise compounded to provide the advantage of prolonged action. For example, a tablet or pill can be provided that contains an inner dosage component. and an outer dosage component, the latter being in the form of a shell that covers the former. It is resistant to disintegration in the stomach and allows the inner components to pass directly into the duodenum or be released slowly. The drug may be separated by an enteric layer which serves to allow the drug to be Various materials can be used for the coating, including some Polymeric acids and polymeric acids with shellac, cetyl alcohol, and cellulose acetate This includes mixtures with other materials.

[0062] Liquid forms that can incorporate the novel composition of the present invention for oral or injectable administration include , appropriately flavored aqueous solutions of syrups, aqueous or oily suspensions, and flavored emulsions having edible oils (such as cottonseed oil , sesame oil, coconut oil, or peanut oil, etc.), as well as elixirs agents, and similar pharmaceutical vehicles.

[0063] 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 composition is administered by the oral or nasal respiratory route for local or systemic effects. Preferably, the composition in a pharmaceutically acceptable solvent can be nebulized by using an inert gas. The nebulized solution can be breathed directly from the nebulizer device, or the nebulizer device can be attached to a face mask, tent , or an intermittent positive pressure breathing device. Solution, suspension, or powder compositions can be preferably administered orally or nasally from a device that delivers the formulation in a suitable manner .

[0064] <Compound for the treatment of AD or related diseases> "Acyl" refers to a ketone substituent, C(O)R. Here, R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein .

[0065] "Alkenyl" refers to an unsaturated "alkyl" group containing a double bond.

[0066] "Alkoxy" refers to an -OR group (where R is alkyl) or a substituted analog thereof . Suitable alkoxy groups include, for example, methoxy, ethoxy, t-butoxy, etc. It can be obtained.

[0067] "Alkyl" means a branched or unbranched, saturated or unsaturated, monovalent or divalent hydrocarbon radical. and generally about 1 to 30 carbons, preferably 4 to 20 carbons, more preferably It refers to those with 6 to 18 carbon atoms. If the alkyl group has 1 to 6 carbon atoms, , referred to as "lower alkyl." Branched structures include i-propyl, t-butyl, i-butyl, As used herein, the term "branching motif" refers to a branching motif similar to 2-ethylpropyl. The term encompasses "substituted alkyl" and "cyclic alkyl." (C1-C8) alkyl , refers to alkyl having 1 to 8 carbon atoms.

[0068] "Alkynyl" refers to an unsaturated "alkyl" group containing a triple bond.

[0069] "Amino" refers to -NRR', where R and R' are independently H, alkyl, , aryl, or substituted analogs thereof. "Amino" refers to secondary and tertiary amines. and "acylamino" which refers to the group RC(O)NR'.

[0070] "Aryl" refers to an aromatic substituent, which may be a single aromatic ring. fused together, covalently bonded or diazo, methylene or ethylene moieties The aromatic rings may be linked to a common group such as benzophenone. The aromatic ring may be a carbonyl such as that contained in phenone. The term "aromatic" may include phenyl, biphenyl, diphenylmethyl, and benzophenone. "Aryl" encompasses "arylalkyl" and "substituted aryl."

[0071] "Arylalkyl" refers to an alkyl group in which the aryl group is substituted by an alkyl group as defined herein. refers to the subset of "aryl" attached to the group

[0072] "Aryloxy" refers to an aromatic group directly bonded to another group through an oxygen atom. The term refers to "substituted aryl" in which an aromatic group is substituted, as described above for "substituted aryl." Exemplary aryloxy moieties include phenoxy, substituted phenoxy, Examples include phenoxy, benzyloxy, phenethyloxy, and the like.

[0073] "Aryloxyalkyl" refers to an alkyl group, as defined herein, joined via an oxygen atom. The term "aryloxyalkyl" refers to an aromatic group bonded to a substituted aryl "substituted aryloxyalkyl" in which the aromatic group is substituted as described for "aryloxyalkyl"; Includes parts.

[0074] An "electron-withdrawing group" is a group that attracts electron density from neighboring atoms by resonance or inductive effects. This refers to an atom or group containing -NO2, -CN, -C(O)H, -C(O)R (where where "R" is an alkyl group), -COR (where "R" is an alkyl group), and This includes groups such as CO2H.

[0075] "Halogen" refers to fluorine, bromine, chlorine and iodine atoms.

[0076] "Heteroaryl" means an aromatic ring in which one or more carbon atoms is substituted with an alkyl group, such as nitrogen, oxygen, or sulfur. "Heteroaryl" refers to an aromatic ring substituted with a heteroatom. A structure that may be one or more aromatic rings or one or more aromatic rings bonded to one or more non-aromatic rings In structures having multiple rings, the rings may be fused together or covalently linked. or may be bonded to a common group such as a diazo, methylene or ethylene moiety. The group may also be a carbonyl, as in phenylpyridyl ketone. When used, thiophene, pyridine, isoxazole, phthalimide, pyrazole Rings such as , indole, furan, etc., or benzo-fused analogs of these rings are included in the term "heterocyclic rings." Aryl is defined as

[0077] "Heteroarylalkyl" means an alkyl group, as defined herein, in which the alkyl group is a heteroaryl Refers to a subset of "heteroaryl" that links a group to another group.

[0078] "Heterocyclic" means a heterocyclic ring selected from 1 to 12 carbon atoms and nitrogen, sulfur, or oxygen in the ring. monovalent saturated or unsaturated heterocyclic rings having one or more condensed rings consisting of 1 to 4 heteroatoms It refers to an aromatic group. Examples of such heterocyclic rings include tetrahydrofuran, morpholine, and the like. , piperidine, pyrrolidine, etc.

[0079] "Heterocyclic alkyl" refers to an alkyl group, as defined herein, that converts a heterocyclic group into another group. "Heterocyclic" refers to a subset of "heterocyclic."

[0080] "Hydroxy" refers to the group --OH.

[0081] "Mercapto" refers to a moiety of the general structure -SR, where R is as defined herein. is H, alkyl, aryl or heterocyclic.

[0082] "Saturated cyclic hydrocarbons" include cyclopropyl, cyclobutyl, cyclopentyl, etc. These cyclic hydrocarbons may be monocyclic or polycyclic. It may be a ring structure.

[0083] "Substituted alkenyl" refers to an "alkenyl" containing one or more substituents. Examples of groups include lower alkyl, aryl, acyl, halogen (e.g., alkylhalides), and the like. b), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamide, Acyloxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, o These groups include alkyl, aryl, saturated and unsaturated cyclic hydrocarbons, heterocyclic compounds, etc. They may be attached to any carbon or substituent of the alkenyl moiety. It may be pendent from or integral to the alkenyl chain.

[0084] "Substituted alkyl" refers to an "alkyl" that contains one or more substituents. Examples include lower alkyl, aryl, acyl, halogen (e.g., alkylhalo), hydroxyl, and the like. Hydroxy, amino, alkoxy, alkylamino, acylamino, thioamide, acylamino oxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo, saturated These groups include saturated and unsaturated cyclic hydrocarbons, heterocyclic compounds, etc. These groups may be attached to any carbon atom or substituent of the alkyl group. It may be attached to an alkyl chain or may be attached to an alkyl chain.

[0085] "Substituted alkynyl" refers to an "alkynyl" containing one or more substituents. Examples of groups include lower alkyl, aryl, acyl, halogen (e.g., alkylhalo), , hydroxy, amino, alkoxy, alkylamino, acylamino, thioamide, acyl Roxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo , saturated and unsaturated cyclic hydrocarbons, heterocyclic compounds, etc. These groups are These groups may be attached to any carbon or substituent of the alkynyl moiety. It may be pendent or integral to the alkynyl chain.

[0086] "Substituted aryl" refers to an "aryl" that contains one or more functional groups. Examples include lower alkyl, acyl, halogen, alkylhalo (e.g., CF3), hydroxyl, and the like. hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, phenoxy hydroxy, mercapto, and covalently bonded or fused to an aromatic ring, diazo, methyl of saturated and unsaturated cyclic hydrocarbons linked to a common group such as ethylene or ethylene moieties The linking group may be a carbonyl group such as cyclohexyl phenyl ketone. The term "substituted aryl" includes "substituted arylalkyl." .

[0087] "Substituted arylalkyl" means a substituted aryl group with an alkyl group as defined herein. "Substituted aryl" refers to the subset of "substituted aryl" that is attached to another group via an alkyl group.

[0088] "Substituted heteroaryl" refers to a heteroaryl group in which the heteroaryl nucleus is substituted with one or more functional groups. The functional group includes, for example, lower alkyl, acyl, halo, gen, alkylhalo (e.g., CF3), hydroxy, amino, alkoxy, alkyla amino, acylamino, acyloxy, mercapto, etc. amines, pyridines, isoxazoles, phthalimides, pyrazoles, indoles, and furans. Substituted analogs of such heteroaromatic rings or benzo-fused analogs of these rings are included within the term "substituted heteroaromatic rings." It is defined by the "reel".

[0089] "Substituted heteroarylalkyl" refers to an alkyl group, as defined herein, that is heteroaryl. "Substituted heteroaryl" refers to a subset of "substituted heteroaryl" in which the heteroaryl group is linked to another group.

[0090] "Substituted heterocyclic" refers to a heterocyclic ring in which the heterocyclic nucleus is substituted with one or more functional groups. " The functional group includes, for example, lower alkyl, acyl, halogen, alkylhalo ( For example, CF3), hydroxy, amino, alkoxy, alkylamino, acylamino, Examples include acyloxy and mercapto.

[0091] "Unsaturated cyclic hydrocarbon" means a hydrocarbon having at least one cyclic group, such as cyclopentene and cyclohexene. These cyclic carbon atoms are referred to as monovalent non-aromatic groups with two double bonds and their substituted analogues. The hydrogen hydride may be a single ring structure or a multi-ring structure.

[0092] Figures 9-29 show specific compounds according to the present invention for the treatment of AD or related disorders. Where thiones are shown (e.g., compounds 102 and 106), negatively charged pharmaceutical Acceptable counterions (eg, AcO-) are suggested.

[0093] Referring to FIG. 9, the substituents R1, R3-R6, R 20 -R 29 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0094] Referring to FIG. 9, the substituents R1-R6, R 20 -R 29 is independent and hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl , arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen , heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy , mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, Substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl , substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., all the same). may be the same or different).

[0095] Referring to FIG. 9, the substituents R3-R6, R 20 -R 29 is independent and hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl , arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing group, halogen , heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy , mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, Substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl , substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., all the same). may be the same or different).

[0096] Referring to FIG. 10, the substituents R3-R6, R 20 , R 22 , R 24 , R 25 -R 29 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0097] Referring to FIG. 10, the substituents R3-R6, R 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0098] Referring to FIG. 10, the substituents R3-R6, R 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0099] Referring to FIG. 11, the substituent R in compound 112 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0100] Referring to FIG. 11, the substituent R in compound 114 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0101] Referring to FIG. 11, the substituent R in compound 116 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0102] Referring to FIG. 12, the substituent R in compound 118 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0103] Referring to FIG. 12, the substituents R1, R3-R8, R 20 -R 29 teeth , independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., They may all be the same or different).

[0104] Referring to FIG. 12, the substituents R1-R8, R 20 -R 29 is independent The groups include hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, and aryl. Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogen heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy thio, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, Substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl cyclic, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., all may be the same or different).

[0105] Referring to FIG. 13, the substituents R3-R8, R 20 , R 22 , R 24 , R 25 -R 29 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0106] Referring to FIG. 13, the substituents R3-R8, R 20 , R 22 , R 24 , R 25 -R 29 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0107] Referring to FIG. 13, the substituents R3-R8, R 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, aryl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyal alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkenyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, Selected from the group consisting of substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. are selected (e.g., they may all be the same or different).

[0108] Referring to FIG. 14, the substituent R in compound 130 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0109] Referring to FIG. 14, the substituent R in compound 132 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0110] Referring to FIG. 14, the substituent R in compound 134 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0111] Referring to FIG. 15, the substituent R in compound 136 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0112] Referring to FIG. 15, the substituents R, R-R in compound 138 10, R 20 -R 29 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino , aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups , halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, Hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl Quinyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., , may all be the same or different).

[0113] Referring to FIG. 15, the substituents R1-R2 in compound 140 10 , R 20 -R 29 is German In particular, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl alkyl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro Oxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl , substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl aryl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., may be the same or different).

[0114] Referring to FIG. 16, the substituents R3-R in compound 142 10 , R 20 -R 29 is German In particular, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl alkyl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro Oxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl , substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl aryl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., may be the same or different).

[0115] Referring to FIG. 16, the substituents R3-R in compound 144 10 , R 20 -R 29 is German In particular, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl alkyl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro Oxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl , substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl aryl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., may be the same or different).

[0116] Referring to FIG. 16, the substituents R3-R in compound 146 10 , R 20 , R 22 , R2 4. R 25 -R 29 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxya alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, Heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted Alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl , substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; are selected (e.g., may all be the same or may be different).

[0117] Referring to FIG. 17, the substituents R3-R in compound 148 10 , R 20 , R 22 , R2 4. R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, Alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxya alkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, Heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted Alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl , substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; are selected (e.g., may all be the same or may be different).

[0118] Referring to FIG. 17, the substituent R in compound 150 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0119] Referring to FIG. 17, the substituent R in compound 152 20 , R 22 , R 24 , R 26 -R 28 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0120] Referring to FIG. 18, the substituent R in compound 154 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0121] Referring to FIG. 18, the substituent R in compound 156 22 , R 26 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0122] Referring to FIG. 18, the substituent R in compound 158 40 , R 42 -R 48 , R 50 -R 54 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0123] Referring to FIG. 19, the substituent R in compound 160 40 -R 48 , R 50 -R 54 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0124] Referring to FIG. 19, the substituent R in compound 162 40 , R 44 -R 46 , R 50 -R 54 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0125] Referring to FIG. 19, the substituent R in compound 164 40 , R 41 , R 44 -R 46 , R 50 -R 54 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkyl Nyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl , electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocycle Formula alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl aryl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted Heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. (e.g., they may all be the same or different).

[0126] Referring to Figure 20, the substituent R in compound 166 40 , R 44 , R 50 -R 54 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0127] Referring to Figure 20, the substituent R in compound 168 40 , R 41 , R 44 , R 50 -R 54 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0128] Referring to FIG. 20, the substituent R in compound 170 40 , R 50 -R 54 is independently , hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl alkyl, aryloxy, aryloxy alkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, Mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., all the same may be the same or different).

[0129] Referring to FIG. 21, the substituent R in compound 172 40 , R 41 , R 50 -R 54 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0130] Referring to Figure 21, the substituent R in compound 174 40 , R 51 -R 53 is independently , hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl alkyl, aryloxy, aryloxy alkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, Mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., all the same may be the same or different).

[0131] Referring to Figure 21, the substituent R in compound 176 40 , R 41 , R 51 -R 53 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0132] Referring to Figure 22, the substituent R in compound 178 40 , R 52 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0133] Referring to FIG. 22, the substituent R in compound 180 40 , R 41 , R 52 is independently , hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl alkyl, aryloxy, aryloxy alkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, Mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., all the same may be the same or different).

[0134] Referring to FIG. 22, the substituent R in compound 182 60 , R 62 -R 69 , R 80 -R 84 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa aryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., For example, they may all be the same or different).

[0135] Referring to Figure 23, the substituent R in compound 184 60 , R 61 , R 62 -R 69 , R 80 -R 84 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkyl Nyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl , electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocycle Formula alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl aryl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted Heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. (e.g., they may all be the same or different).

[0136] Referring to Figure 23, the substituent R in compound 186 60 , R 64 -R 67 , R 80 -R 84 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0137] Referring to Figure 23, the substituent R in compound 188 60 , R 61 , R 64 -R 67 , R 80 -R 84 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkyl Nyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl , electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocycle Formula alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl aryl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted Heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. (e.g., they may all be the same or different).

[0138] Referring to Figure 24, the substituent R in compound 190 60 , R 81 -R 83 is independently , hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl alkyl, aryloxy, aryloxy alkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, Mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., all the same may be the same or different).

[0139] Referring to Figure 24, the substituent R in compound 19260 , R 61 , R 81 -R 83 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., (They may all be the same or different).

[0140] Referring to Figure 24, the substituent R in compound 194 60 , R 82 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0141] Referring to Figure 25, the substituent R in compound 196 60 , R 61 , R 82 is independently , hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl alkyl, aryloxy, aryloxy alkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, Mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbons (e.g., all the same may be the same or different).

[0142] Referring to Figure 25, the substituent R in compound 198 60 are independently hydrogen, acyl, Alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl , aryloxy, aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, Heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto, saturated Cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls, substituted a arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or are selected from the group consisting of unsaturated cyclic hydrocarbons (e.g., may all be the same, or may be different).

[0143] Referring to FIG. 25, the substituent R in compound 200 60 , R 61 are independently hydrogen, Acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryl Alkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halogens, heteroaromatic groups Aryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto saturated cyclic hydrocarbons, substituted alkenyls, substituted alkyls, substituted alkynyls, substituted aryls , substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted hetero cyclic, or unsaturated cyclic hydrocarbons (e.g., all the same) may be the same or different).

[0144] Referring to FIG. 26, the substituent R in compound 202 91 , R 93 -R 96 , R 100 - R 108 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl , amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, Electron-withdrawing groups, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, Substituted alkynyl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted hetero arylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., they may all be the same or different).

[0145] Referring to Figure 26, the substituent R in compound 204 91 -R 96 , R 100 -R 108 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino , aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups , halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, Hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl Quinyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., , may all be the same or different).

[0146] Referring to Figure 26, the substituent R in compound 206 111 , R 113 -R 116 , R1 20 -R 127 , R 129 are independently hydrogen, acyl, alkenyl, alkoxy, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxy oxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, hetero Cyclic, heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl , substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl aryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon selected from a group (eg, which may all be the same or different).

[0147] Referring to Figure 27, the substituent R in compound 208 111 -R 116 , R 120 -R1 27 , R 129 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkoxy, quinyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl Heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkynyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; (e.g., they may all be the same or different).

[0148] Referring to FIG. 27, the substituent R in compound 210 131 , R 133 -R 136 , R1 40 -R 146 , R 148 , R 149 are independently hydrogen, acyl, alkenyl, alkoxy, oxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, Aryloxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkanoic acid alkyl, heterocyclic, heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted Alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon are selected from the group consisting of (e.g., may all be the same or may be different) ).

[0149] Referring to Figure 27, the substituent R in compound 212 131 -R 136 , R 140 -R1 46 , R 148 , R 149 are independently hydrogen, acyl, alkenyl, alkoxy, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxy oxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, hetero Cyclic, heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl , substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl aryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon selected from a group (eg, which may all be the same or different).

[0150] Referring to Figure 28, the substituent R in compound 214 151 , R 153 -R 156 , R1 63 -R 167 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkoxy, quinyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl Heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkynyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; X may be O, S, or is NR, where R is hydrogen or alkyl.

[0151] Referring to Figure 28, the substituent R in compound 216 151 -R 156 , R 163 -R1 67 teeth, Independently, hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, halo halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydro alkoxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl aryl, substituted aryl, substituted aryl alkyl, substituted heteroaryl, substituted heteroaryl alkyl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon (e.g., X is O, S, or NR, and R is hydrogen or alkyl.

[0152] Referring to Figure 28, the substituent R in compound 218 171 , R 173 -R 176 , R1 80 -R 186 , R 188 are independently hydrogen, acyl, alkenyl, alkoxy, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxy oxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, hetero Cyclic, heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl , substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl aryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon X is selected from the group (e.g., all the same or different). O, S, or NR, where R is hydrogen or alkyl.

[0153] Referring to Figure 29, the substituent R in compound 220 171 -R 176 , R 180 -R1 86 , R 188 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkoxy, quinyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl Heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkynyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; X may be O, S, or is NR, where R is hydrogen or alkyl.

[0154] Referring to Figure 29, the substituent R in compound 222 191 , R 193 -R 196 , R2 00 -R 206 , R 209 are independently hydrogen, acyl, alkenyl, alkoxy, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxy oxyalkyl, electron-withdrawing group, halogen, heteroaryl, heteroarylalkyl, hetero Cyclic, heterocyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl , substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl aryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon selected from a group (eg, which may all be the same or different).

[0155] Referring to Figure 29, the substituent R in compound 224191 -R 196 , R 200 -R2 06 , R 209 are independently hydrogen, acyl, alkenyl, alkoxy, alkyl, alkoxy, quinyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl Heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Cyclic alkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkynyl alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; (e.g., they may all be the same or different).

[0156] Other non-limiting examples of compounds according to the present invention for the treatment of AD or related disorders include , N-[4-({[2-(3-chlorophenyl)ethyl]amino}methyl)phenyl]a Cetoamide (A0101); (2,3-dihydro-1,4-benzodioxin-6-yl Methyl)({4[(dimethylamino)methyl]phenyl}methyl)amine (A0102) 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl- 2-Phenylacetamide (A0103); 3-[({[4-(morpholin-4-ylmethyl 4-({[3 -(1-pyrrolidinylmethyl)benzyl]amino}methyl)benzonitrile (AC010 5);4-{1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1,2 ,3,6-tetrahydropyridin-4-yl}phenol (A0106); or 4-[( {[3-(pyrrolidin-1-ylmethyl)phenyl]methyl}amino)methyl]benzodi Trill, it could be.

[0157] Specific Embodiments A compound having the following structure: [ka]

[0158] where R 40 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa arylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 42 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 43 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 44 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 45 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 46 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 47 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 48 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 50 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 51 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 52 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 53 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 54 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl It may be an alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon.

[0159] R 40 The above compound wherein is hydrogen, alkyl, or acyl. R 42 , R 43 , R 47 and R 48 are independently hydrogen or alkyl. R 44 ~R 46 The above compound wherein is hydrogen or alkyl. R 50 ~R 54 The above compound wherein is hydrogen, alkyl or halogen.

[0160] A compound having the following structure: [ka]

[0161] where R 60 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, aryl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-loving heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl aryl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted Alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroa arylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 62 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 63 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 64 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 65 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 66 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 67 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 68 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 69 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 80 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 81represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 82 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 83 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; and R 84 represents hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, Aryl, arylalkyl, aryloxy, aryloxyalkyl, electron-withdrawing groups, Halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, hydroxy hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkyl Nyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroaryl It may be an alkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon.

[0162] R 60 The above compound wherein is hydrogen, alkyl or acyl. R 62 , R 63 , R 68 , and R 69 are independently hydrogen or alkyl. R 64 , R 65 , R 66 , and R 67 are independently hydrogen or alkyl. R 80 ~R 84 are independently hydrogen, alkyl or halogen.

[0163] A method for reducing or disrupting the formation of Aβ42 oligomers in a subject, comprising administering to a subject a therapeutically effective amount of 100, 10 2, 104, 106, 108, 110, 112, 114, 116, 118, 120, 12 2, 124, 126, 128, 130, 132, 134, 136, 138, 140, 14 2, 144, 146, 148, 150, 152, 154, 156, 158, 160, 16 2, 164, 166, 168, 170, 172, 174, 176, 178, 180, 18 2, 184, 186, 188, 190, 192, 194, 196, 198, 200, 20 2, 204, 206, 208, 210, 212, 214, 216, 218, 220, 22 2, 224, Benzaldo 1, Fluorophenyl, Aminofluorophenyl, and Dimethicone A therapeutically effective amount of a pharmaceutical composition containing a compound selected from the group consisting of A method comprising the step of administering to a subject.

[0164] 1. A method of improving cognitive function in a subject with cognitive decline, comprising: AC010l, AC0102, AC0103, AC0104, AC0105, AC01 06, AC0107, Benzaldo 1, fluorophenyl, aminofluorophenyl, and a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of dimethoxy The method comprises administering to a subject in need thereof.

[0165] 1. A method of treating macular degeneration in a subject, comprising administering to a subject a compound selected from the group consisting of AC0101, AC0102, AC0103, AC0104, AC0105, AC0106, AC0107, AC0108, AC0109, AC01010, AC01011, AC0102, AC0103, AC0104, AC0105, AC0106, 3, AC0104, AC0105, AC0106, AC0107, Benzald 1, Fluo a compound selected from the group consisting of fluorophenyl, aminofluorophenyl, and dimethoxy Administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

[0166] A method for treating glaucoma in a subject, comprising administering to a subject a compound selected from the group consisting of AC0101, AC0102, AC0103 , AC0104, AC0105, AC0106, AC0107, Benzaldo 1, Fluoro a compound selected from the group consisting of phenyl, aminofluorophenyl, and dimethoxy The method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: [Example]

[0167] example Specific Compounds of the Invention [Table 1]

[0168] <Membrane transport assay> Seven drug candidates (A0101-A0107) (Figure 2) have been shown to induce primary rodent neurotransmission in vitro. Primary cells that can measure changes in membrane trafficking induced by Aβ oligomers in cell culture By primary cell biological screening assay It was tested over a 21-day period (see Izzo et al., PLoS ONE 9(11):e111899, 2014). Briefly, cultures were incubated with oligomeric Aβ, or oligomeric Aβ spiked with a candidate compound, The cells were treated with either Aβ or β-glucan for 24 hours. Cells not treated with Aβ served as a control.

[0169] Next, a membrane-impermeant dye (MTT) is added to the dish for 1 hour, during which time the dye is absorbed into the endosome. After 1 hour, the dye-containing medium was removed and the cells were The cells were then thoroughly rinsed with an isotonic buffer solution. Finally, the washed cells were washed with Triton-10 The membranes were extracted with 0 buffer to solubilize and release the dye, which was quantified. Gomer dose-dependently reduced the amount of intracellular vesicles containing reduced amounts of purple MTT. The EC50 was 400 nMA (assuming 50% of it was oligomeric).

[0170] [Table 2]

[0171] All seven compounds inhibited the deleterious effects of Aβ in this assay (Table 1). . Importantly, previous studies have demonstrated EC50 values ​​of up to 3-4 μM in this membrane transport assay. The compound also inhibited Aβ effects in mouse behavioral assays (Cheng et al., Journal of Biological Chemistry, 282(33):23818-23828, 2007).

[0172] <Permeability assay> Next, the AB and BA permeability tests (pH 7.4) of Caco-2 were performed. This assay was performed on 07 molecules to evaluate human intestinal permeability and drug efflux. In vivo transport rates of compounds across the colon carcinoma-derived Caco-2 cell line The cells form a polarized monolayer with clearly defined apical surfaces and cell-cell junctions. They have characteristics similar to intestinal epithelial cells, such as forming a well-defined brush border. Assess transport in the apical-to-basolateral (AB) and basolateral-to-apical (BA) directions This allows us to obtain an efflux ratio, which is an indicator of whether a compound undergoes active efflux. The results of this evaluation are shown in columns 2 and 3 of Table 2. The permeability of three reference compounds is shown at the bottom of the table. Of these, propranolol High fluid-brain barrier (BBB) ​​permeability.

[0173] [Table 3]

[0174] Toxicity assay Finally, for compound A0101-107, we performed a randomized controlled trial of the human Ether-a-go-go Related Gene (hE Cardiotoxicity testing was performed in a RG) cell assay. Contract laboratories were used to evaluate the cardiac safety of Provided a screening of ERG ion channel cell lines. Drug candidates are expressed in mammalian hearts and should not block the hERG channel, which is essential for the repolarization and relaxation of all myocardial cells during every heartbeat. Potassium efflux occurs when the channel opens and the membrane potential of myocardial cells is higher than the equilibrium potential of potassium. The prolongation of the QT interval measured by electrocardiogram indicates a side effect of drugs that may cause lethal ventricular arrhythmia. The "patch-clamp" assay of cells provides data required by the guidelines of the International Conference on Harmonization of Pharmaceutical Regulations. The results of this assay are shown in the fourth column (hERG toxicity) of Table 2. Six of the compounds show weak or no inhibition, while AC0101 shows moderate potency. All seven compounds assayed have low molecular weights (300 - 380 amu), are chemically stable, and are formulated as HCl salts containing monoamines or diamines, and thus are "related to alkaloids". Here, the IMS-MS method used to evaluate drug candidate A0107 is described. Aβ42 and a physiologically relevant solution of the drug candidate are incubated for various times, then loaded into a special spray capillary, and the solution is nanoelectrosprayed, captured in an ion funnel, transported, dehydrated, continuously supplied to a quadrupole mass spectrometer, and detected. A mass spectrum is obtained by this process. To obtain either structural information or oligomer information, the ions are then stored at the end of the funnel and then filled with helium gas

[0175] <Aβ42 Selective Inhibitor Activity IMS-MS Assay> ​​​​​​​​​​​​​​​A low-energy pulse is injected into the drift cell, which is then exposed to a low electric field, causing ions to flow through the cell. The quadrupole is set to pass a specific mass-to-charge ratio (m=z), and this m= The arrival time distribution (ATD) of ions at z is obtained from the detector (e.g., Bernstein et al. , Journal of the American Chemical Society, 127(7):2075-2084, 2005). The molecule was at a concentration of 10 μM in 10 mM ammonium acetate.

[0176] Figure 3 shows two peaks (z / n = -4, -3) corresponding to the monomer and two peaks corresponding to the dimer and higher-order A peak representative of wild-type Aβ42 (z / n=-5 / 2) corresponds to an oligomer. Typical mass spectra are shown. Arrival time distributions (ATDs) for each of these charge states were collected. This allows ions of the same mass-to-charge ratio (m / z) to be separated by their size and shape. I was separated.

[0177] Figure 4 shows the arrival time distribution (ADT) of wild-type Aβ42. The plot shows the distribution of Aβ42wt. A typical ATD for the charge state z / n=-5 / 2 is shown. The kinetic and experimental parameters are When used, the arrival time is related to the mobility of the ions within the drift cell, which is related to the collision time of the ions. In the charge state z / n=-5 / 2, the dimer (n=2) is converted to a dode Oligomerization up to 1000 kcal (n=12) is shown.

[0178] Figure 5 shows that the earlier arrival time is associated with higher order oligomers or the same oligomers in wild-type Aβ42. We show that it corresponds to one of the more compact structures of the Gomer order. For example, 98Å 2The peak at z / n = -3ATD with a collision cross section of This corresponds to the solution-phase monomer structure. 2 The peak in the figure corresponds to a more compact gas phase structure. handle.

[0179] Figure 6 shows that the formation of wild-type Aβ42 dodecamer occurs after 1 h of Aβ42wt to A0107 compound. :10 is inhibited by the introduction of 10 (day 1).

[0180] Figure 7 shows that the cross section on day 2 was comparable to that of the wild type. This reduced the relative abundance of early-arriving structures with z / n = -4ATD.

[0181] Figure 8 shows that the presence of early-arrival structures at z / n = -3ATD is due to the 26- It was shown that the α-glucan disappeared during the 30-hour incubation period. Even after 29 hours, At z=-5 / 2ATD, dodecamer formation is inhibited.

[0182] These observations are consistent with the A0107 is an inhibitor of Aβ42wt dodecamer formation and The assays performed showed that cinacalcet also retarded summer growth. did not inhibit dodecamer formation.

Claims

1. A pharmaceutical composition for use in reducing the formation of Aβ42 oligomers or disrupting Aβ42 oligomers in a patient, The pharmaceutical composition comprises a compound, The pharmaceutical composition, wherein the compound is 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-N,N-dimethyl-2-phenylacetamide.

2. 10. The pharmaceutical composition of claim 1, wherein the patient is at risk of developing Alzheimer's disease.

3. The pharmaceutical composition of claim 1, wherein the patient is genetically predisposed to Alzheimer's disease.

4. The pharmaceutical composition of claim 1, wherein the patient has a gene for early-onset familial Alzheimer's disease.

5. 10. The pharmaceutical composition of claim 1, wherein the patient has been diagnosed with Alzheimer's disease.

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