Composition for treating dry age-related macular degeneration (AMD)

Abstract

The present disclosure relates to a method of treating dry age-related macular degeneration (dry AMD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to any embodiment described herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 124,695, filed on 11 December 2020, the contents of which are incorporated herein by reference. [Overview of the project] [Means for solving the problem]

[0002] This disclosure provides a method for treating dry age-related macular degeneration (dry AMD) and other retinal diseases, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to any embodiment described herein to a subject in need thereof.

[0003] Some embodiments are methods for treating dry age-related macular degeneration (dry AMD), comprising the step of administering a therapeutically effective amount of a compound selected from the group consisting of the following to a subject in need: A. A compound of formula I or a pharmaceutically acceptable salt thereof, [ka] Here, each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR', where, if present in R1 and R2, each R' is independently H or C1-C6 alkyl. Each of R3, R4, R5, and R6 is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyC1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n R' is independently selected from the group consisting of C(O)O(C1-C4 alkyl), OC(O)N(R')2, C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl); where, if present in R3, R4, R5, and R6, each R' is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or an optional substituted aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, where the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acyl. Alternatively, R3 and R4, together with the C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl group, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R3 and R4 are linked together to form -OC1- forms a C2 methylene O-group, or R4 and R5 together with the C atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R4 and R5 are linked together to form an -O-C 1-2 methylene O-group, R7, R8, R9, R 10 and R 11 each is independently selected from the group consisting of H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), O(CO)R', F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n R', C(O)O(C1-C4 alkyl), OC(O)N(R')2, C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl), where R7, R8, R9, R 10 and R 11Each R' present is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2. Alternatively, R7 and R8, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R7 and R8 are linked together to form -OC 1-2 Forms a methylene-O- group, Alternatively, R8 and R9, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R8 and R9 are linked together to form -OC 1-2 Forms a methylene O-group, Each n is independently 0, 1, or 2. However, R7, R8, R9, R 10 , and R 11 Not all of them are H, and However, the following compounds, [ka] or a compound of formula I or a pharmaceutically acceptable salt thereof, excluding a pharmaceutically acceptable salt thereof, B. Compounds of formula IA or pharmaceutically acceptable salts thereof, [ka] Here, R a , R b , R c , R d , and R e Each of these is independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino. R 1A is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH3)2, and R 2A is a compound of formula IA or a pharmaceutically acceptable salt thereof, wherein the cyclic amino group is optionally substituted.

[0004] Some embodiments of this disclosure are methods for treating age-related macular degeneration (AMD) of the dry type: [ka] The method includes the step of administering a therapeutically effective amount of a compound selected from the group consisting of TIFF2023553414000006.tif127141 and TIFF2023553414000007.tif137141 to a subject in need of it.

[0005] Some embodiments describe the manufacture of pharmaceuticals for the treatment of age-related macular degeneration, [ka] This document describes the use of a compound selected from the above, or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments describe the manufacture of pharmaceuticals for the treatment of age-related macular degeneration, [ka] The use of a composition comprising a compound selected from, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is described.

[0007] Some embodiments describe methods for treating age-related macular degeneration with dryness, comprising administering a therapeutically effective amount of a pharmaceutical composition according to any embodiment described herein.

[0008] Some embodiments describe the use of compounds according to any embodiment described herein in the manufacture of pharmaceuticals for the treatment of age-related macular degeneration. [Brief explanation of the drawing]

[0009] [Figure 1A] The cell viability of retinal pigment epithelial cells after treatment with sigma-2 receptor modulators (Figure 1A = compound B and compound C; Figure 1B = compound A) is shown. [Figure 1B] The cell viability of retinal pigment epithelial cells after treatment with sigma-2 receptor modulators (Figure 1A = compound B and compound C; Figure 1B = compound A) is shown. [Figure 2A] The trafficking of the photoreceptor outer segments after treatment with Aβ oligomers in or out of the presence of sigma 2 receptor modulators (Figure 2A = Compound A and Compound C; Figure 2B = Compound B) is depicted. [Figure 2B] The trafficking of the photoreceptor outer segments after treatment with Aβ oligomers in or out of the presence of sigma 2 receptor modulators (Figure 2A = Compound A and Compound C; Figure 2B = Compound B) is depicted. [Figure 3A] The images depict extrareceptor segmentation trafficking after treatment with oxidative stressors in or out of the presence of sigma-2 receptor modulators (Figure 3A = Compound A and Compound C; Figure 3B = Compound B). [Figure 3B]The images depict extrareceptor segmentation trafficking after treatment with oxidative stressors in or out of the presence of sigma-2 receptor modulators (Figure 3A = Compound A and Compound C; Figure 3B = Compound B). [Figure 4] Figure 4 shows the quantification of autophagy-related proteins after oxidative stress induced by an oxidative stressor, with and without the presence of a sigma-2 receptor modulator. [Figure 5] Figure 5 shows the quantified concentrations of sigma-2 receptor modulator compound A in rat uvea / retina and brain. [Figure 6] Figure 6 shows the quantified concentrations of sigma-2 receptor modulator compound A in mouse plasma, brain, and retina. [Figure 7] Figure 7 shows the quantitative concentrations of compound B, a sigma-2 receptor modulator, in mouse plasma, brain, and retina. [Figure 8] Figure 8 shows the quantification of retinal ganglion cell density in an in vivo model of glaucoma with and without a sigma-2 receptor modulator. [Figure 9A] This study quantifies the electrical activity of retinal ganglion cells in an in vivo model of glaucoma, with and without the presence of a sigma-2 receptor modulator. [Figure 9B] This study quantifies the electrical activity of retinal ganglion cells in an in vivo model of glaucoma, with and without the presence of a sigma-2 receptor modulator. [Modes for carrying out the invention]

[0010] The present invention is not limited to the specific processes, compositions, or methodologies described herein, as these may vary. The terms used herein are for illustrative purposes only to describe specific versions or embodiments and are not intended to limit the scope of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications referenced herein are incorporated by reference in their entirety. Nothing in this specification shall be construed as admitting that the present invention does not have prior rights to such disclosure by prior art.

[0011] definition Where a range of values ​​is provided, each intervention value between the upper and lower limits of that range, as well as any other stated or intervening values ​​within that stated range, are intended to be included within this disclosure. For example, if the range is 1 μm to 8 μm, then 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also intended to be expressly disclosed.

[0012] Throughout this specification, substituents of the compounds of the Disclosure are disclosed in groups or ranges. Embodiments of the Disclosure are particularly intended to include each and all individual subordinate bonds of members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to disclose, for example, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C2-C3 alkyl, C2-C4 alkyl, C3-C6 alkyl, C4-C5 alkyl, and C5-C6 alkyl individually, as well as methyl (C1 alkyl), ethyl (C2 alkyl), propyl (C3 alkyl), butyl (C4 alkyl), pentyl (C5 alkyl), and hexyl (C6 alkyl).

[0013] As used herein, the articles "a" and "an" mean "one or more" or "at least one" unless otherwise indicated. That is, any reference to any element of the present invention using the indefinite article "a" or "an" does not preclude the possibility that there may be multiple such elements.

[0014] As used herein, the term "about" means plus or minus 10% of the number in which it is used. Therefore, about 50 mL means within the range of 45 mL to 55 mL.

[0015] "Aβ species" or "A" also includes compositions containing soluble amyloid peptide-containing components, such as Aβ monomers, Aβ oligomers, or Aβ peptides (in monomer, dimer, or polymer form) in complexes with other soluble peptides or proteins, as well as other soluble Aβ aggregates, including any processed products of amyloid precursor proteins. Soluble A oligomers are known to be neurotoxic. Even Aβ1-42 dimers are known to impair synaptic plasticity in mouse hippocampal slices. One theory known in the art is that native Aβ1-42 monomers are neuroprotective, and the self-association of Aβ monomers into soluble Aβ oligomers is required for neurotoxicity. However, certain Aβ mutant monomers (Arctic mutation (E22G)) have been reported to be associated with familial Alzheimer's disease.

[0016] Unless otherwise specified, the term “active ingredient” is understood to refer to the compound in any embodiment described herein.

[0017] "Administer" or "Deliver" means, when used in combination with the compounds of this disclosure, providing the compound or pharmaceutical composition according to any of the embodiments described herein to a subject in need of treatment. Preferably, the subject is a mammal, more preferably a human. The present invention includes administering the pharmaceutical composition of the present invention alone or in combination with other therapeutic agents. When the pharmaceutical composition of the present invention is administered in combination with other therapeutic agents, the pharmaceutical composition of the present invention and the other therapeutic agents may be administered simultaneously or at different times.

[0018] The term "agonist" refers to a compound that brings about the biological activity of a receptor, meaning that its presence is equivalent to the biological activity that results from the presence of a naturally occurring ligand for that receptor.

[0019] As used herein, the terms "alkanoyl" or "alkylcarbonyl" refer to an alkyl group bonded to a carbonyl radical. Examples of alkanoyls include: [ka] That is the case.

[0020] As used herein, the term “alkyl” means a saturated hydrocarbon group that is linear or branched. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and analogues. Alkyl groups may contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. 10 "Alkyl" or "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to contain alkyl groups. Furthermore, for example, "C1-C6 alkyl" or "C 1-6"Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The term "alkylene" refers to a divalent alkyl linking group. An example of alkylene is methylene (CH2).

[0021] As used herein, “alkenyl” is intended to include a straight or branched hydrocarbon chain having one or more, preferably 1 to 3, carbon-carbon double bonds, which may occur at any stable point along the chain. For example, “C2-C6 alkenyl” or “C 2-6 An "alkenyl" (or alkenylene) is intended to contain C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyls include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-protenyl, and 4-methyl-3-pentenyl.

[0022] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-C6 alkoxy" or "C 1-6 "Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.

[0023] The term "alkoxyalkoxy" refers to an alkoxy group bonded to another alkoxy group. Examples of alkoxy groups include -O-(CH2)2-OCH3.

[0024] As used herein, “alkynyl” is intended to include a linear or branched hydrocarbon chain having one or more, preferably one to three, carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, “C2-C6 alkynyl” is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0025] As used herein, “amyloid-beta effect,” e.g., “non-lethal amyloid-beta effect,” or “Aβ oligomer effect” refers to the effect on cells in contact with Aβ species, particularly non-lethal effects. For example, when nerve cells come into contact with soluble amyloid-beta ("Aβ") oligomers, the oligomers have been shown to bind to synapses on a subset of nerve cells in vitro. This binding can be quantified, for example, by assays that measure abeta oligomer binding in vitro. Another documented effect of Aβ species is a decrease in synapse number, which has been reported to be about 18% in the human hippocampus (Scheff et al, 2007), and can be quantified (for example, in assays that measure synapse number). In another example, it has been found that contact of nerve cells with amyloid-beta (hereinafter, Aβ) oligomers modulates membrane transport and causes changes in membrane transport. This abnormality can be visualized in many assays, including but not limited to MTT assays. For example, the yellow tetrazolium salt is endocytized by cells and reduced to insoluble purple formazan by enzymes in vesicles of the endosomal pathway. The level of purple formazan reflects the number of actively metabolizing cells in culture, and a decrease in formazan levels is considered an indicator of cell death or metabolic toxicity in culture. When cells exposed to the yellow tetrazolium salt are observed under a microscope, the purple formazan is first seen in vesicles that fill the cells. Subsequently, the vesicles are expelled from the cell, and the insoluble formazan precipitates as needle-shaped crystals on the outer surface of the cell membrane upon exposure to an aqueous medium environment. Further effects of Aβ species include cognitive impairment such as a reduced ability to form new memories and memory loss, which can be measured in assays using in vivo animal models. In some embodiments, the Aβ effect is selected from those observed in patients requiring it, such as Aβ oligomer-induced synaptic dysfunction, Aβ oligomer-mediated caspase 3 activation of sigma 2 receptors, Aβ-induced neuronal dysfunction, Aβ-mediated reduction in long-term potentiation (LTP), or cognitive impairment in behavioral assays, as seen in in vitro assays such as membrane trafficking assays or synaptic loss assays.

[0026] In some embodiments, a test compound is considered effective for treating cognitive decline or related diseases if it can inhibit effects related to soluble abeta oligomer species on nerve cells by about 10% or more, preferably 15% or more, and preferably 20% or more, compared to a negative control. In some embodiments, a test agent is considered effective if it can suppress effects mediated by amyloid precursor protein by about 10% or more, preferably 15% or more, and preferably 20% or more, compared to a positive control. This specification focuses on inhibiting non-lethal effects of Aβ species such as neuronal metabolic abnormalities and synapse reduction, which have been shown to correlate with cognitive function. Furthermore, it is expected that the test compound can reduce (compared to untreated subjects) measurable symptoms downstream of amyloid pathology, particularly 1) accumulation of fibers and plaques measured with amyloid imaging agents such as fluorbetapir and PittB, and 2) clinical symptoms such as synaptic loss and cell death measured by glucose metabolism reduction detected by FDG-PET, and 3) obtained from patients by imaging or ELISA. These include: 4) changes in protein expression or metabolite levels in the brain or body detectable by protein / metabolite detection in cerebrospinal fluid, brain biopsy, or plasma (such as changes in the levels and / or ratios of Aβ42, phosphorylated tau, total tau, or patterns of protein expression changes detectable by an ELISA panel); 4) the presence of angioedema or microbleeds detectable by MRI, and other symptoms detectable by imaging techniques; and 5) cognitive decline measured by any administered cognitive test such as ADAS-Cog, MMSE, CBIC, or other cognitive testing equipment.

[0027] As used herein, the term “animal” includes, but is not limited to, humans and wild animals, laboratory animals, livestock, farm animals and pets, and other non-human vertebrates.

[0028] The term “antagonist” refers to an entity, such as a compound, antibody, or fragment, that results in a reduction in the magnitude of the biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of the biological activity of the receptor. As used herein, the term “sigma-2 receptor antagonist” is used to describe a compound that acts as a “functional antagonist” of the sigma-2 receptor, for example, in in vitro assays such as membrane trafficking assays, synaptic loss assays, or caspase-3 Aβ oligomer-mediated sigma-2 receptor activation, or behavioral assays, or as seen in patients requiring it, in that it blocks the Aβ effect, e.g., Aβ oligomer-induced synaptic dysfunction. Functional antagonists may act directly, for example, by inhibiting the binding of abeta oligomers to the sigma-2 receptor, or indirectly by interfering with downstream signaling resulting from the binding of abeta oligomers to the sigma-2 receptor.

[0029] As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons such as phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, indenyl, and analogues. In some embodiments, the aryl group has 6 to about 20 carbon atoms. In some embodiments, the aryl group has 5 to about 10 carbon atoms.

[0030] As used herein, “arylalkyl” refers to an aryl group bonded to an alkyl radical. In preferred embodiments, the alkyl is C 1-6 It is alkyl.

[0031] As used herein, the terms "aloyl" or "arylcarbonyl" refer to an aryl group bonded to a carbonyl radical. Examples of aroyl include, but are not limited to, benzoyl.

[0032] As used herein, the term “brain permeability” means the ability of a drug, antibody, or fragment to cross the blood-brain barrier. In some embodiments, brain permeability can be determined or predicted using animal pharmacokinetic (pK) studies, e.g., mouse pharmacokinetic / blood-brain barrier studies. In some embodiments, various concentrations of the compound or pharmaceutical composition according to any embodiment described herein, e.g., 3, 10, and 30 mg / kg, e.g., po, can be administered for 5 days, and various pK properties can be measured, e.g., in an animal model. In some embodiments, dose-related plasma and brain levels are determined. In some embodiments, brain Cmax > 100, 300, 600, 1000, 1300, 1600, or 1900 ng / mL. In some embodiments, good brain permeability is defined as a brain / plasma ratio > 0.1, > 0.3, > 0.5, > 0.7, > 0.8, > 0.9, preferably > 1, more preferably > 2, > 5, or > 10. In other embodiments, good brain permeability is defined as greater than about 0.1%, 1%, 5%, about 10%, and preferably about 15% of the dose crossing the blood-brain barrier after a predetermined period. In certain embodiments, the dose is administered orally (po). In other embodiments, the dose is administered intravenously (iv) before measuring pK properties.

[0033] As used herein, “cognitive decline” may be any negative change in an animal’s cognitive function. For example, cognitive decline includes, but is not limited to, memory loss (e.g., behavioral memory loss), inability to acquire new memories, confusion, impaired judgment, personality changes, disorientation, or any combination thereof. Compounds effective in treating cognitive decline may thus be effective by restoring balance to long-term potentiation (LTP) or long-term depression (LTD) or electrophysiologically measured synaptic plasticity; inhibiting, treating, and / or mitigating neurodegeneration; inhibiting, treating, and / or mitigating general amyloidosis; inhibiting, treating, or mitigating one or more of amyloidogenesis, amyloid aggregation, amyloid condensation, and amyloid oligomer binding; inhibiting, treating, or mitigating the non-lethal effects of one or more Aβ species on neuronal cells (such as synaptic loss or dysfunction and membrane transport abnormalities); and any combination thereof. In addition, the compound may also be effective in treating Aβ-related neurodegenerative diseases and disorders, including Alzheimer's disease (AD), including mild Alzheimer's disease, Down syndrome, vascular dementia (cerebral amyloid angiopathy and stroke), Lewy body dementia, HIV dementia, and mild cognitive impairment (MCI); and age-related memory impairment (AAMI), age-related cognitive decline (ARCD), preclinical Alzheimer's disease (PCAD), and no cognitive impairment (CIND).

[0034] As used herein, the term “contact” means bringing together or combining molecules (or molecules having a higher-order structure, such as a cell or cell membrane) so that they are within a distance that allows for intermolecular interactions, such as non-covalent interactions between two peptides or non-covalent interactions between one protein and another protein or other molecule, such as a small molecule. In some embodiments, contact occurs in a solution in which the bound or contacted molecules are mixed in a common solvent and allowed to freely associate. In some embodiments, contact can occur in a cell, or otherwise within a cell, or in a cell-free environment. In some embodiments, the cell-free environment is a lysate produced from a cell. In some embodiments, the cell lysate may be a whole cell lysate, a nuclear lysate, a cytoplasmic lysate, or a combination thereof. In some embodiments, the cell-free lysate is a lysate obtained from nuclear extraction and isolation, in which the nuclei of a cell population are removed from the cells and then lysed. In some embodiments, the nuclei are not lysed, but it is still considered a cell-free environment. Molecules can be brought together by mixing, such as vortexing or shaking.

[0035] As used herein, the term "cyclic amino" or "cyclic amino group" refers to a heterocycloalkyl or heteroaryl group containing a nitrogen radical, and thus enabling bonding via the nitrogen atom. This group can be represented by the formula:

[0036] [ka] This is any heterocyclic or heteroaromatic ring containing 0 to 3 additional heteroatoms selected from nitrogen, sulfur, and oxygen.

[0037] As used herein, the terms "cycloalkanoyl" or "cycloalkylcarbonyl" refer to a cycloalkyl group bonded to a carbonyl radical. Examples of cycloalkanoyls are shown below. [ka] These include, but are not limited to, the following:

[0038] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons containing cycloalkyl, alkenyl, and alkynyl groups with up to 20 ring-forming carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, as well as spirocyclic systems. Cycloalkyl groups may contain 3 to about 15, 3 to about 10, 3 to about 8, 3 to about 6, 4 to about 6, 3 to about 5, or 5 to about 6 ring-forming carbon atoms. The ring-forming carbon atoms of cycloalkyl groups can optionally be substituted with oxo or sulfide. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and analogues. Furthermore, the definition of cycloalkyl includes moieties having one or more aromatic rings condensed (i.e., sharing a common bond) to a cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl, or 1H-inden-2(3H)-on-1-yl). Preferably, "cycloalkyl" refers to a cyclized alkyl group containing up to 20 ring-forming carbon atoms. Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and analogues.

[0039] The term "cycloalkylalkyl" refers to a cycloalkyl group bonded to an alkyl radical. In preferred embodiments, the alkyl group is C 1-6 It is alkyl.

[0040] In this specification, the term "drug-like properties" is used to describe the pharmacokinetic and stability properties of a compound at administration, including brain permeability, metabolic stability, and plasma stability.

[0041] As used herein, the term “effective dose” means an amount that results in a measurable inhibition of at least one symptom or parameter of a particular disorder or pathological process. For example, an amount of the compound disclosed in any embodiment described herein that provides a measurably low synaptic reduction in the presence of an abeta oligomer is modified to “effective dose” because it reduces the pathological process at least immediately, without altering the clinical symptoms of amyloid pathology.

[0042] As used herein, "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0043] As used herein, “haloalkoxy” refers to a haloalkyl group as defined herein, having the indicated number of carbon atoms bonded via an oxygen bridge. For example, “C1-C6 haloalkoxy” or “C 1-6 "Haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. An example of a haloalkoxy group is OCF3. As used herein, "trihalomethoxy" means a methoxy group having three halogen substituents. Examples of trihalomethoxy groups include, but are not limited to, -OCF3, -OCClF2, -OCCl3, and analogues.

[0044] As used herein, “haloalkyl” is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogens. Exemplary haloalkyls include, but are not limited to, CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, CH2CF3, and analogues.

[0045] As used herein, the “heteroaryl” group refers to an aromatic heterocycle having up to 20 ring-forming atoms and at least one heteroatomic ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatomic ring-forming atoms independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic systems (e.g., having two, three, or four fused rings). Examples of heteroaryl groups include, but are not limited to, pyridyl (also known as pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl (also known as pyrrolyl), oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, prinyl, carbazolyl, benzimidazolyl, indolinyl, and analogues. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and in further embodiments, it has about 1 to about 5, about 1 to about 4, about 1 to about 3, and about 1 to about 2 carbon atoms as ring-forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0046] As used herein, the term "heterocycloalkoxy" means -O-heterocycloalkyl group. Examples of heterocycloalkoxy groups are shown below. [ka] That is the case.

[0047] As used herein, “heterocycloalkyl” or “heterocyclyl” refers to a non-aromatic heterocyclyl group having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more of the ring-forming carbon atoms are substituted with heteroatoms such as O, N, or S atoms. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., both condensed and spiro systems). For example, “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidine-2-on-3-yl, and analogues. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted with oxos or sulfides. For example, a ring-forming sulfur atom can be substituted with one or two oxos (i.e., forming S(O) or S(O)2). For example, a ring-forming carbon atom can be substituted with an oxo (i.e., forming a carbonyl). The definition of a heterocycloalkyl group also includes a site where one or more aromatic rings are fused (i.e., share a common bond). Examples include pyridinyl, thiophenyl, phthaliumidyl, naphthaliumidyl, and heterocyclic benzo derivatives such as indoline, isoindoline, isoindoline-1-on-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridine-7(4H)-on-5-yl, and 3,4-dihydroisoquinoline-1(2H)-on-3-yl groups. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be substituted with oxo or sulfide. In some embodiments, the heterocycloalkyl group has 2 to about 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms.In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0048] In this application, the term "high affinity" means, in a sigma receptor binding assay, for example, a K content of less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 80 nM, less than 60 nM, or preferably less than 50 nM relative to [3H]-DTG. i The values ​​are intended for compounds, as incorporated herein by reference, Weber et al., Proc. Natl. Acad. Sci (USA) 83:8784-8788 (1986), which measure the binding affinity of a compound to both sigma 1 and sigma 2 receptor sites. Particularly preferred compounds have a K of less than about 150 nM, preferably less than 100 nM, less than about 60 nM, less than about 10 nM, or less than 1 nM relative to [3H]-DTG. i Show the value.

[0049] The terms "hydroxyl" and "hydroxy" are used interchangeably to mean the OH group.

[0050] The term “improve” is used to convey that the Disclosure modifies any of the characteristics and / or physical attributes of the tissue to which it is provided, applied, or administered. The term “improve” may also be used in relation to a disease condition, such that when the disease condition is “improved,” the symptoms or physical characteristics associated with the disease condition are reduced, lessened, eliminated, delayed, or avoided.

[0051] The term “inhibit” includes blocking, abolishing, or restoring an adverse outcome or process. In terms of prevention or treatment by administration of the compounds of this disclosure, “inhibit” includes protecting (partially or entirely) from symptoms, delaying the onset of symptoms, alleviating symptoms, or protecting, reducing, or eliminating a disease, condition, or disorder.

[0052] The term "inhibit trafficking deficit" refers to the ability to block soluble A oligomer-induced membrane trafficking deficits in cells, preferably nerve cells. Compounds that can inhibit trafficking deficits are those that perform EC in membrane trafficking assays. 50 The concentrations are <20 μM, less than 15 μM, less than 10 μM, less than 5 μM, preferably less than 1 μM, and furthermore, as described in Example 6, for example, it is possible to suppress the effect of soluble abeta oligomers on membrane trafficking defects by at least 50%, preferably at least 60%, and more preferably at least 70%.

[0053] "logP" refers to the partition coefficient of a compound. The partition coefficient is the ratio of the concentrations of a non-ionized compound in each of two solution phases, such as octanol and water. To measure the partition coefficient of an ionizable solute compound, the pH of the aqueous phase is adjusted so that the dominant form of the compound is non-ionized. The logarithm of the concentration ratio of the non-ionized solute compound in the solvent is called logP, and logP serves as an indicator of lipophilicity. For example... log P oct / wat =log([solute] オクタノール / [Solute] 非イオン化、水 ).

[0054] As used herein, the term “metabolic stability” refers to the ability of a compound to withstand first-pass metabolism (intestinal and hepatic degradation or conjugation of an orally administered drug). This can be assessed in vitro, for example, by exposure of the compound to mouse or human liver microsomes. In some embodiments, good metabolic stability is demonstrated when the compound is exposed to mouse or human liver microsomes. 1 / 2 This refers to >5 minutes, >10 minutes, >15 minutes, >20 minutes, preferably >30 minutes. In some embodiments, good metabolic stability is <300 uL / min / mg, preferably < 200 uL / min / mg, more < Intrinsic clearance rate (Cl) of 100 uL / min / mg int ) refers to.

[0055] The term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms in a site where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl group.

[0056] As used herein, the term “natural ligand” refers to a ligand present in the subject that can bind to a protein, receptor, membrane lipid or other binding partner in vivo, or that can be replicated in vitro. Natural ligands may be of synthetic origin, but they must also be naturally present in the subject without artificial intervention. For example, abeta-oligomers are known to be present in human subjects. Therefore, abeta-oligomers present in the subject are considered natural ligands. The binding of abeta-oligomers to their binding partners can be replicated in vitro using recombinant or synthetic techniques, but regardless of how the abeta-oligomers were prepared or manufactured, they would still be considered natural ligands. Synthetic small molecules that can also bind to the same binding partner cannot be considered natural ligands if they are not present in the subject. For example, the compounds described herein are not typically present in subjects and therefore would not be considered natural ligands.

[0057] As used herein, the term “neuron” may be used to refer to a single cell or a population of cells. In some embodiments, the neuron is a primary neuron. In some embodiments, the neuron is an immortalized or transformed neuron, or a stem cell. A primary neuron is a neuron that cannot differentiate into other types of neurons, such as glial cells. A stem cell is one that can differentiate into neurons and other types of neurons, such as glial cells. In some embodiments, an assay utilizing a composition comprising at least one neuron does not include glial cells. In some embodiments, the composition contains about 30%, 25%, 20%, 15%, 10%, 5%, or less than 1% of glial cells known to internalize and accumulate Aβ. Primary neurons may originate from any part of the animal brain. In some embodiments, the neuron is a hippocampal cell or a cortical cell. The presence of glial cells can be determined by any method. In some embodiments, glial cells are detected by the presence of GFAP, and neurons can be detected by staining positively with an antibody directed against MAP2.

[0058] As used herein, the term “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and sites. “Substituted” atom or site indicates that any hydrogen on a given atom or site can be replaced by a selection from the substituents shown, provided that the substitution does not exceed the normal valence of the given atom or site and the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, up to three hydrogen atoms on the carbon atom can be substituted with substituents. Substituents include alkanoyl, alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, alyloxy, aliroyl, cycloalkanoyl, substituted or unsubstituted C3-C 10Cycloalkyl, -OC(O)NCH(CH3)2, (N,N-dimethylamino)pyridinyl, (N,N-dimethylamino)sulfonyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonyl, methylsulfonylphenyl, morpholinylpyridinyl, optional substitution C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optional substitution C3-C 10 This includes, but is not limited to, heteroaryl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydrapyryl, and CF3. A substituted alkyl group indicates, for example, that one or more hydrogen atoms on the alkyl group are replaced by substituents selected from, but not limited to, halo, hydroxyl, alkoxy, heterocycloalkoxy, alkoxyalkoxy, C(O)OMe, and C(O)OEt. A substituted aryl group indicates, for example, that one or more hydrogen atoms on the aryl group are replaced by substituents selected from, but not limited to, -SO2Me or phenyl groups. A substituted heteroaryl group indicates, for example, that one or more hydrogen atoms on the heteroaryl group are replaced by substituents selected from, but not limited to, heterocycloalkyl, heteroaryl, and N,N-dimethylamino groups. For example, a substituted heterocycloalkyl group indicates that one or more hydrogen atoms on the heterocycloalkyl group are substituted with a subposition that can be selected from, but is not limited to, heterocycloalkyl, heteroaryl, N,N-dimethylamino, hydroxyl, alkoxy, alkoxycarbonyl, alkyl, aryl, sulfonyl, dimethylaminosulfonyl, aroyl, cycloalkanoyl, alkanoyl, and -OC(O)NCH(CH3)2. In some embodiments, for example, two hydrogen atoms on the same carbon of a heterocyclyl group or alkyl group are substituted with a group, for example, [ka] They form spiro compounds selected from, but not limited to, these.

[0059] A "partial agonist" refers to a compound whose biological activity of a receptor is of the same type as the activity brought about by the presence of a ligand for a naturally occurring receptor, but is smaller in size.

[0060] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered safe and non-toxic. In particular, pharmaceutically acceptable carriers, diluents, or other excipients used in the pharmaceutical compositions of this disclosure are physiologically acceptable, compatible with other components, and do not typically cause allergic or similar unpleasant reactions (e.g., stomach upset, dizziness, etc.) when administered to a patient. Preferably, as used herein, the term "pharmaceutically acceptable" means that it is approved by a federal or state regulatory agency or is listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, more specifically in humans.

[0061] As used herein, the term “pharmaceutically acceptable salts” includes salts of the compounds of the Disclosure that are safe and effective for use in mammals and possess the desired biological activity. pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the Disclosure or in compounds identified according to the methods of the Disclosure. Pharmacovigilant acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, tartrates, ascorbic acidates, succinates, maleates, gentates, fumarates, glucons, glucarons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of this disclosure can form pharmaceutically acceptable salts with a variety of amino acids. Preferred base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, and diethanolamine salts. pharmaceutically acceptable base addition salts are also formed with amines such as organic amines. Examples of preferred amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0062] As used herein, the term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions such as oil / water or water / oil emulsions, and various types of wetting agents. The term also includes any drug approved by a U.S. federal regulatory agency or listed in the United States Pharmacopeia for use in animals, including humans.

[0063] "Selectivity" or "selective" refers to the binding affinity (K) of a compound to a sigma receptor, such as the sigma 2 receptor.i This term means that it is different from non-sigma receptors. This compound has high selectivity for sigma receptors in synaptic neurons. K for sigma 2 receptors, or for both sigma 2 receptors and sigma 1 receptors. i This is K for non-sigma receptors. i It is compared to the following. In some embodiments, the compound is a selective sigma-2 receptor antagonist or a sigma-1 receptor ligand, with different receptor binding and dissociation constants K i Value, or IC 50 As evaluated by comparing values ​​or binding constants, K in different receptors has at least 10, 20, 30, 50, 70, 100, or 500 times higher affinity to bind to sigma receptors compared to non-sigma receptors. i Value or IC 50 To evaluate the values, any known assay protocol can be used, for example, by monitoring competitive substitution of radiolabeled compounds from receptors with known dissociation constants by the method of Cheng and Prusoff (1973) (Biochem. Pharmacol. 22, 3099-3108), or specifically as provided herein, the values ​​of K or IC can be evaluated.

[0064] As used herein, the term "plasma stability" refers to the degradation of a compound in plasma by enzymes such as hydrolases and esterases. Any of a variety of in vitro assays can be employed. The test compound is incubated in plasma for a variety of time periods. The percentage of the parent compound (analyte) remaining at each time point reflects the stability of the plasma. Poor stability tends to result in low bioavailability. Good plasma stability can be defined as the presence of more than 50% of the analyte after 30 minutes, more than 50% after 45 minutes, and preferably more than 50% after 60 minutes.

[0065] A "sigma-2 ligand" refers to a compound that binds to the sigma-2 receptor, and includes agonists, antagonists, partial agonists, inverse agonists, and mere competitors to other ligands for this receptor or protein.

[0066] A "sigma-2 receptor antagonist compound" refers to a compound that binds to the sigma-2 receptor in a measurable amount and acts as a functional antagonist in relation to Aβ-effect oligomer-induced synaptic dysfunction caused by sigma-2 receptor binding.

[0067] The terms “subject,” “individual,” or “patient” are used interchangeably and, as used herein, are intended to include humans and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, sheep, dogs, cats, cattle, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cattle, horses, etc. Preferred subjects include human patients. The method is particularly suitable for treating human patients having the diseases or disorders described herein.

[0068] "Test compound" is a compound according to any embodiment described herein that has been tested in any test. Tests include any in vivo or in vitro test, computer models or simulations, virtual drug tests, stem cell and gene testing methods, non-invasive imaging techniques, etc.

[0069] As used herein, the term “treatment” means a drug used to treat, combat, improve, protect against or improve an undesirable condition or disease in a subject.

[0070] The “therapeutic effective dose” of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any embodiment described herein is an amount sufficient to produce a selected effect on at least one symptom or parameter of a particular disease or disorder. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., a subject shows signs of an effect or feels an effect, or a physician observes a change). The therapeutically effective doses of the compounds according to any embodiment described herein are, broadly speaking, 0.01 mg / kg to about 500 mg / kg, about 0.01 to about 250 mg / kg, about 0.01 to about 25 mg / kg, about 0.05 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 400 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 to about 10 mg / kg, about 0.2 to about 5 mg / kg, about 1 mg / kg to about 300 mg / kg, about 10 mg / kg to about 100 mg / kg, and body weight. The effects intended herein appropriately include both medical treatment and / or prophylactic measures. The specific dose of a compound administered pursuant to this disclosure to obtain therapeutic and / or prophylactic effects depends on the specific circumstances surrounding the case, such as the compound administered, the route of administration, co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the patient's age, weight, general health, sex, and diet, the timing of administration of the specific compound employed, the route of administration and excretion rate, and the duration of treatment. The therapeutically effective amount administered is determined by a physician, in light of the aforementioned relevant circumstances, through the exercise of sound medical judgment. The therapeutically effective amount of a compound in any embodiment described herein is typically an amount sufficient to achieve an effective systemic concentration or local concentration in tissue when administered in a physiologically acceptable excipient composition. The total daily dose of the compound according to any embodiment described herein, administered to humans or other animals in a single dose or divided doses, is, for example, about 0.01 mg / kg to about 500 mg / kg, about 0.01 to about 250 mg / kg, about 0.01 to about 25 mg / kg, about 0.05 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 400 mg / kg by body weight.The ranges are approximately 0.1 mg / kg to approximately 200 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0.1 to approximately 10 mg / kg, approximately 0.2 to approximately 5 mg / kg, and approximately 10 mg / kg to approximately 100 mg / kg. A single-dose pharmaceutical composition of any embodiment described herein may contain such amounts or submultiples to constitute a daily dose. For example, a compound according to any embodiment described herein may be administered in a regimen of 1 to 4 doses, such as once, twice, three times, or four times per day. In some embodiments, the therapeutically effective dose of a compound according to any embodiment disclosed herein may be between approximately 0.01 and approximately 25 mg / kg / day. In some embodiments, a therapeutically effective dose, with a lower limit of approximately 0.01 mg / kg body weight, approximately 0.1 mg / kg body weight, approximately 0.2 mg / kg body weight, approximately 0.3 mg / kg body weight, approximately 0.4 mg / kg body weight, approximately 0.5 mg / kg body weight, approximately 0.60 mg / kg body weight, approximately 0.70 mg / kg body weight, approximately 0.80 mg / kg body weight, approximately 0.90 mg / kg body weight, approximately 1 mg / kg body weight, approximately 2.5 mg / kg body weight, approximately 5 mg / kg body weight, approximately 7.5 mg / kg body weight, approximately 10 mg / kg body weight, approximately 12.5 mg / kg body weight, approximately 15 mg / kg body weight, approximately 17.5 mg / kg body weight, approximately 20 mg / kg body weight, approximately 22.5 mg / kg body weight, and about 25 mg / kg of body weight; and the upper limit is one of 25 mg / kg of body weight, about 22.5 mg / kg of body weight, about 20 mg / kg of body weight, about 17.5 mg / kg of body weight, about 15 mg / kg of body weight, about 12.5 mg / kg of body weight, about 10 mg / kg of body weight, about 7.5 mg / kg of body weight, about 5 mg / kg of body weight, about 2.5 mg / kg of body weight, about 1 mg / kg of body weight, about 0.9 mg / kg of body weight, about 0.8 mg / kg of body weight, about 0.7 mg / kg of body weight, about 0.6 mg / kg of body weight, about 0.5 mg / kg of body weight, about 0.4 mg / kg of body weight, about 0.3 mg / kg of body weight, about 0.2 mg / kg of body weight, and about 0.1 mg / kg of body weight. In some embodiments, the therapeutically effective dose is about 0.1 mg / kg / day to about 10 mg / kg / day, and in some embodiments, the therapeutically effective dose is about 0.2 and about 5 mg / kg / day. In some embodiments, the treatment regimens according to this disclosure are administered to patients requiring such treatment in a single or multiple dose per day.The compounds, or pharmaceutically acceptable salts thereof, in amounts of about 1 mg to about 5000 mg, about 10 mg to about 200 mg, about 20 to about 500 mg, about 20 to about 400 mg, about 40 to about 800 mg, about 50 to about 500 mg, about 80 to about 1600 mg, and about 50 mg, according to any embodiment disclosed herein. In some embodiments, the therapeutically effective dose is a total daily dose of 50 mg to 500 mg. In some cases, the daily dose is approximately 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, approx. 190mg, about 195mg, about 200mg, about 250mg, 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, Approximately 265mg, approximately 270mg, approximately 275mg, approximately 280mg, approximately 285mg, approximately 290mg, approximately 295mg, 300mg, approximately 305mg, approximately 310mg, approximately 315mg approximately 320mg, approximately 325mg, approximately 330mg, approximately 335mg, About 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395, 400mg, about 405mg, about 410mg, approx. 415 mg approx. 420 mg, approx. 425 mg, approx. 430 mg, approx. 435 mg, approx. 440 mg, approx. 445 mg, approx. 450 mg, approx. The lower limits are approximately 490mg, 495mg, and 500mg, and approximately 495mg, 490mg, 485mg, 480mg, 475mg, 500mg, 465mg, 460mg, 455mg, 450mg, 445mg, 440mg, 435mg, 430mg, 425mg, 420mg, 415mg, 410mg, 405mg, 400mg, 395mg, 390mg, 385mg, 380mg, 375mg, and 370mg.365mg, 360mg, about 355mg, 350mg, 345mg, about 340mg, about 335mg, about 330mg, about 325mg, about 320mg, about 315mg, about 310mg, about 305mg about 300mg, about 295mg, about 290mg, about 285mg, about 280mg, about 275mg, about 270mg, 265mg, about 260mg, about 255mg, about 250mg, about 245mg, about 240mg, 235mg, 230mg, about 225mg, about 220mg, about 215mg, about 210mg, about 205m200mg, about 19 The compound according to any embodiment of this specification is between the upper limits of 5 mg, approximately 190 mg, approximately 185 mg, approximately 180 mg, approximately 175 mg, approximately 170 mg, approximately 165 mg, approximately 160 mg, approximately 155 mg, approximately 150 mg, approximately 145 mg, approximately 140 mg, approximately 135 mg, approximately 130 mg, approximately 125 mg, approximately 120 mg, approximately 115 mg, approximately 110 mg, approximately 105 mg, approximately 100 mg, approximately 95 mg, approximately 90 mg; approximately 85 mg, approximately 80 mg, approximately 75 mg, approximately 70 mg, approximately 65 mg, approximately 60 mg, approximately 55 mg, and approximately 50 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 150 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 250 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 350 mg. In some embodiments, the total daily dose is approximately 50 mg to 450 mg. In some embodiments, the total daily dose is approximately 50 mg. Since such an effective dose can be achieved by administering multiple divided doses of such a pharmaceutical formulation, it will be understood that the pharmaceutical formulations of this disclosure do not necessarily need to contain the entire amount of the compound effective in treating the disorder. The compound can be administered in regimens of 1 to 4 times per day, such as once, twice, three or four times per day.

[0071] The term "therapeutic phenotype" is used to describe the activity pattern of a compound in an in vitro assay that can predict behavioral efficacy. A compound that (1) selectively binds to sigma-2 receptors with high affinity and (2) acts as a functional antagonist with respect to Aβ oligomer-induced effects in neurons is said to have a "therapeutic phenotype" if it (i) blocks or reduces A-induced membrane trafficking impairment, (ii) blocks or reduces A-induced synaptic loss, and (iii) does not affect trafficking or synapse number in the absence of Aβ oligomers. This activity pattern in an in vitro assay is called a "therapeutic phenotype" and predicts behavioral efficacy.

[0072] The term "therapeutic profile" is used to describe compounds that satisfy the phenotype of a therapeutic agent and also possess good brain permeability (the ability to cross the blood-brain barrier), plasma stability, and metabolic stability.

[0073] "Tissue" refers to a collection of similarly specialized cells that have come together to perform a specific function.

[0074] As used herein, the terms “to treat,” “to treat,” or “treating” refer to both therapeutic and preventive or protective measures aimed at obtaining beneficial or desirable clinical outcomes, such as protection (partial or whole) or deceleration (e.g., mitigating or delaying the onset) of an undesirable physiological condition, disorder, or disease, or partial or whole recovery or suppression of a decline in a parameter, value, function, or outcome that was or would become abnormal. For the purposes of this disclosure, beneficial or desirable clinical outcomes include, but are not limited to, relief of symptoms, reduction of the degree or severity or rate of onset of a condition, disorder, or disease, stabilization of the condition (i.e., no worsening), stabilization of the condition, disorder, or disease (i.e., no worsening), delay of the onset or progression of a condition, disorder, or disease, improvement of the condition, disorder, or disease, and remission (whether partial or complete), regardless of whether it leads to immediate relief of actual clinical symptoms, enhancement or improvement of the condition, disorder, or disease. Treatment aims to elicit a clinically significant response without excessive side effects. Treatment includes extending survival time compared to the expected survival time if no treatment is received.

[0075] Human amyloid-beta and sigma-2 antagonists Dysfunction of retinal pigment epithelial (RPE) cells is thought to play a crucial role in the development of geographical atrophy (GA) and dry age-related macular degeneration (AMD). There is strong evidence linking amyloid-beta (Aβ) protein to Alzheimer's disease. Smaller, soluble Aβ oligomers interfere with many signaling pathways.

[0076] A subset of sigma-2 receptor binding sites / signaling pathways are linked to Aβ oligomer signaling in Alzheimer's disease, and sigma-2 receptor knockdown protects retinal pigment epithelial cells (RPEs) from oxidative stress-induced cell death. Sigma-2 receptors are involved in numerous signaling pathways, including heme binding, cytochrome P450 metabolism, cholesterol synthesis, progesterone signaling, apoptosis, and membrane transport. Dysfunction of retinal pigment epithelial (RPE) cells plays a crucial role in the development of geographically atrophic (GA) dry age-related macular degeneration (AMD), and there is strong evidence that the Alzheimer's disease-associated amyloid-beta (Aβ) protein is involved in this process.

[0077] As the population ages, vision loss is becoming a major public health issue. According to the American Foundation for the Blind, blindness or low vision affects 32.2 million Americans aged 18 and older. The most common eye diseases among Americans aged 40 and older are age-related macular degeneration, glaucoma, cataracts, and diabetic retinopathy. The causes of these diseases are diverse and include injury, exposure to 15 types of toxins, underlying medical conditions (such as diabetes and arteriosclerosis), and genetic factors (such as excessive aqueous humor secretion). Except for cataracts, where the lens can be removed and replaced, there is no cure for these diseases, and vision loss is generally permanent.

[0078] Protective compounds are needed to slow, mitigate, or treat vision impairment or its progression. These protective compounds are useful in the context of damage resulting from impact or toxic chemicals, including counteracting toxic side effects associated with certain chemotherapy regimes, or improving the quality of life for populations experiencing progressive vision impairment.

[0079] Without being constrained by theory, it has been proposed that the sigma 2 receptor is a receptor for abeta oligomers in retinal pigment epithelial cells (RPE) and retinal ganglion cells (RGC) of the eye. Various receptors for soluble abeta oligomers have been proposed in the literature, including prion proteins, insulin receptors, β-adrenergic receptors, and RAGE (receptor for advanced glycation end products). Lauren, J. et al, 2009, Nature, 457(7233):1128-1132; Townsend, M. et al, J. Biol. Chem. 2007, 282:33305-33312; Sturchler, E. et al, 2008, J. Neurosci. 28(20):5149-5158. In fact, many researchers believe that abeta oligomers may bind to multiple receptor proteins. Without being bound by theory, the inventors hypothesize additional receptors for abeta oligomers located in the eye.

[0080] Without being constrained by theory, abeta oligomers are sigma receptor agonists that bind to sigma protein complexes, causing abnormal transport and cell damage. It is demonstrated herein that compounds described herein that antagonize this interaction and / or sigma receptor function in RPE and / or RGC compete with or otherwise interfere with abeta oligomers to prevent further cell damage and cell death. Such compounds are considered functional sigma 2 receptor antagonists for the treatment of ocular neurodegenerative diseases such as age-related macular degeneration.

[0081] In some embodiments, the compounds of any embodiment described herein may act as functional antagonists in RPE or RGC with respect to inhibiting soluble A oligomer-induced cell damage or cell death, and inhibiting soluble A oligomer-induced deficiencies in membrane trafficking assays and cell health assays.

[0082] In some embodiments, compounds according to any embodiment described herein, acting as functional antagonists that meet specific in vitro assay criteria detailed herein, are expected to exhibit or have behavioral efficacy in one or more relevant in vitro assays or animal behavior models.

[0083] According to the in vitro assay platform, the compounds of any embodiment described herein may bind with high affinity to the sigma 2 receptor; act as functional antagonists with respect to abeta-oligomer-induced effects in RPE and RGCs; inhibit abeta-oligomer-induced cell damage or death in RPE or RGCs; and may not affect membrane transport or cell health in the absence of abeta-oligomers. This pattern of activity in the in vitro assay is referred to as the “therapeutic phenotype.” The ability of the compounds of any embodiment described herein to block the Aβ-oligomer effect in RPE and RGCs without affecting normal function in the absence of Aβ-oligomers meets the criteria for a therapeutic phenotype. Compounds of any embodiment described herein having a therapeutic phenotype can block abeta-oligomer-induced RPE and RGC cell damage or death.

[0084] In some embodiments, compounds according to any embodiment described herein exhibit sigma-2 antagonist activity, high affinity for sigma-2 receptors, and the ability to block soluble Aβ oligomer binding or Aβ oligomer-induced RPE and RGC cell damage or death.

[0085] In some embodiments, the compounds according to any embodiment described herein block the binding between the soluble abeta oligomer and the sigma 2 receptor.

[0086] In some embodiments, the compounds according to any embodiment described herein exhibit high affinity for the sigma 2 receptor.

[0087] How to use Various embodiments relate to methods for treating ocular neurodegenerative diseases, comprising the step of administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0088] Some embodiments of the invention relate to the manufacture of therapeutic drugs for age-related macular degeneration described herein. [ka] The use of compounds selected from or pharmaceutically acceptable salts thereof is permitted.

[0089] Some embodiments of the invention relate to the manufacture of a pharmaceutical product for the treatment of age-related macular degeneration described herein. [ka] The use of compositions comprising a compound selected from or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0090] In some embodiments, ocular neurodegenerative diseases are selected from the group consisting of glaucoma, lattice dystrophy, retinitis pigmentosa, age-related macular degeneration (AMD), photoreceptor degeneration associated with wet or dry AMD, other retinal degenerations, optic tympanic membrane, optic neuropathy, and optic neuritis.

[0091] Various embodiments relate to methods for treating age-related macular degeneration (AMD), comprising the step of administering a therapeutically effective amount of the compound described herein to a subject in need of such treatment.

[0092] Some embodiments relate to methods for treating wet age-related macular degeneration (wet AMD), comprising the step of administering a therapeutically effective amount of one of the compounds described herein to a subject in need of such treatment.

[0093] Some embodiments relate to methods for treating dry age-related macular degeneration (dry AMD), comprising the step of administering a therapeutically effective amount of one of the compounds described herein to a subject in need of such treatment.

[0094] Some embodiments relate to methods for treating geographical atrophy (GA) dry age-related macular degeneration (AMD), comprising the step of administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0095] Some embodiments relate to methods for preventing cell death in nerve cells, comprising the step of administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0096] Some embodiments relate to a method for preventing cell death in retinal pigment epithelial cells (RPE), comprising the step of administering a therapeutically effective amount of the compound described herein to a subject in need thereof.

[0097] Some embodiments relate to a method for preventing cell death in retinal ganglion cells (RGCs), comprising the step of administering a therapeutically effective amount of the compound described herein to a subject in need thereof.

[0098] In some embodiments, the compounds according to any embodiment described herein may be protective against cellular dysfunction of retinal pigment epithelial (RPE) cells and retinal ganglion cells (RGCs) associated with dry AMD. In some embodiments, the compounds according to any embodiment described herein may prevent cellular dysfunction associated with dry AMD. In some embodiments, the compounds according to any embodiment described herein may prevent cellular dysfunction associated with dry AMD. Here, cellular dysfunction may be caused by inflammatory stimuli, oligomeric Aβ, 4-hydroxynonenal, or 4-hydroxy-2nonena (4-HNE), hydrogen peroxide, oxidative stress, and exposure to complement C3 activity.

[0099] Some embodiments relate to methods for treating or preventing oxidative stress in RPE and RGC, comprising the step of administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0100] In some embodiments, oxidative stress in RPE and RGC results in cell damage. In some embodiments, cell damage is selected from the group consisting of cytotoxicity, lipid peroxidation, carbonyl formation, reactive oxygen species formation, alteration of mitochondrial membrane potential, alteration of mitochondrial mass, alteration of mitochondrial function, alteration of autophagic flux, loss of lysosome integrity, alteration of lysosome activity, defects in photoreceptor extrasegment (POS) transport, accumulation of toxic macromolecules, axonal damage, cellular senescence, apoptosis, and cell death. In some embodiments, a method for treating or preventing oxidative stress includes administering to a subject in need of it a therapeutically effective amount of a pharmaceutical composition containing any compound described herein.

[0101] Some embodiments relate to methods for treating or preventing cytotoxicity in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0102] Some embodiments relate to methods for treating or preventing alterations in lysosomal activity in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0103] Some embodiments relate to methods for treating or preventing changes in the autophagic flux in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0104] Some embodiments relate to methods for treating or preventing defects in photoreceptor extrasegment (POS) transport in RPE, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0105] Some embodiments relate to methods for preventing cell death in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0106] Some embodiments relate to methods for preventing apoptosis in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0107] Some embodiments relate to methods for treating or preventing complement C3 dysfunction in RPE and RGC, comprising the step of administering a therapeutically effective amount of any compound described herein to a subject in need thereof.

[0108] In some embodiments, complement C3 dysfunction in the RPE and RGC results in cell damage. In some embodiments, cell damage is selected from the group consisting of cell death, transepithelial electrical resistance (TEER) deficiency, and RPE barrier deficiency.

[0109] Some embodiments relate to methods for treating or preventing inflammation in RPE and RGC, comprising the step of administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0110] In some embodiments, inflammation is caused by an inflammatory stimulus. In some embodiments, the inflammatory stimulus is selected from the group consisting of tumor necrosis factor-α (TNF-α), interferon-γ (IFNg), 4-hydroxynonenal, or 4-hydroxy-2-nonena, rotenone, terbutyl hydroperoxide, and hydrogen peroxide. In some embodiments, there are methods for treating or preventing inflammation caused by any of the inflammatory stimuli disclosed herein.

[0111] Some embodiments relate to methods for slowing the progression of dry age-related macular degeneration (dry AMD), comprising the step of administering a therapeutically effective amount of any of the compounds described herein to a subject in need thereof.

[0112] Some embodiments relate to methods for preventing dry age-related macular degeneration (dry AMD), comprising the step of administering a therapeutically effective amount of any of the compounds described herein to a subject in need thereof.

[0113] Some embodiments relate to methods for slowing the progression of symptoms associated with dry age-related macular degeneration (dry AMD), comprising the step of administering a therapeutically effective amount of any of the compounds described herein to a subject in need thereof.

[0114] In some embodiments, symptoms associated with dry age-related macular degeneration (dry AMD) are selected from the group consisting of the number of drusen, the size of drusen, intraocular hypertension, and decreased visual acuity. In some embodiments, a method for treating or preventing symptoms associated with dry AMD as described herein comprises administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising any of the compounds described herein.

[0115] Compounds used in the present invention In some embodiments, the compounds used in the present invention are selected from the group consisting of: A. A compound of formula I or a pharmaceutically acceptable salt thereof, [ka] Here, each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR'; Here, if present in R1 and R2, each R' is independently H or C1-C6 alkyl; Each of R3, R4, R5, and R6 is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), F, Cl, Br, I, CF3, CF, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n R' is selected from the group consisting of C(O)O(C1-C4 alkyl), OC(O)N(R')2, C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl); where, if present in R3, R4, R5, and R6, each R' is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, where the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acyl; Alternatively, R3 and R4, together with the C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl group, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, or R3 and R4 are linked together to form -OC 1- Forms a C2 methylene O-group, Alternatively, R4 and R5, together with the C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl group, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, or R4 and R5 are linked together to form -OC 1-2 Forms a methylene O-group, R7, R8, R9, R 10 , and R 11 Each of these is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), O(CO)R', F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) nR', S(O) n NR'2, S(O) n Independently selected from the group consisting of R', C(O)O(C1-C4alkyl), OCO(O)N(R')2, C(O)(C1-C4alkyl), and C(O)NH(C1-C4alkyl), where R7, R8, R9, R 10 , and R 11 Each R' present is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2. Alternatively, R7 and R8, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R7 and R8 are linked together to form -OC 1-2 Forms a methylene-O- group, Alternatively, R8 and R9, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R8 and R9 are linked together to form -OC 1-2 Forms a methylene O-group, Each n is independently 0, 1, or 2. However, R7, R8, R9, R 10 , and R 11 are not all H, and However, the following compounds: [Chemical formula] the compound of formula I or a pharmaceutically acceptable salt thereof, excluding or or B. A compound of formula IA or a pharmaceutically acceptable salt thereof, wherein [Chemical formula] wherein each of R a , R b , R c , R d , and R e is independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino; R 1A is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH3)2, and R 2A is an optionally substituted cyclic amino group, the compound of formula IA or a pharmaceutically acceptable salt thereof.

[0116] The compound of formula I In some embodiments, the compounds for use in the present invention are selected from the compounds of formula I or pharmaceutically acceptable salts thereof, [Chemical formula] each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR', where, when present in R1 and R2, each R' is independently H or C1-C6 alkyl; Each of R3, R4, R5, and R6 is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n Independently selected from R', C(O)O(C1-C4alkyl), OCO(O)N(R')2, C(O)(C1-C4alkyl), and C(O)NH(C1-C4alkyl). Here, if present in R3, R4, R5, and R6, each R' is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, where the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acyl. Alternatively, R3 and R4 together with the C atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R3 and R4 are linked together to form an -O-C1-C2 methylene O- group, Alternatively, R4 and R5 together with the C atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R4 and R5 are linked together to form an -O-C 1-2 methylene O- group, Each of R7, R8, R9, R 10 , and R 11 is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), O(CO)R', F, Cl, Br, I, CN, CF3, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O)n NR'2, S(O) n Independently selected from the group consisting of R', C(O)O(C1-C4alkyl), OCO(O)N(R')2, C(O)(C1-C4alkyl), and C(O)NH(C1-C4alkyl), where R7, R8, R9, R 10 , and R 11 Each R' present is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2. Alternatively, R7 and R8, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R7 and R8 are linked together to form -OC 1-2 Forms a methylene-O- group, Alternatively, R8 and R9, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R8 and R9 are linked together to form -OC 1-2 It becomes a methylene O-group, Each n is independently 0, 1, or 2. However, R7, R8, R9, R10 , R 11 are not all H, and provided that the following compounds, [Chemical formula] or a pharmaceutically acceptable salt thereof are excluded.

[0117] In some embodiments, the compound for use in the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from H or CH3; R3, R4, R5, and R6 are each independently H, C1-C6 alkyl, OH, OCH3, O(C1-C6 alkyl), O(C1-C6 haloalkyl), F, Cl, CF3, aryl, heteroaryl, C 3-7 cycloalkyl, CO2R', C(O)R', OC(O)N(R') 2, CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n R' independently selected from; where n = 0, 1, or 2; R' is each independently H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl; or optionally substituted piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, or aryl, where the optionally substituted groups are selected from C1-C6 alkyl or C2-C7 acyl; or R3 and R4 together with the C atom to which they are attached form a 5- or 6-membered C 3-7 cycloalkyl, or aryl; or R4 and R5 together with the C atom to which they are attached form a C 3-7 siloalkyl, or a 5- or 6-membered aryl; or R3 and R4 are linked to form an -O-C 1-2 methylene -O- group; or R4 and R5 are linked to form an -O-C 1-2 methylene -O- group; and R7, R8, R9, R 10 , and R 11These are independently H, OH, CH3, CH2CH3, F, Cl, CF3, OCF3, C1-C6 haloalkyl, OCH3, O(C1-C6 alkyl), OCH2CH2OH, O(C1-C6 alkyl)OH, aryl, heteroaryl, C 3-7 Cycloalkyl, alkylaryl, CO2R', CONR'2, S(O) n NR'2, S(O) n R', C(O)O(C 1-4 Alkyl), OCO(O)N(R')2, and C(O)NH(C 1-4 Selected from alkyl; where n = 0, 1, or 2; R' is independently H, C1-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, or C 1-6 It shows an alkoxy.

[0118] In some embodiments, the compound used in the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R7, R 10 , R 11 Each of these is H; R3 and R4 are independently H, F, Cl, and S(O). n R' is selected from C(O)R', where n=2, and R' is selected from CH3, piperazine-1-yl, piperidine-1-yl, or morpholinyl; R8 is selected from OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, or OC(CH3)3; and R9 is OH.

[0119] In some embodiments, the compound for use in the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] Selected from the group consisting of TIFF2023553414000023.tif161140.

[0120] In further embodiments, the compound used in the present invention is the compound of formula II, or a pharmaceutically acceptable salt thereof. [ka] Here, R3, R4, R 5, And R6 are independently H, Cl, F, OH, CH3, and C, respectively. 1-6 Alkyl, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, OC 1-6 Alkyl, aryl, heteroaryl, heterocycloalkyl, CO2R', CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n R', C(O)R', OC(O)N(R')2, or C(O)NH(C 1-4 Selected from alkyl, where n=0, 1, or 2; and R' is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1-6 Alkoxy, NH(C 1-4 Alkyl), or NH(C 1-4 Alkyl)2, where the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acyl; Alternatively, R3 and R4, together with the C atom to which they are bonded, form a 6-membered aryl group; or, R3 and R4 together form -OC 1-2 Forming a methylene-O- group; or, R4 and R5 together with the C atom to which they are bonded, form a 6-membered aryl group; or, R4 and R5 together form an -OC group. 1-2 Forms a methylene-O- group; and R8 and R9 are independently H, Cl, F, OH, CH3, and C, respectively. 1-6 Alkyl, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(CO)R', OC 1-6 Alkyl, aryl, heteroaryl, heterocycloalkyl, CO2R', CONR'2, NC(O)R', NS(O)n R', S(O) n NR'2, S(O) n R', OC(O)N(R')2, or C(O)NH(C 1-4 Selected from alkyl; Alternatively, R8 and R9, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, and R 9 and R 10 Each is independently bonded, selected from C, N, S, and O; or R8 and R9 are linked to -OC 1-2 It forms a methylene-O- group.

[0121] In further embodiments, the compound for use in the present invention is a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein at least one of R3, R4, R5, and R6 is not H; and at least one of R8 and R9 is not H.

[0122] In other embodiments, the compound for use in the present invention is the compound of formula II, or a pharmaceutically acceptable salt thereof, R7, R 10 , R 11 Each of these is H; R3 and R4 are independently H, F, Cl, and S(O). n R' is selected from C(O)R', where n=2, and R' is selected from CH3, or optionally substituted piperazine-1-yl, piperidine-1-yl, or morpholinyl, where any substituent is selected from C1-C6 alkyl or C2-C7 acyl; R8 is selected from OH, Cl, OCH3, OCH(CH3)2, OCH2CH(CH3)2, or OC(CH3)3, and R9 is OH or Cl.

[0123] In a further embodiment, the compound for use in the present invention is a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently H, F, Cl, S(O) n R', C(O)R', where n is selected from 2, and R' is selected from CH3, piperazin-1-yl, piperidin-1-yl, or morpholinyl; R5 and R6 are each H; R8 is selected from OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, or OC(CH3)3; R9 is OH.

[0124] In a further embodiment, the compound for use in the present invention, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

Chemical formula

[0125] In a further embodiment, the compound for use in the present invention, or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of:

Chemical formula

[0126] In a further embodiment, the compound for use in the present invention, or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of:

Chemical formula

[0127] In some embodiments, the compound for use in the present invention:

Chemical formula

[0128] In some embodiments, the compounds used in the present invention are: [ka] That is the case.

[0129] In some embodiments, the compounds used in the present invention, or pharmaceutically acceptable salts thereof, are R1, R2, R3, R4, R5, R6, R7, R8, R9, R of formula I. 10 , and R 11 Each of these is as defined herein, and R1, R6, R7, R 10 , and R 11 It is a compound in which each of the following is H; R2 is CH3; R8 is OCH3 or Cl; and R9 is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF. 3

[0130] In some embodiments, the compound used in the present invention is the compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, Here, R3, R4, R5, R6, R8, and R9 are as described herein.

[0131] In another embodiment, the compound used in the present invention is the compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, where R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 The following are provided herein, and each __________ is independently selected from single, double, or triple bonds.

[0132] In some embodiments, the compounds used in the present invention are compounds according to formula III, selected from the group consisting of: [ka] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the compounds for use in the present invention include racemic mixtures or enantiomers of the compound of formula I, where R3, R4, R5, R6, R8, and R9 are as described herein.

[0134] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are OH, C 1-6 Alkoxy and hydroxy C 1-6 It is selected independently of alkoxy.

[0135] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are OH and NH(C) 1-4 It is selected independently of alkyl.

[0136] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are H, halo, and C. 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0137] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are independently OH, halo, and C. 1-6 Alkoxy and C 1-6 Selected from haloalkoxys, R1 and R2 are independently C 1-6 It is alkyl.

[0138] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R1 and R2 are methyl, respectively.

[0139] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where one of R1 and R2 is methyl and the other is H.

[0140] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are independently OH and C 1-6 Selected from alkoxys, R1 and R2 independently exhibit methyl properties.

[0141] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R8 and R9 are H, halo, and C. 1-6 Selected independently from haloalkyl groups, R1 and R2 are methyl groups, respectively.

[0142] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R 8 and R 9 These are H, Halo, and C, respectively, independently. 1-6 Selected from haloalkyl groups.

[0143] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R7 and R 11 These are H.

[0144] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3, R4, R 5, And R6 are independently H, Halo, and C1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy.

[0145] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3, R4, and R5 are independently H, H, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy.

[0146] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3, R4, R5, and R6 are each independently H, halo, and S(O). n R' is selected from R', C(O)OR', C(O)N(R')2, and C(O)R'; where n=2; R' is independently selected from H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally C1-C6 alkyl or C2-C7 acyl-substituted aryl, alkylaryl, piperadinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl.

[0147] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3, R4, and R5 are independently H, halo, and S(O). n R' is selected from and C(O)R'; where n=2; R' is independently CH3, CH2CH3, C3-C6 alkyl, aryl, piperazine-1-yl, piperidine-1-yl, and morpholinyl-4-yl.

[0148] In some embodiments, the compounds used in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3, R4, and R5 are independently H, halo, and S(O). nR' and C(O)R' are selected; where n=2; R' is independently CH3, CH2CH3, C3-C6 alkyl, aryl, piperazine-1-yl, piperidine-1-yl, and morpholinyl-4-yl; R8 and R9 are independently OH, halo, and C 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys; and R1 and R2 are methyl, respectively.

[0149] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 or R4 and R5, together with the C atom to which they are bonded, form a six-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring.

[0150] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R3 and R4 or R4 and R5 are O, and together they are linked to -OC 1-2 It forms a methylene-O- group.

[0151] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2 and R 3 H, OH, halo, C 1-6 Alkoxy and C 1-6 It is independently selected from haloalkyl groups.

[0152] In some embodiments, the compounds used in the present invention include the compound of formula II, or a pharmaceutically acceptable salt thereof, where R3 and R4 are H, Cl, F, -OMe, -CF3, S(O) nR' and C(O)R' are independently selected; where n=2; R' is independently H, CH3, CH2CH3, C3-C6 alkyl, aryl, piperazine-1-yl, piperidine-1-yl, and morpholinyl-4-yl, respectively; R8 and R9 are independently OH and C 1-6 Selected from alkoxy.

[0153] In some embodiments, the compounds for use in the present invention include the compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2 and R 3 R is independently selected from H, OH, Cl, F, -OMe, and -CF3, where R 7 and R 8 H and C 1-6 Each alkyl is independently selected, where R 9 H, R 5 , and R 6 H and C 1-6 Each is independently selected from the haloalkyl groups.

[0154] In some embodiments, any compound of formulas I to III according to any embodiment described herein may include a provision for removing one or more of the following compounds: [ka]

[0155] Compounds of formula IA In some embodiments, the compound used in the present invention is the compound of formula IA. [ka] or containing a pharmaceutically acceptable salt thereof, Here, R a , R b , R c , R d , and R eEach of these is independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino; R 1A is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH3)2; and R 2A This is an arbitrarily substituted cyclic amino group.

[0156] In some embodiments, the compound used in the present invention is substituent R a , R b , R c , R d , and R e Each of these contains a compound of formula IA, independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino.

[0157] In some embodiments, the compound used in the present invention is substituent R a , R b , R c , R d , and R e Each of these comprises a compound of formula IA, independently selected from the group consisting of H, Cl, F, and CF3.

[0158] In some embodiments, the compound used in the present invention is substituent R a , R b , R d , and R e Each of them is independently H; and R c The compound comprises a compound of formula IA selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0159] In some embodiments, the compound used in the present invention is substituent R a , R b , R d , and R eEach of them is independently H; and R c This includes compounds of formula IA selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino.

[0160] In some embodiments, the compound used in the present invention is substituent R a , R b , R d , and R e Each of them is independently H; and R c This includes compounds of formula IA selected from the group consisting of H, Cl, F, and CF3.

[0161] In various embodiments, the compounds used in the present invention are R 2A However, the compound of formula IA is any heterocycloalkyl or heteroaryl containing nitrogen in the ring bonded to the aliphatic chain of formula IA via a nitrogen atom. In some embodiments, for example, R 2A teeth: [ka] and an optionally substituted cyclic amino group selected from analogs, where each nitrogen-containing heterocycloalkyl or heteroaryl is hydroxyl, halo, CF3, alkoxy, aryloxy, or optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optional substitution C3-C 10 Heteroaryl, substituted or unsubstituted C3-C 10 Contains siloalkyl or heterocycloalkyl.

[0162] In various embodiments, the compounds used in the present invention are R 2AHowever, it includes compounds of formula IA selected from the group of optionally substituted azilidinyl, optionally substituted pyrrolidinyl, optionally substituted imidizolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted oxopiperazinyl, and optionally substituted morpholinyl.

[0163] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A If is a substituted cyclic amino, one or more hydrogen atoms of the cyclic amino group are substituted with a group selected from alkanoyl, alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, alyloxy, aliroyl, cycloalkanoyl, -OC(O)NCH(CH3)2, (N,N-dimethylamino)pyridinyl, (N,N-dimethylamino)sulfonyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydrosyl, hydroxyalkyl, methylpiperidinyl, methylsulfonyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF3. In some embodiments, two hydrogen atoms on the same carbon of the cyclic amino group are substituted with a compound selected from the following: [ka] , forming a spiro compound.

[0164] In some embodiments, the compound used in the present invention is R 2A It contains the compound, where R 2A is a pyrrolidinyl, or a substituted pyrrolidinyl substituted with one or more substituents selected from the group consisting of alkoxyalkyl, alkoxycarbonyl, alkyl, hydroxyl, and hydroxyalkyl. In some embodiments, R 2AR is a substituted pyrrolidine substituted with a single substituent selected from the group consisting of alkoxyalkyl, alkoxycarbonyl, alkyl, hydroxyl, and hydroxyalkyl. In some embodiments, R 2A This is a substituted pyrrolidinyl compound substituted with a single substituent selected from the group consisting of hydroxyl, hydroxymethyl, methoxymethyl, methoxycarbonyl, and methyl.

[0165] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A is a substituted piperidinyl, or a substituted piperidinyl substituted with one or more substituents selected from the group consisting of piperidinyl, alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC(O)NCH(CH3)2, (N,N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridine, tetrahydropyranyl, and CF3. In some embodiments, R 2A This is a piperidinyl or substituted piperidinyl substituted with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC(O)NCH(CH3)2, (NN-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF3. In some embodiments, R 2AThis is a piperidinyl or substituted piperidinyl substituted with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC(O)NCH(CH3)2, (NN-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF3. In some embodiments, R 2A This includes piperidinyl or methyl, isopropyl, isobutyl, CF3, hydroxymethyl, hydroxyethyl, (isopropyloxy)ethyl, -(CH2)2O(CH2)2OCH3, -(CH2)3OCH3, -C(OMe), -C(O)OEt, hydroxyl, methoxy, isopropyloxy, phenyloxy, phen, ethoxy, phenyl, [ka] A piperidinyl or substituted piperidinyl substituted with a single substituent selected from the group consisting of the following. In some embodiments, R 2A This is piperidinyl or substituted piperidinyl, which is piperidinyl or substituted piperidinyl substituted at the 4-position of piperidinyl with a single substituent selected from the group consisting of piperidinyl, or piperidinyl, or alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC(O)NCH(CH3)2, (N,N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridanyl, tetrahydropyranil, and CF3. In some embodiments, R 2AThis includes piperidinyl, or isopropyl, isobutyl, CF3, hydroxymethyl, hydroxyethyl, (isopropyloxy)ethyl, -(CH2)2O(CH2)2OCH3, -(CH2)3OCH3, -C(O)Ome, -C(O)OEt, hydroxyl, methoxy, isopropyloxy, phenyloxy, ethoxy, phenyl, [ka] A piperidinyl or substituted piperidinyl, in which a single substituent selected from the group consisting of is substituted at the 4-position of piperidinyl.

[0166] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A is a piperidinyl independently selected from the group consisting of alkoxyalkyl, alkyl, -OC(O)NCH(CH3)2, hydroxyl, and phenyl, or a substituted piperidinyl obtained by substituting two substituents on the same carbon of piperidinyl. In some embodiments, R 2A is a piperidinyl or a substituted piperidinyl substituted with two substituents at the 4-position, independently selected from the group consisting of alkoxyalkyl, alkyl, -OC(O)NCH(CH3)2, hydroxyl, and phenyl. In some embodiments, R 2A This is a piperidinyl or substituted piperidinal in which two substituents are substituted at the 4-position, selected from the group consisting of hydroxyl and methyl; hydroxyl and ethyl; hydroxyl and -(CH2)2OCH3; hydroxyl and phenyl; methyl and phenyl; methyl and -OC(O)NCH(CH3)2; and butyl and -OC(O)NCH(CH3)2. In some embodiments, two hydrogen atoms on the same carbon of piperidinyl are [ka] It is substituted with a compound selected from to form a spiro compound. In some embodiments, the two hydrogen atoms at the 4-position of piperidinyl are [ka] It is substituted with a compound selected from the list to form a spiro compound.

[0167] In some embodiments, the compounds used in the present invention include the compound of formula IA, where R 2A R is piperidinyl or substituted piperidinyl, which is substituted with one or more substituents selected from the group consisting of piperidinyl, alkoxycarbonyl, ariloyl, cycloalkanoyl, (N,N-dimethylamino)sulfonyl, heterocyclyl, methylsulfonyl, and phenyl. In some embodiments, R 2A R is a substituted piperidinyl that is substituted with a single substituent selected from the group consisting of alkanoyl, alkoxycarbonyl, ariloyl, cycloalkanoyl, (N,N-dimethylamino)sulfonyl, heterocyclyl, methylsulfonyl, and phenyl. In some embodiments, R 2A -C(O)OC(CH3)3, -C(O)OCH2CH(CH3)2, -C(O)OCH2CH3, -C(O)OCH3, phenyl [ka] A substituted piperazinyl is a substituted piperazinyl that is substituted with a single substituent selected from the group consisting of -C(O)CH3, -C(O)Ph, -SO2Me, and -SO2N(CH3)2. In some embodiments, R 2A is -C(O)OC(CH3)3, -C(O)OCH2CH(CH3)2, -C(O)OCH2CH3, -C(O)OCH3, phenyl, -C(O)CH3, -C(O)Ph, -SO2Me, -SO2N(CH3)2, [ka] A substituted piperazinyl selected from the group consisting of the following, which is substituted at the 4-position with a single substituent.

[0168] In a particular embodiment, the compound used in the present invention is R 2A, is a compound of formula IA, where R is the substituted piperdinyl of formula IA: [ka] Here, R 3A R is hydrogen or C1-C8 alkyl, 4A C1-C is a hydrogen, hydroxyl, halogen, CF3, alkoxy, aryloxy, or optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C3-C 10 Heteroaryl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 It is heterocycloalkyl.

[0169] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A teeth, [ka] And, Here, R 5A and R 6A Each of them independently consists of hydrogen, hydroxyl, sulfonyl, dialkylamino, and optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl arbitrarily substituted C3-C 10 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 It is heterocycloalkyl. In some embodiments, R 5A is hydrogen, dialkylamino, or C3-C 10 It is heterocycloalkyl. In some embodiments, R 5A R is hydrogen, dialkylamino, pyrrolidinyl, or morpholinyl. In some embodiments, R 6A is a sulfonyl. In some embodiments, R 6A It is methylsulfonyl.

[0170] In some embodiments, the compound used in the present invention is R 2A The compound is of formula IA, where R 2A teeth: [ka] The filename is TIFF2023553414000049.tif167141. Here, R 3a n is selected from the group consisting of hydrogen and C1-C8 alkyl groups. A is an integer selected from 0, 1, and 2.

[0171] In some embodiments, the compounds used in the present invention include compounds of formula IA, Here, R 2A teeth, [ka] That is the case.

[0172] In some embodiments, the compound used in the present invention is R 2A The compound comprises a compound of formula IA in which is optionally substituted morpholinyl. In some embodiments, R 2A It is morpholinyl.

[0173] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A is, formula [ka] It is a piperazinyl that is optionally substituted for, Here, R 7 C1-C1 is a hydrogen atom, hydroxyl atom, sulfonyl atom, dialkylaminosulfonyl atom, alkoxycarbonyl atom, acyl atom, benzoyl atom, cycloalkylcarbonyl atom, or optionally substituted C1-C1. 10 Alkyl, optionally substituted C5-C 10Aryl, optionally substituted C3-C 10 Heteroalkyl, optionally substituted C3-C 10 Siloalkyl or optionally substituted C3-C 10 It is heterocycloalkyl. In some embodiments, R 7A These include sulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, acyl, benzoyl, cycloalkylcarbonyl, and C5-C 10 Aryl, or optionally substituted C3-C 10 It is heterocycloalkyl.

[0174] In some embodiments, the compounds used in the present invention include the compound of formula IA, where R 2A teeth, [ka] That is the case.

[0175] In various embodiments, the compounds for use in the present invention include compounds of formula IA, where R 2A is an optionally substituted pyrrolidinyl: [ka] Here, R 8A C1-C is a hydrogen atom, hydroxyl atom, sulfonyl atom, or optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C3-C 10 Heteroaryl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 It is heterocycloalkyl. In some embodiments, R 8A C1-C is a hydrogen atom, a hydroxyl atom, or an optionally substituted C1-C atom. 10 It is alkyl.

[0176] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A teeth: [ka] That is the case.

[0177] In some embodiments, the compound used in the present invention is R 2A The compound comprises a compound of formula IA in which is an optionally substituted bicyclic ring or an optionally substituted fused ring. For example, in some embodiments, R 2A teeth: [ka] Selected from the group consisting of, Here, R 9A C1-C is a hydrogen atom, hydroxyl atom, sulfonyl atom, or optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C3-C 10 Heteroaryl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 It is heterocycloalkyl.

[0178] In some embodiments, the compounds used in the present invention include compounds of formula IA, where R 2A teeth, [ka] And, Here, R 11a , R 11b , R 11c , and R 11d Each of them independently consists of hydrogen, hydroxyl, sulfonyl, and optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C3-C 10 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 Selected from heterocycloalkyls. In certain embodiments, R 2A teeth, [ka] The filename is TIFF2023553414000058.tif114131.

[0179] In some embodiments, the compounds used in the present invention are each R a , R b , R c , R d and R e However, R a , R b , R c , R d , and R e A compound of formula IA selected from any embodiment disclosed herein for each of the following; R 1A R 1A Any embodiment disclosed herein is selected for R 2A R 2A Any embodiment disclosed herein is selected for this purpose.

[0180] In some embodiments, the compounds used in the present invention are selected from the group consisting of: [ka] TIFF2023553414000060.tif188141TIFF2023553414000061.tif170141TIFF2023553414000062.t if169141TIFF2023553414000063.tif184141TIFF2023553414000064.tif180141TIFF2023553414 000065.tif169141TIFF2023553414000066.tif175141TIFF2023553414000067.tif177141TIFF20 23553414000068.tif176141TIFF2023553414000069.tif167141TIFF2023553414000070.tif21014 1TIFF2023553414000071.tif175141TIFF2023553414000072.tif176141TIFF2023553414000073. tif171141TIFF2023553414000074.tif171141TIFF2023553414000075.tif179141TIFF2023553414 000076.tif163141TIFF2023553414000077.tif172141TIFF2023553414000078.tif191138TIFF20 23553414000079.tif164141TIFF2023553414000080.tif195141TIFF2023553414000081.tif77168

[0181] In some embodiments, the compounds used in the present invention are: [ka] It is a compound selected from the group consisting of the following:

[0182] In some embodiments, the compounds used in the present invention are compounds of formula IIA or pharmaceutically acceptable salts thereof: [ka] That is the case.

[0183] Substituent R of formula IIA f , R g , R h , R i , and R j Each of these is independently selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0184] Substituent R of formula IIA 10A is an arbitrarily substituted cyclic amino group, m A x is an integer between 0 and 3.

[0185] In some embodiments, substituent R of formula IIA f , R g , R h , R i , and R j Each of these is independently selected from the group consisting of H, hydroxyl, and alkoxy. In some embodiments, substituent R of formula IIA is used. f , R g , R h , R i , and R j Each of these is independently selected from the group consisting of H, hydroxyl, and methoxy. In some embodiments, substituent R f , R g , and R j Each of them is H, and R g , and R h Each of these is independently selected from hydroxyl or methoxy.

[0186] In some embodiments, R of formula IIA 10AThis is any azilidinyl, any substituted pyrrolidinyl, any substituted imidizolidinyl, any substituted piperidinyl, any substituted piperazinyl, any substituted oxopiperazinyl, or any substituted morpholinyl, and any of the individual substituted or unsubstituted piperidinyls, substituted or unsubstituted morpholinyls, substituted or unsubstituted piperazinyls, substituted or unsubstituted pyrrolidinyls, substituted or unsubstituted bicyclic rings, or substituted or unsubstituted fusion rings as described above in relation to Formula I.

[0187] In some embodiments, R of formula IIA 10A is an arbitrarily substituted condensed ring, for example: [ka] And, Here, R 11e , R 11f , R 11g , and R 11h Each of them independently consists of hydrogen, hydroxyl, sulfonyl, and optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C3-C 10 Heteroalkyl, optionally substituted C3-C 10 Cycloalkyl or optionally substituted C3-C 10 Select heterocycloalkyl. In certain embodiments, R 10A is, m A When it is 2, [ka] isn't it.

[0188] In some embodiments, R 10A Equation f IIA is, [ka] The filename is TIFF2023553414000087.tif188141.

[0189] In some embodiments, the compound used in the present invention is the compound of formula IIa: [ka] That is the case.

[0190] Substituent R of formula IIa k and R l Each of these is independently selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0191] Substituent R of formula IIa 12A aryloxy, alkenyloxy, alkoxy, aminoalkyl, N,N-dimethylaminoalkyl, pyrrolidinyl, n-methylpyrrolidinyl, N-acylpyrrolidinyl, carboxyaminoalkyl, hydroxyalkyl, -O(CH2)2OC(O)CH, [ka] A selection is made from the group consisting of the following.

[0192] In some embodiments, substituent R of formula IIa k and R l Each of these is independently selected from the group consisting of H, hydroxyl, and methoxy. In some embodiments, R lA is methoxy, and R k It is a hydroxyl group.

[0193] In some embodiments, substituent R of formula IIa 12A These are phenyloxy, -OCH2CH=CH2, methoxy, -CH2NH2, -CH(NH2)CH3, -CH2N(Me)2, -CH(CH3)N(Me)2, -CH2NHC(O)CH3, -CH(OH)CH3, -O(CH2)2OC(O)CH3, [ka] It is selected from the group consisting of the following.

[0194] In some embodiments, the compounds used in the present invention are: [ka] The compound is selected from the group consisting of TIFF2023553414000092.tif170141 and TIFF2023553414000093.tif91141.

[0195] In some embodiments, the compounds used in the present invention are: [ka] The compound is selected from the group consisting of TIFF2023553414000095.tif173141TIFF2023553414000096.tif171141TIFF2023553414000097.tif207141TIFF2023553414000098.tif162131.

[0196] Additional embodiments include salts, solvates, stereoisomers, prodrugs, and active metabolites of compounds according to any embodiment described herein.

[0197] Some embodiments relate to the free base form of the compound according to any embodiment described herein. Other embodiments relate to salts of the compound, such as pharmaceutically acceptable acid addition salts or pharmaceutically acceptable addition salts of the free base. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nitric acid, phosphoric acid, sulfuric acid, or hydrogen bromide, hydrochloric acid, hydrogen iodide, hydrogen fluoride, phosphoric acid, as well as salts derived from aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxylalkanoates, alkanedios, aromatic acids, aliphatic and aromatic sulfonic acids, as well as non-toxic organic acids such as acetic acid, maleic acid, succinic acid, or citric acid. Non-limiting examples of such salts include napadisylates, besilates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorine, bromides, iodides, acetates, trifluoroacetic acid, propionic acid, caprylates, isobutyrates, oxalates, malons, succinates, sverates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartroots, methanesulfonates, and analogues. Additional salt forms of the above compounds include salts of amino acids such as alginates, glucons, and galacturons (see, for example, Berge, et al. "Pharmaceutical Salts," J. Pharma. Sci. 1977; 66:1).

[0198] pharmaceutically acceptable base addition salts are formed from metals and amines such as alkali metals, alkaline earth metals, and organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and analogues. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of the acidic compounds are prepared by contacting the free acid form with a desired base in an amount sufficient to produce a salt by conventional methods. The free acid form can be regenerated by contacting the salt form with the acid and isolating the free acid.

[0199] Various embodiments include total salts and partial salts, i.e., salts having 1, 2, or 3 equivalents, preferably 1 equivalent, of acid per mole of base of the compound according to any embodiment described herein, and salts having 1, 2, or 3 equivalents, preferably 2 equivalents, of salt per mole of acid of the compound or salt described herein. Typically, pharmaceutically acceptable salts of the compounds according to any embodiment described herein can be readily prepared by using the desired acid or base as appropriate. The salts can be precipitated from the solution and recovered by filtration or by evaporation of the solvent. For example, an aqueous solution of an acid, such as hydrochloric acid, may be added to an aqueous suspension of the compound according to any embodiment described herein, and the resulting mixture may be evaporated and dried (freeze-dried) to obtain an acid-added salt as a solid. Alternatively, the compound according to any embodiment described herein may be dissolved in a suitable solvent, such as an alcohol such as isopropanol, and an acid may be added in the same solvent or another suitable solvent. The resulting acid-added salt can then be precipitated directly or by adding a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

[0200] Many organic compounds can form complexes with the solvents they react with or with which they precipitate or crystallize. Such complexes are called “solvates.” For example, a complex with water is known as a “hydrate.” Various embodiments include solvates of compounds according to any embodiment described herein. In some embodiments, salts of these compounds may form solvates.

[0201] Further embodiments include N-oxides of compounds according to any embodiment described herein. The N-oxides otherwise contain unsubstituted sp 2 These include heterocycles containing a N atom. Examples of such N-oxides include pyridyl N-oxide, pyrimidyl N-oxide, pyrazinyl N-oxide, and pyrazolyl N-oxide.

[0202] Compounds according to any embodiment described herein may have one or more chiral centers and, depending on the properties of the individual substituents, may also have geometric isomers. Thus, embodiments include stereoisomers, diastereomers, and enantiomers of compounds according to any embodiment described herein. Chiral compounds may exist as either individual enantiomers or mixtures of enantiomers. A mixture containing enantiomers in equal proportions is called a “racemic mixture.” A mixture containing unequal portions of enantiomers is described as having an “enantiomer excess” (ee) of either the R or S compound. An excess of one enantiomer in a mixture is often expressed as a % enantiomer excess. The ratio of enantiomers can also be defined by “optical purity,” which compares the degree to which a mixture of enantiomers rotates plane-polarized light to that of the individual optically pure R and S compounds. Compounds may also be substantially pure (+) or (-) enantiomers of the compounds described herein. In some embodiments, the composition may contain a substantially pure enantiomer that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one enantiomer. In certain embodiments, the composition may contain a substantially pure enantiomer that is at least 99.5% of one enantiomer.

[0203] The above description encompasses all individual isomers of the compounds according to any embodiment described herein, and the description or naming of specific compounds herein and in the claims is intended to include both individual enantiomers and mixtures thereof. Methods for determining stereochemistry and for separating or stereosynthesizing stereoisomers are well known in the art. Diastereomers differ in both physical properties and chemical reactivity. Mixtures of diastereomers can be separated into enantiomer pairs based on solubility, crystallization, or chromatographic properties, e.g., thin-layer chromatography, column chromatography, or HPLC. Purifying complex mixtures of diastereomers into enantiomers usually requires two steps. In the first step, the mixture of diastereomers is broken down into enantiomer pairs as described above. In the second step, the enantiomer pairs are further purified to obtain a composition concentrated with one or the other enantiomer, or more preferably, a composition containing the pure enantiomer. Separation of enantiomers usually requires reaction or molecular interaction with a chiral agent, e.g., a solvent or column matrix. Decomposition can be achieved, for example, by converting a mixture of enantiomers, such as a racemic mixture, into a mixture of diastereomers by reaction with a second agent, i.e., a pure enantiomer of the decomposing agent. The two resulting diastereomer products can then be separated. The separated diastereomers are then converted back into pure enantiomers by reversing the initial chemical reaction.

[0204] Enantiomer separation can also be achieved by differences in non-covalent bonding to chiral substances. Non-covalent bonding between an enantiomer and a chromatographic adsorbent forms a diastereomer complex, which differentially leads to separation in the mobile and bound states within the chromatographic system. Therefore, two enantiomers can move at different rates within a chromatographic system, such as a column, and be separated.

[0205] Further embodiments include prodrugs of compounds according to any embodiment described herein, i.e., compounds that, when administered to a mammalian subject, release in vivo the active compound according to any embodiment described herein. A prodrug is a pharmacologically active compound or, more typically, an inactive compound that is converted into a pharmacologically active agent by metabolic transformation. Prodrugs of compounds according to any embodiment described herein are prepared by modifying a functional group present in the compound according to any embodiment described herein so that the modification can be cleaved in vivo to release the parent compound. In vivo, the prodrug readily undergoes chemical transformation under physiological conditions (e.g., by hydrolysis or by action by naturally occurring enzymes), releasing the pharmacologically active agent. Prodrugs include compounds according to any embodiment described herein in which a hydroxyl group, an amino group, or a carboxyl group is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, an amino group, or a carboxyl group, respectively. Examples of prodrugs include, but are not limited to, esters of the compounds according to any embodiment described herein (e.g., acetate, formate, and benzoate derivatives), or any other derivatives that are converted to the active parent compound when brought to physiological pH or by enzymatic action. Conventional procedures for the selection and preparation of suitable prodrug derivatives have been described in the Art (see, for example, Bundgaard. Design of Prodrugs. Elsevier, 1985).

[0206] In some embodiments, one or more hydrogen atoms of a compound according to any embodiment described herein are substituted with deuterium. Deuteration of physiologically active compounds is well established to offer the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively impacting metabolic outcomes. Selective substitution of one or more hydrogen atoms with deuterium in a compound according to any embodiment described herein may improve the safety, tolerability, and efficacy of the compound compared to its total hydrogen counterpart.

[0207] Methods for incorporating deuterium into compounds are well-established. Using established metabolic studies in the art, compounds according to any embodiment described herein can be tested to identify sites for the selective placement of deuterium isotopes that are not metabolized. Furthermore, these studies identify metabolic sites as locations where deuterium atoms will be positioned.

[0208] Pharmaceutical composition used in the present invention Some embodiments describe pharmaceutical compositions comprising compounds according to any embodiment described herein, pharmaceutically acceptable salts thereof, solvates thereof, stereoisomers thereof, prodrugs thereof, or active metabolites thereof; and pharmaceutically acceptable carriers or diluents. Pharmaceutical compositions can be prepared by methods well known in pharmaceutical technology and can be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated.

[0209] While the compounds described in any embodiment of this specification can be administered as bulk substances, it is preferable to present the compounds in a pharmaceutical formulation, for example, in a mixture with a pharmaceutically acceptable carrier selected with respect to the intended route of administration and standard pharmaceutical practice.

[0210] In particular, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any embodiment described herein, and optionally a pharmaceutically acceptable carrier.

[0211] combination With respect to the pharmaceutical compositions and methods disclosed herein, the compounds according to any embodiment described herein may be used in combination with other therapeutic agents and / or activators.

[0212] In some embodiments, the compounds according to any embodiment described herein can be combined with one or more of the following: anti-vascular endothelial growth factor (VEGF) therapy, vascular occlusion, and glaucoma treatment. In some embodiments, the compounds are combined with VEGF inhibitors selected from brolucizumab (BEOVU®; Novartis), aflibercept (Eylea®; Regeron), ranibizumab (Lucentis®; Genentech), bevacizumab (Avastin®; Genentech), and pegaptanib (Macugen®; Bausch+Lomb). In some embodiments, the compounds are combined with vascular occlusion treatment selected from verteporfin (Visudyne®; Bausch+Lomb) and laser therapy. In some embodiments, the compound is combined with a complementary cascade of therapeutic agents selected from POT-4 (Compstatin®, Alcon), ARC1905 (Ophthotech), Eculizumab (Soliris®, Alexion Pharmaceuticals), FCFD4514S (Genentech), TA106 (Taligen Therapeutics and Alexion Pharmaceuticals), JSM-7717 (EvaluatePharma), CR2-fH, and C1INH (ViroPharma). In some embodiments, the compound is combined with a glaucoma treatment selected from brimonidine (Alpagan®; Allergan), apraclonidine (Iopidine®; Novartis), and netaludil (Rhopressa®, Aerie Pharmaceuticals). In some embodiments, the compound is used in combination with a glaucoma treatment selected from beta-blockers, carbonic anhydrase inhibitors, cholinergics, and prostaglandins.

[0213] In some embodiments, the compounds according to any embodiment described herein can be combined with one or more of the following: anti-vascular endothelial growth factor (VEGF) therapy, vascular occlusion, and glaucoma treatment. In some embodiments, the compounds are combined with VEGF inhibitors selected from brolucizumab (BEOVU®; Novartis), aflibercept (Eylea®; Regeron), ranibizumab (Lucentis®; Genentech), bevacizumab (Avastin®; Genentech), and pegaptanib (Macugen®; Bausch+Lomb). In some embodiments, the compounds are combined with vascular occlusion treatment selected from verteporfin (Visudyne®; Bausch+Lomb) and laser therapy. In some embodiments, the compound is combined with a complementary cascade therapeutic agent selected from POT-4 (Compstatin®, Alcon), ARC1905 (Ophthotech), Eculizumab (Soliris®, Alexion Pharmaceuticals), FCFD4514S (Genentech), TA106 (Taligen Therapeutics and Alexion Pharmaceuticals), JSM-7717 (EvaluatePharma), CR2-fH, and C1INH (ViroPharma). In some embodiments, the compound is combined with a glaucoma treatment selected from brimonidine (Alpagan®; Allergan), apraclonidine (Iopidine®; Novartis), and netaludil (Rhopressa®, Aerie Pharmaceuticals). In some embodiments, the compound is combined with a glaucoma therapeutic agent selected from β-blockers, carbonic anhydrase inhibitors, cholinergics, and prostaglandins.

[0214] Accordingly, in a further embodiment, the present disclosure provides a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable derivative thereof according to any embodiment described herein; a second activator; and an optional pharmaceutically acceptable carrier.

[0215] When combined in the same formulation, it will be understood that two or more compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation in the manner known for such compounds in the art.

[0216] Preservatives, stabilizers, dyes, and flavorings may be provided in any pharmaceutical composition described herein. Examples of preservatives include esters of sodium benzoate, ascorbic acid, and p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0217] For combinations involving biologics such as monoclonal antibodies or fragments, appropriate excipients will generally be employed to prevent aggregation and stabilize the antibody or fragment in a low-endotoxin solution, typically for parenteral administration, such as intravenous administration. See, for example, *Formulation and Delivery Issues for Monoclonal Antibody Therapeutics*, Daugherty et al., in *Current Trends in Monoclonal Antibody Development and Manufacturing*, Part 4, 2010, Springer, New York, pp. 103-129.

[0218] Compounds according to any embodiment described herein may be ground using known grinding procedures, such as wet grinding, to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticle) preparations of the compounds may be prepared by processes known in the art, for example, referring to WO 02 / 00196 (SmithKline Beecham).

[0219] Compounds according to any embodiment described herein, or pharmaceutically acceptable salts thereof, solvates thereof, stereoisomers thereof, prodrugs thereof, or active metabolites thereof, can be formulated for any route of administration.

[0220] Regarding the route of administration and unit dosage form Routes of administration (delivery) include, but are not limited to, one or more of the following: topical administration (e.g., subconjunctival, intravitreous, retrobulbar, intracavitary), oral administration (e.g., as tablets, capsules, or ingestible solutions), topical administration, mucosal administration (e.g., as nasal spray or inhaled aerosol), parenteral administration (e.g., by injection), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraventricular, or other depot administration.

[0221] Accordingly, pharmaceutical compositions according to any embodiment described herein include forms specifically formulated for a mode of administration. In certain embodiments, the pharmaceutical compositions of this disclosure are formulated in a form suitable for oral delivery. In some embodiments, the compounds are orally bioavailable compounds suitable for oral delivery. In other embodiments, the pharmaceutical compositions of this disclosure are formulated in a form suitable for parenteral delivery.

[0222] Compounds in any embodiment described herein can be formulated for administration in any convenient manner for use in human or veterinary medicine, and therefore this disclosure includes, within its scope, pharmaceutical compositions comprising compounds in any embodiment described herein that are adapted for use in human or veterinary medicine. Such pharmaceutical compositions may be presented for use in conventional methods with the help of one or more suitable carriers. Carriers acceptable for therapeutic use are well known in pharmaceutical technology and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro edit. 1985). The choice of pharmaceutical carrier may be made in relation to the intended route of administration and standard pharmaceutical practice. In addition to the carrier, the pharmaceutical composition may consist of any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizer(s).

[0223] Different requirements for pharmaceutical compositions / formulations may exist depending on the different delivery systems. It will be understood that not all compounds need to be administered via the same route. Similarly, if a pharmaceutical composition contains multiple active ingredients, those ingredients may be administered via different routes. For example, the pharmaceutical compositions of this disclosure may be formulated to be delivered via a local ocular route, for example, as a subconjunctival or intravitreal injection, in which case the pharmaceutical composition is formulated for delivery by injection into the eye. Alternatively, the formulation may be designed to be delivered systemically, in which case the pharmaceutical composition is formulated for delivery, for example, by an intravenous or oral route. Alternatively, the formulation may be designed to be delivered via multiple routes.

[0224] Combinations of compounds according to any embodiment described herein with antibodies or antibody fragment molecules can be formulated and administered by any of a number of routes to be administered at therapeutically effective concentrations for the desired indication or purpose. To achieve this purpose, antibodies can be formulated with a variety of acceptable excipients known in the art. Typically, antibodies are administered by injection, for example, intravenous injection. Methods for achieving this administration are known to those skilled in the art. For example, Gokarn et al., 2008, J Pharm Sci 97(8):3051-3066, incorporated herein by reference, describe a variety of high-concentration antibody self-buffered formulations. For example, monoclonal antibodies in self-buffered formulations may be, for instance, 50 mg / mL mAb in 5.25% sorbitol, pH 5.0; or 60 mg / mL mAb in 5% sorbitol, 0.01% polysorbate 20, pH 5.2; or conventional buffered formulations, for example, 50 mg / mL mAb in 5.25% sorbitol, 5.25% sorbitol, 25 or 50 mM acetic acid, glutamic acid, or succinic acid, pH 5.0; or 60 mg / mL in 10 mM acetic acid or glutamic acid, 5.25% sorbitol, 0.01% polysorbate 20, pH 5.2; other lower concentration formulations may be employed as known to those skilled in the art.

[0225] Since some of the compounds of this disclosure cross the blood-brain barrier, they can be administered by various methods, including, for example, systemic (e.g., via IV, SC, oral, mucosal, or percutaneous routes) or topical (e.g., intracranial).

[0226] When a compound according to any embodiment described herein is administered directly to the eye, the compound may be administered topically to the eye or eyelid, for example, using eye drops, ointments, creams, gels, suspensions, etc. The compound(s) may be formulated with excipients such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidine, neutral poly(meth)acrylate esters, and other viscosity improvers. The compound(s) may be injected into the eye, for example, by injection under the conjunctiva or Tenon capsule, intravitreous injection, or posterior bulb injection. The compound(s) may be administered using sustained-release drug delivery systems, such as polymers, matrices, microcapsules, or other delivery systems formulated from, for example, glycolic acid, lactic acid, a combination of glycolic acid and lactic acid, liposomes, silicones, polyvinyl acetate alone or in combination with polyethylene glycol, etc. The delivery device may be implanted in the eye for long-term drug delivery, for example, by implantation under the conjunctiva, implantation in the wall of the eyeball, or sutured to the sclera.

[0227] Pharmaceutically acceptable excipients and additives for ophthalmic use are known to those skilled in the art (carriers, stabilizers, solubilizers, tonics, buffers, preservatives, thickeners, complexing agents, and other excipients). Examples of such additives and excipients can be found in U.S. Patents 5,891,913, 5,134,124, and 4,906,613. In some embodiments, the pharmaceutical compositions of the present invention are prepared, for example, by mixing an activator with the corresponding excipient and / or additive to form the corresponding ophthalmic composition. Compounds according to any embodiment described herein can be administered in the form of eye drops, and the activator is conventionally dissolved, for example, in a carrier. The solution is adjusted to a desired pH and / or buffered as needed, and stabilizers, solubilizers, or tension enhancers are added as needed. Preservatives and / or other excipients are added as needed to the ophthalmic formulation of the present invention.

[0228] If a compound according to any embodiment described herein is to be delivered mucosally through the gastrointestinal mucosa, it should be able to maintain stability during passage through the gastrointestinal tract; for example, it should be resistant to proteolysis, stable at acidic pH, and resistant to the lavage effect of bile. For example, a compound according to any embodiment described herein, prepared for oral administration, may be coated with an enteric coating layer. The enteric coating layer material can be dispersed or dissolved in either water or a suitable organic solvent. As the enteric coating layer polymer, one or more solutions or dispersions of, for example, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyphthalic acid acetate, cellulose acetate trimellit, carboxymethyl ethylcellulose, shellac, or other suitable enteric coating layer polymers(s) can be used separately or in combination. In some embodiments, the aqueous enteric coating layer is a methacrylic acid copolymer.

[0229] Where appropriate, pharmaceutical compositions according to any embodiment described herein may be administered orally by inhalation, by use of a skin patch, in the form of a tablet containing an excipient such as starch or lactose, or in the form of a capsule or egg formulation, alone or in combination with an excipient, or in the form of an elixir, solution or suspension containing a fragrance or coloring agent, or they may be administered parenterally, for example, by intravenous, intramuscular or subcutaneous injection. For buccal or sublingual administration, pharmaceutical compositions according to any embodiment described herein may be administered in the form of a tablet or lozenge, which may be formulated in the conventional manner.

[0230] When a pharmaceutical composition according to any embodiment described herein is administered parenterally, such administration includes, but is not limited to, administering the compounds of the disclosure intravenously, intra-arterially, intracerebrally, intracranially, intramuscularly, or subcutaneously; and / or using infusion techniques. Antibodies or fragments are typically administered parenterally, for example, intravenously.

[0231] Pharmaceutical compositions according to any embodiment described herein, suitable for injection or infusion, may be in the form of a sterile aqueous solution, dispersion, or sterile powder containing the active ingredient, adjusted as necessary for the preparation of such sterile solutions or dispersions suitable for injection or infusion. The preparation may optionally be encapsulated in liposomes. In any case, the final preparation must be sterile, liquid, and stable under manufacturing and storage conditions. To improve storage stability, such formulations may also contain preservatives to prevent microbial growth. Prevention of microbial action can be achieved by the addition of various antimicrobial and antifungal agents, such as parabens, chlorobutanol, or ascorbic acid. Often, isotonic substances, such as sugars, buffers, and sodium chloride, are recommended to ensure osmotic pressure similar to that of body fluids, particularly blood. Long-term absorption of such injectable mixtures can be achieved by introducing absorption retarders, such as aluminum monostearate or gelatin.

[0232] The dispersion can be prepared in a liquid carrier or intermediate such as glycerin, liquid polyethylene glycol, triacetin oil, and mixtures thereof. The liquid carrier or intermediate may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, etc.), vegetable oils, non-toxic glycerin esters, and suitable mixtures thereof. Appropriate fluidity can be maintained by liposome formation, administration of appropriate particle size in the case of dispersions, or addition of surfactants.

[0233] For parenteral administration, the compounds according to any embodiment described herein are best used in the form of a sterile aqueous solution containing other substances, such as a salt or glucose sufficient to make the solution isotonic with blood. The aqueous solution should be appropriately buffered as needed (preferably to a pH of 3 to 9). The preparation of a suitable parenteral formulation under sterile conditions is readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0234] A sterile injection solution can be prepared by mixing the compound according to any embodiment described herein with a suitable solvent and one or more of the aforementioned carriers, and then by sterile filtration. For sterile powders suitable for use in the preparation of sterile injection solutions, preferred preparation methods include drying in vacuum and freeze-drying, which provide a powdered mixture of the compound and the desired excipient for the subsequent preparation of a sterile solution.

[0235] Compounds according to any embodiment described herein are formulated for human or veterinary use by injection (e.g., by intravenous bolus injection or infusion, or by intramuscular, subcutaneous, or intrathecal routes) and may be presented in unit dose form, ampoules, or other unit dose containers, or in multi-dose containers with preservatives as appropriate. The pharmaceutical compositions for injection may be in the form of suspensions, solutions, or emulsions in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers, solubilizers, and / or dispersants. Alternatively, the active ingredient may be in the form of a sterile powder for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0236] Compounds according to any embodiment described herein may be administered in the form of tablets, capsules, lozenges, eggs, elixirs, solutions, or suspensions for immediate release, delayed release, modified release, sustained release, pulsed release, or controlled release applications.

[0237] Compounds according to any embodiment described herein may also be presented for human or veterinary use in forms suitable for oral or buccal administration, such as solutions, gels, syrups, or suspensions, or as dry powders for reconstitution with water or other suitable vehicles before use. Solid pharmaceutical compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powders, pastes, granules, bullets, or premix formulations may also be used. Solid and liquid pharmaceutical compositions for oral use may be prepared according to methods well known in the art. Such pharmaceutical compositions may also include one or more pharmaceutically acceptable carriers and excipients, which may be in solid or liquid form.

[0238] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or tapioca starch); sodium starch glycolate, croscarmellose sodium, certain complex silicates; and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia.

[0239] Furthermore, it may contain lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc.

[0240] Pharmaceutical compositions according to any embodiment described herein may be administered orally in the form of rapid-release or controlled-release tablets, microparticles, minitablets, capsules, sachets, and oral solutions or suspensions, or powders for their preparation. Oral formulations may optionally contain a variety of standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, slicks, pigments, disintegrants, flavoring agents, sweeteners, surfactants, release agents, anti-adhesion agents, and coating agents. Some excipients may have multiple roles in the pharmaceutical composition, for example, acting as both a binder and a disintegrant.

[0241] Examples of pharmaceutically acceptable disintegrants for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, sodium croscarmellose, microcrystalline cellulose, alginates, resins, surfactants, foaming compositions, aqueous aluminum silicates, and crosslinked polyvinylpyrrolidone.

[0242] Examples of pharmaceutically acceptable binders for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, acacia; cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylate, polyvinylpyrrolidone, sorbitol, starch, pregeratinized starch, tragacanth, xanthine resin, alginate, magnesium aluminum silicate, polyethylene glycol, or bentonite.

[0243] Examples of pharmaceutically acceptable fillers for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (especially fine crystalline cellulose), calcium dihydro or anhydrophosphate, calcium carbonate, and calcium sulfate.

[0244] Examples of pharmaceutically acceptable lubricants useful in pharmaceutical compositions according to any embodiment described herein include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

[0245] Examples of suitable pharmaceutically acceptable fragrances for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, as well as similar aromas. Their use depends on many factors, the most important of which is organological tolerance for the population that will be taking the pharmaceutical composition.

[0246] Examples of pharmaceutically acceptable pigments suitable for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, synthetic and natural pigments such as titanium dioxide, β-carotene, and grapefruit peel extract.

[0247] Examples of useful pharmaceutically acceptable coatings for oral pharmaceutical compositions according to any embodiment described herein typically include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and acrylate-methacrylate copolymers, which are used to facilitate swallowing, modify release properties, improve appearance, and / or mask taste of pharmaceutical compositions.

[0248] Preferred examples of pharmaceutically acceptable sweeteners for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, aspartame, saccharin, sodium saccharin, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, and sucrose.

[0249] Preferred examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate, and magnesium hydroxide.

[0250] Preferred examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbate.

[0251] Similar types of solid compositions may also be used as fillers for gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, lactose, or high molecular weight polyethylene glycol. In the case of aqueous suspensions and / or elixirs, the agent may be combined with various sweeteners or flavorings, colorants or dyes, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0252] As shown, the compounds according to any embodiment described herein can be administered nasally or by inhalation, and conveniently delivered in the form of a dry powder inhaler or aerosol spray using a pressurized vessel, pump, spray, or nebulizer, with a suitable propellant, e.g., a hydrofluoroalkane such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA134AT), or 1,1,1,2,3,3-heptafluoropropane (HFA227EA), carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for supplying a metered amount. The pressurized vessel, pump, spray, or nebulizer may contain a solution or suspension of the active compound, e.g., a mixture of ethanol and a propellant as a solvent, and may additionally contain a lubricant, e.g., sorbitan trioleate.

[0253] Capsules and cartridges for use in inhalers or air inhalers (e.g., made from gelatin) may be formulated to contain a powder mixture of the compound according to any embodiment described herein, and a suitable powder base such as lactose or starch.

[0254] For topical administration by inhalation, the compounds according to any embodiment described herein may be delivered via a nebulizer for human or veterinary use.

[0255] The pharmaceutical compositions of this disclosure may contain 0.01 to 99% by weight of the active substance per volume. For topical administration, for example, the pharmaceutical composition will generally contain 0.01 to 10%, more preferably 0.01 to 1%, of the active material.

[0256] Compounds according to any embodiment described herein may be administered in the form of liposome delivery systems such as small monolayer vesicles, large monolayer vesicles, and multiple monolayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine.

[0257] Pharmaceutical compositions or unit dosage forms according to any embodiment described herein may be administered in accordance with doses and administration regimens defined by routine testing in light of the guidelines given above, in order to obtain optimal activity while minimizing toxicity or adverse effects to a particular patient. The dosage of a compound or unit dosage form may vary depending on various factors such as the state of the underlying disease, the individual's condition, weight, sex, and age, as well as the mode of administration. The exact amount to administer to a patient will vary depending on the state and severity of the disorder and the patient's physical condition. Measurable improvement of any symptom or parameter may be determined by those skilled in the art or reported to a physician by the patient. It will be understood that any clinically or statistically significant attenuation or improvement of any symptom or parameter is within the scope of this disclosure. Clinically significant attenuation or improvement means that it is perceptible to the patient and / or physician.

[0258] In some embodiments, the amount of compound administered may be between approximately 0.01 and approximately 25 mg / kg / day. Generally, a daily dose between 0.01 and 25 mg / kg of body weight is administered to a patient, e.g., a human. In some embodiments, the therapeutically effective dose is approximately 0.01 mg / kg of body weight, approximately 0.1 mg / kg of body weight, approximately 0.2 mg / kg of body weight, approximately 0.3 mg / kg of body weight, approximately 0.4 mg / kg of body weight, approximately 0.5 mg / kg of body weight, approximately 0.60 mg / kg of body weight, approximately 0.70 mg / kg of body weight, approximately 0.80 mg / kg of body weight, approximately 0.90 mg / kg of body weight, approximately 1 mg / kg of body weight, approximately 2.5 mg / kg of body weight, approximately 5 mg / kg of body weight, approximately 7.5 mg / kg of body weight, approximately 10 mg / kg of body weight, approximately 12.5 mg / kg of body weight, approximately 15 mg / kg of body weight, approximately 17.5 mg / kg of body weight, approximately 20 mg / kg of body weight, and approximately 22.5 mg of body weight. The upper limits include approximately 25 mg / kg of body weight, approximately 22.5 mg / kg of body weight, approximately 20 mg / kg of body weight, approximately 17.5 mg / kg of body weight, approximately 15 mg / kg of body weight, approximately 12.5 mg / kg of body weight, approximately 10 mg / kg of body weight, approximately 7.5 mg / kg of body weight, approximately 5 mg / kg of body weight, approximately 2.5 mg / kg of body weight, approximately 1 mg / kg of body weight, approximately 0.9 mg / kg of body weight, approximately 0.8 mg / kg of body weight, approximately 0.7 mg / kg of body weight, approximately 0.6 mg / kg of body weight, approximately 0.5 mg / kg of body weight, approximately 0.4 mg / kg of body weight, approximately 0.3 mg / kg of body weight, approximately 0.2 mg / kg of body weight, and approximately 0.01 mg / kg of body weight. In some embodiments, the therapeutically effective dose is about 0.1 mg / kg / day to about 10 mg / kg / day, and in some embodiments, the therapeutically effective doses are about 0.2 and about 5 mg / kg / day. Since such effective doses can be achieved by administering multiple divided doses of such pharmaceutical formulations, it will be understood that the pharmaceutical formulations of this disclosure do not necessarily have to contain the entire amount of the compound effective in treating the disorder. The compound can be administered in regimens of one to four times per day, such as once, twice, three, or four times per day.

[0259] In some embodiments of this disclosure, the compounds according to any embodiment described herein are typically formulated into capsules or tablets containing about 10 to about 200 mg of the compound. In some embodiments, the capsules or tablets contain approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 135 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 160 mg, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, and approximately 19 The dosage ranges from approximately 5 mg to approximately 200 mg, with an upper limit of approximately 200 mg, and including lower limits of approximately 200 mg, approximately 195 mg, approximately 190 mg, approximately 185 mg, approximately 180 mg, approximately 175 mg, approximately 170 mg, approximately 165 mg, approximately 160 mg, approximately 155 mg, approximately 150 mg, approximately 145 mg, approximately 140 mg, approximately 135 mg, approximately 130 mg, approximately 125 mg, approximately 120 mg, approximately 115 mg, approximately 110 mg, approximately 105 mg, approximately 100 mg, approximately 95 mg, approximately 90 mg, approximately 85 mg, approximately 80 mg, approximately 75 mg, approximately 70 mg, approximately 65 mg, approximately 60 mg, approximately 55 mg, approximately 50 mg, approximately 45 mg, approximately 40 mg, approximately 35 mg, approximately 30 mg, approximately 25 mg, approximately 20 mg, approximately 15 mg, and approximately 10 mg.

[0260] In some embodiments, the compounds according to any embodiment herein are administered to a patient in a total daily dose of 50 mg to 500 mg. In some embodiments, the daily dose is approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 135 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 160 mg, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg mg, approx. 200 mg, approx. 250 mg, 210 mg, approx. 215 mg approx. 220 mg, approx. 225 mg, approx. 230 mg, approx. 235 mg, approx. 240 mg, approx. 245 mg, approx. mg, approx. 285 mg, approx. 290 mg, approx. 295 mg, 300 mg, approx. 305 mg, approx. 310 mg, approx. 315 mg, approx. 320 mg, approx. 325 mg, approx. 330 mg, approx. 335 mg, approx. mg, approximately 370 mg, approximately 375 mg, approximately 380 mg, approximately 385 mg, approximately 390 mg, approximately 395 mg, 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, and approximately 500 mg and the upper limit, and approximately 500 mg, approximately 495 mg, approximately 490 mg, approximately 485 mg, 480 mg, 475 mg, approx. 500 mg, approx. 465 mg, approx. 460 mg, approx. 455 mg, approx. 450 mg, approx. 445 mg, approx. 440 mg, approx. 435 mg, approx. 430 mg, approx. 0mg, approx. 385mg, approx. 380mg, approx. 375mg, 370mg, 365mg, 360mg, approx. 355mg, 350mg, 345mg, approx. 340mg, approx. 335mg, approx. 330mg, approx.About 300mg, about 295mg, about 290mg, about 285mg, about 280mg, about 275mg, about 265mg, about 260mg, about 255mg, about 250mg, about 245mg, about 240mg, 235 mg, 230mg, about 225mg, about 220mg, about 215mg, about 210mg, about 205mg, 200mg, about 195mg, about 190mg, about 185mg, about 180mg, about 175mg, about 1 The upper limits are between 70 mg, approximately 165 mg, approximately 160 mg, approximately 155 mg, approximately 150 mg, approximately 145 mg, approximately 140 mg, approximately 135 mg, approximately 130 mg, approximately 125 mg, approximately 120 mg, approximately 115 mg, approximately 110 mg, approximately 105 mg, approximately 100 mg, approximately 95 mg, approximately 90 mg, approximately 85 mg, approximately 80 mg, approximately 75 mg, approximately 70 mg, approximately 65 mg, approximately 60 mg, approximately 55 mg, and approximately 50 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 150 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 250 mg. In some embodiments, the total daily dose is approximately 50 mg to approximately 350 mg. In some embodiments, the total daily dose is approximately 50 mg to 450 mg. In some embodiments, the total daily dose is approximately 50 mg.

[0261] The pharmaceutical composition for parenteral administration contains, based on 100% by weight of the total pharmaceutical composition, an active compound according to any embodiment described herein in an amount of about 0.01% to about 100% by weight.

[0262] Generally, the transdermal dosage form contains about 0.01% to about 100% by weight of the active compound according to any embodiment described herein, based on 100% of the total weight of the dosage form.

[0263] The pharmaceutical composition or unit dosage form may be administered once daily, or the total daily dose may be divided and administered in installments. Furthermore, co-administration or sequential administration of other compounds for the treatment of disorders may be desirable. For this purpose, the combined active principle is formulated into a simple dosing unit.

[0264] In some embodiments, the compounds according to any embodiment described herein generally inhibit the Aβ effect on neurons. In some embodiments, the compounds described above are ICs for inhibiting the Aβ effect at concentrations of less than about 100 μM, less than about 50 μM, less than about 20 μM, less than about 15 μM, less than about 10 μM, less than about 5 μM, and less than about 1 μM. 50 The compound has the ability to aggregate or disrupt amyloid, and to bind amyloid (including amyloid oligomers) to neurons (such as neurons in the brain) of about 500 nM, about 100 nM, about 50 nM, or about 10 nM, as well as to deposit amyloid. In some embodiments, the compound according to any embodiment described herein has the ability to inhibit the activity / effect of Aβ species such as oligomers of less than about 100 μM, less than about 50 μM, less than about 20 μM, less than about 15 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, about 500 nM, about 100 nM, about 50 nM, or about 10 nM on neurons (such as neurons in the central nervous system). 50 It holds.

[0265] Compounds according to any embodiment described herein may inhibit the Aβ effect by specifically binding to the sigma-2 receptor. A compound can be said to be "specific" to the sigma-2 receptor if, although it can bind to both sigma-1 and sigma-2 receptors, it binds with at least 10% greater binding affinity than it binds to the sigma-1 receptor. Compounds of such embodiments may exhibit specificity to the sigma-2 receptor at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or 1000% greater than that to the sigma-1 receptor.

[0266] In some embodiments, the percentage inhibition by the compounds according to any embodiment described herein of one or more effects of Aβ species such as oligomers on RPE and RGC, including amyloid-induced oxidative stress, cell damage, cell death, and abnormal membrane trafficking mediated by Aβ oligomers, may be about 1% to about 20%, about 20% to about 50%, about 1% to about 50%, or about 1% to about 80% when measured at concentrations of 10 nM to 10 μM. Inhibition can be evaluated, for example, by quantifying defects in photoreceptor extraseptal (POS) transport before and after exposure to amyloid-β species, or by quantifying defects in photoreceptor extraseptal (POS) transport with the compounds according to any embodiment described herein, either concurrently with β species exposure or in the presence of both preceding and succeeding Aβ species. As another example, inhibition can be evaluated by comparing one or more parameters that determine membrane trafficking and measure the rate and degree of cellular senescence, or other indicators of cellular health and metabolism, in the presence and absence of Aβ species, and in the presence and absence of the compound according to any embodiment described herein.

[0267] In some embodiments, an assay is used to determine whether a compound according to any embodiment described herein can bind to the sigma-2 receptor. In some embodiments, the method further includes determining whether a compound that binds to the sigma-2 receptor acts as a functional antagonist at the sigma-2 receptor by inhibiting soluble A oligomer-induced cytotoxicity.

[0268] Any form of amyloid, including amyloid monomers, oligomers, fibrils, and amyloid associated with proteins ("protein complexes"), more generally amyloid aggregates, can be used in screening methods and assays as disclosed. For example, a screening method may employ various forms of soluble amyloid oligomers, e.g., U.S. Patent Application No. 13 / 021,872, U.S. Patent Publication No. 2010 / 0240868, International Patent Application No. WO / 2004 / 067561, International Patent Application No. WO / 2010 / 011947, U.S. Patent Publication No. 20070098721, U.S. Patent Publication No. 20100209346, International Patent Application No. WO / 2007 / 005359, U.S. Patent U.S. Patent Publication No. 20080044356, U.S. Patent Publication No. 20070218491, WO / 2007 / 126473, U.S. Patent Publication No. 20050074763, International Patent Application No. WO / 2007 / 126473, International Patent Application No. WO / 2009 / 048631, and U.S. Patent Publication No. 20080044406, U.S. Patent No. 7,902,328, and U.S. Patent No. 6,218,506 are incorporated herein by reference, respectively.

[0269] Amyloid forms, including amyloid monomers or oligomers, can be obtained from any source. For example, in some embodiments, commercially available amyloid-beta monomers and / or amyloid-beta oligomers can be used in aqueous solutions, and in other embodiments, the amyloid monomers and / or amyloid-beta oligomers used in aqueous protein solutions can be separated and purified by those skilled in the art using any number of known techniques. In general, the amyloid-beta monomers and / or amyloid-beta oligomers used in the preparation of aqueous solutions of proteins and amyloid in various embodiments may be soluble in aqueous solutions. Thus, both the protein and amyloid-beta in the aqueous solution may be soluble.

[0270] The added amyloid may be any isoform. For example, in one embodiment, the amyloid monomer may be amyloid β1-42, and in another embodiment, the amyloid β monomer may be amyloid β1-40. In yet another embodiment, the amyloid β may be amyloid β1-39 or amyloid β1-41. Thus, the amyloid β of various embodiments may encompass any C-terminal isoform of amyloid β. Yet another embodiment includes amyloid β with a frayed N-terminus, and in some embodiments, the N-terminus of any of the above amyloid β C-terminal isomers may be amino acids 2, 3, 4, 5, or 6. For example, amyloid β1-42 may include amyloid β2-42, amyloid β3-42, amyloid β4-42, or amyloid β5-42 and mixtures thereof, and similarly, amyloid β1-40 may include amyloid β2-40, amyloid β3-40, amyloid β4-40, or amyloid β5-40.

[0271] The form of amyloid-beta used in various embodiments may have the same amino acid sequence as the wild-type amyloid-beta, i.e., the amyloid-beta synthesized in vivo by the majority of the population, or in some embodiments, the amyloid-beta may be a mutant amyloid-beta. The embodiments are not limited to any particular variety of mutant amyloid-beta. For example, in some embodiments, the amyloid-beta introduced into the aqueous solution may include known mutations, such as amyloid-beta having the "Dutch" (E22Q) mutation or the "Arctic" (E22G) mutation. Such mutant monomers may include naturally occurring mutations, such as amyloid-beta forms isolated from a population of individuals predisposed to Alzheimer's disease, or familial forms of amyloid-beta. In other embodiments, mutant amyloid-beta monomers may be synthesized using molecular techniques to produce amyloid-beta variants having specific mutations. In yet another embodiment, mutant amyloid-beta monomers may include previously unidentified mutations, such as those found in randomly generated amyloid-beta variants. As used herein, the term "amyloid-beta" is intended to encompass both the wild-type form of amyloid-beta and the mutant form of amyloid-beta.

[0272] In some embodiments, the amyloid-beta in the aqueous protein solution may be a single isoform. In other embodiments, various C-terminal isoforms and / or various N-terminal isoforms of amyloid-beta may be combined to form an amyloid-beta mixture that can be provided in the aqueous protein solution. In yet another embodiment, the amyloid-beta may be derived from an amyloid precursor protein (APP) that is added to a protein-containing aqueous solution and cleaved in situ, in which embodiment, various isoforms of amyloid-beta may be present in the solution. In the aqueous solution after the addition of amyloid-beta, N-terminal fraying and / or removal of C-terminal amino acids may occur. Therefore, aqueous solutions prepared as described herein may contain various amyloid-beta isoforms even if a single isoform was initially added to the solution.

[0273] The amyloid-beta monomer added to the aqueous solution may be isolated from a natural source such as biological tissue, and in other embodiments, the amyloid-beta may be derived from a synthetic source such as transgenic mice or cultured cells. In some embodiments, the amyloid-beta form, including monomers, oligomers, or combinations thereof, is isolated from normal subjects and / or patients diagnosed with cognitive impairment or related diseases such as Alzheimer's disease, but is not limited to these. In some embodiments, the amyloid-beta monomer, oligomer, or combination thereof is an abeta aggregate isolated from a normal subject or a patient with the disease. In some embodiments, the abeta aggregate has a high molecular weight, e.g., 100 kDa or more. In some embodiments, the Aβ aggregate has an intermediate molecular weight, e.g., 10 to 100 kDa. In some embodiments, the Aβ aggregate has less than 10 kDa.

[0274] In some embodiments, amyloid-beta oligomers may consist of any number of amyloid-beta monomers that are consistent with the commonly used definition of "oligomer-beta." For example, in some embodiments, an amyloid-beta oligomer may contain about 2 to about 300, about 2 to about 250, or about 2 to about 200 amyloid-beta monomers, while in other embodiments, an amyloid-beta oligomer may consist of about 2 to about 150, about 2 to about 100, about 2 to about 50, or about 2 to about 25 amyloid-beta monomers. In some embodiments, an amyloid-beta oligomer may contain two or more monomers. Amyloid-beta oligomers in various embodiments can be distinguished from amyloid-beta fibrils and amyloid-beta protofibrils based on monomer identification. In particular, the monomers of amyloid-beta oligomers are generally spherical, consisting of β-pleated sheets, whereas the secondary structure of amyloid-beta monomers in fibrils and protofibrils is a parallel β-sheet.

[0275] Provided herein is Embodiment A, a method for treating dry age-related macular degeneration (dry AMD), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of compounds of formula I. [ka] or a pharmaceutically acceptable salt thereof: where each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR', where each R' is independently H or C1-C6 alkyl if present in R1 and R2; each of R3, R4, R5, and R6 is independently H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O (C1-C6 haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) nR' is selected from the group consisting of C(O)O(C1-C4 alkyl), OC(O)N(R')2, C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl); where R' is present in R3, R4, R5, and R6, each R' is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or an optional substituted aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, where optionally substituted The group is selected from C1-C6 alkyl or C2-C7 acyl; or R3 and R4 together with the C atom to which they are bonded form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl group, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R3 and R4 are linked together to form -OC 1- R4 and R5, together with the C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl group, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, or R4 and R5 are linked together to form an -OC 1-2 Forms a methylene O-group; R7, R8, R9, R 10 , and R 11Each of these is H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), O(CO)R', F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R', C(O)R', NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C7 cycloalkyl), NHC(O)(C1-C4 alkyl), CONR'2, NC(O)R', NS(O) n R', S(O) n NR'2, S(O) n Independently selected from the group consisting of R', C(O)O(C1-C4alkyl), OCO(O)N(R')2, C(O)(C1-C4alkyl), and C(O)NH(C1-C4alkyl), where R7, R8, R9, R 10 , and R 11 Each R' present is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazine-1-yl, piperidine-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, or R7 and R8 together with the N or C atom to which they are bonded to form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R7 and R8 are linked together to form -OC 1-2R8 and R9, together with the N or C atom to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R8 and R9 are linked together to form an -OC 1-2 A methylene O- group is formed; each n is independently 0, 1, or 2; R7, R8, R9, R 10 , and R 11 There is a caveat that not all of them are H; and a caveat that the following compounds, or their pharmaceutically acceptable salts, are excluded. [ka] .

[0276] Provided herein is Embodiment B, a method for treating dry age-related macular degeneration (dry AMD), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of compounds of formula IA: [ka] or a pharmaceutically acceptable salt thereof: where R a , R b , R c , R d , and R e Each of them is independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino; R 1A R is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH3)2. 2A This is an arbitrarily substituted cyclic amino group.

[0277] The method according to Embodiment A, wherein in Embodiment C, the compound is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0278] In Embodiment D, the method according to any one of Embodiments A to C, wherein the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0279] Embodiment E is the method according to any one of Embodiments A to D, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0280] Embodiment F is the method according to any one of Embodiments A to E, wherein the pharmaceutically acceptable salt is a fumarate.

[0281] In Embodiment G, one of the methods from Embodiments A to F, wherein the compound is [ka] That is the case.

[0282] Embodiment H is the method of Embodiment B, wherein the compound is the compound of formula IA or a pharmaceutically acceptable salt thereof.

[0283] Embodiment I is a method according to either Embodiment A or H, where R 2A , piperidinil substituted by choice.

[0284] In Embodiment J, one of the methods of Embodiments A, H, or I, wherein R 2A teeth, [ka] It is selected from the group consisting of the following.

[0285] In Embodiment K, one of the methods of Embodiments A, H, I, or J, wherein the compound or a pharmaceutically acceptable salt thereof is [ka] It is selected from the group consisting of the following.

[0286] Provided herein is Embodiment L, a method for treating dry age-related macular degeneration (AMD), comprising administering a therapeutically effective amount of a compound to a subject in need thereof. [ka] The selection is made from the group consisting of TIFF2023553414000107.tif133141 and TIFF2023553414000108.tif182141.

[0287] Embodiment M is a method for treating age-related macular degeneration in dryness, comprising the step of administering to a subject requiring such treatment a therapeutically effective amount of a pharmaceutical composition containing a compound according to any one of Embodiments A to L and a pharmaceutically acceptable excipient.

[0288] Embodiment N is a method for treating dry age-related macular degeneration, comprising, to a subject in need, a therapeutically effective amount of a compound selected from the group. [ka] A method is provided which includes the step of administering a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0289] In Embodiment O, the method of Embodiment N, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0290] The method according to Embodiment N, wherein in Embodiment P, the pharmaceutically acceptable salt is a fumarate.

[0291] In Embodiment Q, the method of Embodiment P is used, wherein the compound is [ka] That is

[0292] Provided herein is Embodiment R, [ka] The use of a compound selected from, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the treatment of dry age-related macular degeneration.

[0293] Provided herein is Embodiment S, [ka] The use of compounds selected from, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients in the manufacture of pharmaceuticals for the treatment of dry age-related macular degeneration.

[0294] Embodiment T involves the use of a compound or composition of either Embodiment R or S, wherein the compound is a pharmaceutically acceptable salt thereof.

[0295] In Embodiment U, the use of any one of Embodiments R to T is such that the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0296] In Embodiment V, the use of Embodiment U is such that the pharmaceutically acceptable salt is a fumarate.

[0297] In Embodiment W, the use of either Embodiment R or S, wherein the compound is [ka] That is the case.

[0298] In Embodiment X, the use of either Embodiment R or S, wherein the compound is [ka] That is the case.

[0299] In Embodiment Y, the use of either Embodiment R or S, wherein the compound is [ka] That is the case.

[0300] In Embodiment Z, the compound is administered orally, using the methods described in Embodiments A through Y.

[0301] Examples Abeta oligomer preparations are known to those skilled in the art and can be found, for example, in WO2015 / 116923 and WO2018 / 213281, each of which is incorporated in whole by reference, and the methods described herein constitute further aspects of this disclosure. Throughout the examples, the following sigma 2 receptor modulators were used: [ka] [Examples]

[0302] Example 1: Testing of a therapeutic compound for functional disorders associated with dry AMD. Experimental Design Cell Culture: Human retinal pigment epithelial cell line ARPE19, purchased from ATCC, is cultured at 37°C and 5% CO2 in Ham's F-10 medium (Corning) supplemented with 10% fetal bovine serum (FBS) and antibiotics (the medium is refreshed every 48–72 hours). For all experimental purposes, cells are brought to confluence in appropriate culture vessels (assay-dependent) and maintained in Ham's F-10 medium + 5% FBS for two weeks prior to the experiment to allow for the formation of a fully polarized epithelial monolayer. Cells are visualized using an inverted microscope throughout the experiment. Assays to detect protective activity in ocular cells are performed according to Cai, H. et al., "High-Throughput Screening Identifies Compounds that Protect RPE Cells from Physiological Stressors Present in AMD," Exp Eye Res, 185:10764 (2019), which is incorporated herein by reference in its entirety.

[0303] Preparation of the compound: Add the compound of the present invention to the cell culture at a concentration of 10 nM to 10 μM, add the vehicle, and pre-incubate at 37°C and 5% CO2 for 24 hours.

[0304] Oxidative stress protocol: Cultures pretreated with the vehicle or the compound of the present invention are subjected to oxidative stress for 4 hours and 24 hours. In the second protocol, ARPE-19 cells are treated with the compound of the present invention for 24 hours before adding the oxidative stress agent tert-butyl hydroperoxide (tBHP; 150 μM). After 24 hours, cell viability is evaluated by MTT assay, propidium iodide (PI) staining, and / or lactate dehydrogenase (LDH) assay. The experimental controls in this study are as follows: 1) Vehicle (DMSO)-treated cells without oxidative stressor (healthy vehicle control), 2) Vehicle (DMSO)-treated cells with oxidative stressor (injury control), 3) Rescue control (e.g., Nec-7)-oxidative stressor-treated cells (injury + control fully rescued).

[0305] Assay and results: Cell viability assay: Cells were washed three times with PBS, fixed with 4% paraformaldehyde in PBS, and stained with a solution of 0.1% crystal violet (Sigma Aldrich, C-3866) and 10% ethanol. After washing three times with PBS, the remaining stain was dissolved in 10% acetic acid, and the absorbance at 540 nm was measured using a microplate reader. The results are as follows: The compounds of the present invention reduce the degree of cytotoxicity induced by oxidative stressors in a concentration-dependent manner.

[0306] Measurement of Oxidative Damage: Oxidative stress is a significant factor in the development and acceleration of retinal diseases such as macular degeneration (Masuda T. et al., "Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger," Oxidative Medicine and Cellular Longevity Vol.2017, Article ID 9208489, (2017); and Forest, DL, et al., "Cellular Models and Therapies for Age-Related Macular Degeneration," Dis Model Mech 8(5):421-427(2015); these are incorporated herein by reference in their entirety). Oxidative damage is measured by: 1) a human 4HNE (4-hydroxynonenal) ELISA (enzyme-linked immunosorbent assay) kit for lipid peroxidation, and 2) a protein carbonyl assay for detecting oxidative damage to proteins. Results: The compounds of the present invention reduce the degree of oxidative damage induced by oxidative stressors in a concentration-dependent manner, as measured by a reduction in lipid peroxidation and a decrease in protein carbonyl formation.

[0307] Measurement of reactive oxygen species: Cells are harvested and incubated in PBS containing 10 mM CM-H2DCFDA (chloromethyl derivative of 2',7'-dichlorodihydrofluorescein diacetate; Life Technologies, D-399) at 37°C in the dark for 30 minutes to allow the dye to be loaded into the cells. This dye is nonfluorescent in its chemically reduced state, but becomes fluorescent when oxidized in the cell and the acetate group is removed by intracellular esterases. Intracellular reactive oxygen species generation is monitored by flow cytometry, excited at 480 nm and luminescent at 530 nm. Results: The compounds of the present invention reduce the formation of reactive oxygen species induced by oxidative stressors in a concentration-dependent manner, as measured by the decrease in CM-H2DCFDA fluorescence.

[0308] Mitochondrial membrane potential (Δψm): Δψm is determined using the cationic fluorescent dye tetramethylrhodamine (TMRM) (Thermo Scientific), which specifically accumulates in bioenergically active mitochondria. This dye diffuses from mitochondria with low membrane potential. Before the end of the treatment, ARPE19 cells are loaded with TMRM (50 nM) at 37°C for 30 minutes, treated with trypsin, the pellet is resuspended in PBS, and immediately evaluated by flow cytometry (excitation / emission: 510 / 580 nm). Data are analyzed using FlowJo® software. The addition of carbonyl cyanide m-chlorophenylhydrazone CCCP serves as a positive control. Results: The compounds of the present invention, as measured by TMRM fluorescence, prevent oxidative stressor-induced mitochondrial membrane potential changes in a concentration-dependent manner.

[0309] Mitochondrial Mass and Function Assay: Mitochondrial mass is estimated by loading ARPE-19 cells with a final concentration of 100 nM MitoTracker Green dye (excitation / release: 490 / 516 nm) (37°C, 15 min). Cells are washed with PBS, trypsinized with 0.05% trypsin, and then harvested. 10,000 cells per treatment are analyzed for MitoTracker fluorescence intensity using a flow cytometer. Mitochondrial function is measured using an MTT assay kit and normalized to cell viability data, taking into account cell death and proliferation. Results: The compounds of the present invention prevent oxidative stressor-induced changes in mitochondrial mass and function in a concentration-dependent manner, as measured by MitoTracker Green fluorescence and the MTT assay.

[0310] Autophagy flux assay: Cells are lysed in RIPA buffer (Radioimmunoprecipitation Assay Buffer, Thermo Scientific, 89901) containing a protease inhibitor (Roche Applied Science, 11873580001). Cell lysates containing equal volumes of protein are reloaded into each lane and separated on a 12% SDS-PAGE gel (sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel). After separation, the proteins are transferred to a nitrocellulose membrane (0.22 mm; Bio-Rad Laboratories, 162-0112) and treated with 5% skimmed dried milk (Fisher Scientific, NC0339922) or licor blocking buffer (Li-Cor Biosciences, 927-40000) to block nonspecific binding sites. Next, the membrane is incubated with a primary antibody directed against LC3B (1:1000), ATG7 (1:1000), or ATG9 (1:1000). After primary antibody treatment, the membrane is treated with horseradish peroxidase-conjugated secondary antibody (for the ECL detection system) or secondary infrared dye 800-conjugated anti-rabbit dye or Alexa Fluor 680-conjugated anti-mouse IgG (for the Licor Odyssey system) at room temperature for 1 hour. To ensure equal protein loading, the blot is replotted with anti-ACTB (anti-β-actin) antibody (1:5000 dilution) or α-tubulin antibody (1:5000 dilution). For band detection, the membrane is incubated in a Western blot detection system (ECL Plus) and exposed to a single emulsion film (Biomax MR Sigma, Z370398-50EA). Band intensity is determined using software developed by Wayne Rasband (ImageJ; National Institutes of Health, Bethesda, MD; available at http: / / rsb.info.nih.gov / ij / index.html). Statistical significance is calculated using the Mann-Whitney U test. The LC3-II:LC3-I ratio determines the autophagy flux. Autophagosomes are also detected by immunohistochemistry.After each treatment, cells were washed twice with PBS, fixed with 4% paraformaldehyde for 15 minutes, and then immunostained with rabbit polyclonal LC3 antibody (Novus Biologicals, NB100-2220) for autophagy punctates. Fluorescence micrographs of the immunostained LC3s were obtained and analyzed using Axiovision Rel 4.4 software (Zeiss, Oberkochen, Germany). Punctate staining of LC3s formed after oxidative stress indicates autophagosome formation. The results are explained: The compounds of the present invention normalize changes in autophagic flux induced by oxidative stressors in a concentration-dependent manner, as measured by Western blot analysis and immunofluorescence of LC3B, ATG7, and ATG9.

[0311] Cell death assay: Cell death is a key feature of dry AMD (Yang, M., et al., "Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration," Int. J. Mol. Sci., 21(19):7279 (2020), which is incorporated herein by reference in its entirety). A functional cell-based assay was performed in retinal pigment epithelial cells (RPE) to assess cell survival after oxidative stress (cell death trigger). The data show that a sigma-2 receptor modulator rescues oxidative stress-induced cell death in a concentration-dependent manner (Figure 1A and Figure 1B).

[0312] To determine lysosome integrity and activity, retinal pigment epithelial cells are plated in an 8-well covered glass-bottom chamber (Lab-Tek, Naperville, IL), and the cells are incubated for 12 hours in 1 mg / ml pH indicator LysoSensor Yellow / Blue dextran (Molecular Probes, Eugene, OR) in the presence or absence of alternating oxidative stress factors. Labeled cells are observed using a laser scanning confocal microscope with 360 nm excitation and a 450 nm emission filter, and a 515 nm long-pass emission filter. A high 530 / 450 nm ratio (i.e., a shift to green) correlates with a lower pH. Cathepsin D activity is measured in the cell lysate using a fluorescence cathepsin D activity assay kit (Abcam, Cambridge, MA), and the value is expressed as relative fluorescence units per million cells. As a result, the compounds of the present invention protect against loss of lysosome integrity and activity induced by oxidative stressors in a concentration-dependent manner, as measured by LysoSensor Yellow / Blue fluorescence. [Examples]

[0313] Example 2: In vitro model of retinal pigment epithelial cells Spontaneous retinal pigment epithelial (RPE) cells, such as ARPE-19 cells, are cultured as described in Example 1. Briefly, to emulate several aspects (ultrastructure, physiology, and function) of in-situ / ocular RPE cells, senescent cells grown on a Transwell insert that allows for a mature pigmented RPE monolayer are used in experiments to test the efficacy of the compounds of the present invention for the prevention or treatment of cellular dysfunction.

[0314] Human pluripotent stem cell (iPSC)-derived RPE strains retain their barrier function and physiological functions (such as vascular endothelial growth factor (VEGF) secretion), and are considered to be mature pigment monolayers. They are used in experiments to verify the effectiveness of the compounds of the present invention in preventing and treating cellular dysfunction.

[0315] Primary RPE cells from healthy donors and AMD donors are the most physiologically and pathophysiologically relevant cell models for studying phenotypes and functions associated with AMD and are used in experiments to test the efficacy of the compounds of the present invention for the prevention or treatment of cellular dysfunction. [Examples]

[0316] Example 3: In vitro modification of pathways important for dry AMD. Proof-concept studies demonstrate a clear role of sigma-2 receptor modulators in rescuing key aspects of dry AMD. Mechanistic studies and pathway analyses in disease-related assays suggest a crucial role of sigma-2 receptor modulators in dry AMD studied in RPE cells (Table 1). [Table 1]

[0317] Oxidative stress is a critical aspect of AMD, and oxidative damage leads to defects in the transport of extraphotonic segments (POS) in RPE cells, resulting in the accumulation of harmful macromolecules, as well as disruption of the autophagy-lysosome pathway and cellular proteostasis. Hydrogen peroxide (H2O2) is used in the RPE monolayer because it is a mediator of oxidative stress in the human vitreous humor. The RPE monolayer is exposed to various concentrations of oxidative stressors to model the oxidative stress present in AMD and aging retinas. Cultured cells are pretreated with oxidative stressors, and the transport and decomposition capabilities of fluorescently tagged POS are evaluated. This includes measuring late-stage compartments crucial for cargo degradation, such as lysosomes and autophagy bodies. Cells are tested in or out of the presence of the compounds of the present invention. The compounds of the present invention reduce the degree of oxidative damage induced by oxidative stressors in a concentration-dependent manner.

[0318] Complement Dysregulation: Complement abnormalities are a major genetically associated factor in approximately half of AMD patients. Complement C3 is a crucial upstream component of the complement cascade. In donor RPE cells from AMD patients with the Y402H polymorphism of complement factor H, C3 turnover is significantly increased, resulting in enhanced uptake and deposition of terminal complex C5b-9 into lysosomes. Studies of RPE cells from Stargardt disease, which is similar to AMD, have confirmed enlargement of endosomes that transport C3. To mimic complement dysregulation in vitro, complement C3 activity was targeted. Exposure of cultured RPE cells to cobra venom replicates the disruption of the complement pathway by targeting C3. In this model, CD59 recycling and lysosomal exocytosis after complement attack are absent, failing to protect RPE cells. This provides evidence that complement abnormalities disrupt cargo transport and processing in RPE. In this model, cultures are exposed to snake venom, and then the outer photoreceptor segment (POS) is added to media with and without the compound to determine the degree of rescue. This is described in "Study of Intracellular Cargo Trafficking and Co-localization in the Phagosome and Autophagy-Lysosomal Pathway of Retinal Pigment Epithelium Cells" (Ratnayaka JA, Keeling E, Chatelet DS: Methods Mol Biol 2020;2150:167-82). The compounds of the present invention rescue RPE barrier cell death and transepithelial electrical resistance (TEER) deficiencies.

[0319] Aβ oligomer exposure: Aβ mediates pathogenicity in RPE cells characterized by impaired photoreceptor extrasegment transport, barrier (tight junction) integrity, and cell health. RPE cultures are treated with human oligomer Aβ in or out of the presence of the compounds of the present invention. POS transport and barrier integrity are measured, and cell health is determined by lactate dehydrogenase (LDH) assay. The compounds of the present invention rescue the deficiencies in photoreceptor extrasegment transport, barrier integrity, and cell health caused by oligomer Aβ.

[0320] Autophagy assays: Autophagy assays are described in Klionsky et al., "Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy" (4 th edition) Autophagy The procedure was carried out in accordance with 2021;17:1-382, which is incorporated in its entirety by reference. RPE cultures were treated with human oligomer Aβ, either in the presence or absence of the compounds of the present invention. POS trafficking was measured over time after the addition of POS to the RPE cell cultures. Stressors included the addition of Aβ oligomers or H2O2 for 12–48 hours. These studies showed that POS trafficked over time at a normal rate after the addition of POS to the RPE cell cultures. This process was disrupted by the addition of stressors such as Aβ oligomers (Figures 2A and 2B) or oxidative stress (Figures 3A and 3B). The presence of sigma 2 receptor modulators (compounds A and C) restored normal trafficking to autophagosomes after stress (Figures 2A and 2B and Figures 3A and 3B), as measured by the co-localization of POS with microtubule-associated protein 1 light chain 3B (LC3B) after stress.

[0321] Oxidative stressors are associated with the pathogenesis of AMD, which involves changes in autophagy-related proteins. Application of oxidative stressors acutely increased the expression of autophagy-related proteins (Figure 4). Compounds A and C, which are sigma-2 receptor modulators, prevented this increase in autophagy-related proteins (Figure 4). [Examples]

[0322] Example 4. Prevention of aging of retinal pigment epithelial cells Experimental Design: Primary RPE cultures or ARPE-19 cells were treated with non-lethal CSC (tobacco smoke condensate; 150 μM) for 6–10 days in the presence or absence of the compound of the present invention to induce senescence in RPE cells. Cellular senescence was evaluated by β-galactosidase immunocytochemistry 6–10 days after treatment. Experimental Controls: 1) Vehicle (DMSO) treated cells without CSC (healthy vehicle control), 2) Vehicle (DMSO) treated cells with CSC (senescence + control), 3) Rescue + control (e.g., mitochondrial DRP1 mutant protein treated with virus) (partial rescue of senescence + control). Experimental Results: The compound of the present invention prevents senescence of RPE cells induced by CSC administration. [Examples]

[0323] Example 5. Suppression of inflammatory response in retinal pigment epithelial cells. Experimental Design: THP-1 cells were treated with the culture medium of oxidatively stressed RPE cells to induce the expression of inflammatory markers in THP-1 cells. Prior to THP-1 cell treatment, RPE cells (+ / - oxidative stress) were treated with the compound of the present invention to prevent the inflammatory response in THP-1 cells. Experimental Controls: 1) Vehicle (DMSO) treated cells (healthy vehicle control), 2) Vehicle (DMSO) treated RPE-derived medium (THP+ control). Experimental Results: The compound of the present invention prevents the inflammatory response in THP cells caused by administration of RPE-derived medium. [Examples]

[0324] Example 6. Prevention of apoptosis of retinal ganglion cells Experimental Design: In an optic nerve disruption model, immunoexcised retinal ganglion cells (RGCs) were cultured while increasing the concentration of the compounds described herein. Caspase-3 activity and cell viability of retinal ganglion cells were evaluated by calcein-AM staining. Experimental Results: The compounds of the present invention prevent apoptosis of retinal ganglion cells. [Examples]

[0325] Example 7. Prevention of ocular hypertension Experimental Design: In rats, increased intraocular pressure was induced by applying light from a diode laser to a trabecular meshwork in or out of the presence of the compound of the present invention. Optic nerve axons were counted 24 hours after induction of increased intraocular pressure. Experimental Results: The compound of the present invention prevents cell death induced by increased intraocular pressure and prevents functional impairment induced by axonal damage. [Examples]

[0326] Example 8: In vivo penetration into the retina When administered orally, the compound of the present invention penetrates the retina at a concentration exceeding 80% occupancy of sigma-2 receptors.

[0327] After a single oral administration of [14C]-compound A to rats, tissue distribution was measured by autoradiography. Throughout the 24-hour period, [14C]-compound A showed a receptor occupancy rate of over 80% at sigma 2 receptors in the uvea / retina, and this concentration was comparable to that in the brain (Figure 5). A receptor occupancy rate of over 80% indicates efficacy in vivo. Drug concentrations in the brain (cerebellum), retina, and plasma were also measured. Retinal concentrations showed a receptor occupancy rate of over 80% at sigma 2 receptors throughout the 24-hour period, and were higher than those in the brain and plasma (Figure 6). Similarly, after a single oral administration, compound B was detected at concentrations showing a receptor occupancy rate of over 80% at sigma 2 receptors in the retina and plasma, and an occupancy rate of approximately 50% in the brain (Figure 7). [Examples]

[0328] Example 9: Sigma 2 receptor modulators in glaucoma The efficacy of a sigma-2 receptor modulator was tested using an in vivo model of glaucoma (Shah, M., et al., "Translational Preclinical Pharmacologic Disease Models for Opthalmic Drug Development," Development.Pharm.Res.36(4):58(2019); this is incorporated in its entirety by reference).

[0329] To investigate whether sigma-2 receptor modulators can rescue cells from death, we used an in vivo model that induced retinal ganglion cell death similar to that seen in patients with glaucoma and other retinal diseases. Addition of sigma-2 receptor modulator compound B significantly maintained the number of retinal ganglion cells, similar to the benchmark-positive control (p<0.05) (Figure 8).

[0330] Glaucoma can cause abnormalities in the electrical activity of the retina. To measure this electrical activity, pattern electroretinography (PERG) measures the electrical activity of the retina in response to test stimuli such as an inverted checkerboard. PERG is a non-invasive, direct, and objective method for evaluating the function of retinal ganglion cells. In an in vivo model of glaucoma, retinal ganglion cell dysfunction (damage vs. underdevelopment) is observed, similar to that seen in patients with glaucoma and other retinal diseases. Compound A, a sigma-2 receptor modulator, maintains the function of retinal ganglion cells (Figure 9A and Figure 9B; p<0.05). [Examples]

[0331] Example 10: Indications for disease Unbiased pathway analysis of proteomics data obtained from clinical trials provided evidence of a relationship between the sigma-2 receptor complex and dry AMD. To identify the functional disorder ontology potentially affected by compound A administration, cerebrospinal fluid (CSF) analysis revealed that geographical atrophy and macular degeneration were the top two affected indications (Table 2). Furthermore, several subsets of proteins altered by compound A administration that are involved in dry AMD were identified. [Table 2]

[0332] Subsequently, we examined the overlap of altered proteins in CSF and plasma biofluid from AD patients treated with compound A and those altered with placebo, and identified proteins altered by compound A. These proteins have previously been shown to be altered in dry AMD or geographical atrophy in other groups compared to an age-adjusted control group. Furthermore, several pathways involving these proteins have been identified, many of which are known to have genetic or biological associations with processes impaired in dry AMD. The findings from these analyses provide early evidence of the concept that sigma-2 receptor modulators can alter AMD-related proteins and pathways in an aged patient population.

[0333] Example of synthesis Compounds according to any embodiment described herein may be prepared by general and specific methods outlined in WO2013 / 029057, WO2015 / 116923, and WO2018 / 213281, each of which is incorporated in whole by reference, and these methods constitute a further aspect of the present disclosure.

Claims

1. A compound comprising: A. A compound of formula I, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Here, R １ and R ２ Each of １ -C ６ Alkyl, or CH ２ OR′, where R １ , and R ２ When present, each R' is independently H or C １ -C ６ is alkyl, R ３ , R ４ , R ５ , and R ６ Each of １ -C ６ Alkyl, OH, OCH ３ , OCH(CH ３ ) ２ , O.C.H. ２ CH (CH ３ ) ２ , O.C. (CH ３ ) ３ , O(C １ -C ６ alkyl), OCF ３ , O.C.H. ２ CH ２ OH, O(C １ -C ６ alkyl)OH, O(C １ -C ６ haloalkyl), F, Cl, Br, I, CF ３ , C.N., N.O. ２ , N.H. ２ , C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkoxy C １ -C ６ Alkyl, aryl, heteroaryl, C ３ -C ７ Cycloalkyl, heterocycloalkyl, alkylaryl, CO ２ R', C(O)R', NH(C １ -C ４ Alkyl), N(C １ -C ４ Alkyl) ２ , NH(C ３ -C ７ cycloalkyl), NHC(O)(C １ -C ４ alkyl), CONR' ２ , NC(O)R', NS(O) ｎ R', S(O) ｎ N.R. ２ , S(O) ｎ R', C(O)O(C １ -C ４ alkyl), OC(O)N(R') ２ , C(O)(C １ -C ４ alkyl), and C(O)NH(C １ -C ４ alkyl); ３ , R ４ , R ５ , and R ６ When present, each R' is H, CH ３ , C.H. ２ CH ３ , C ３ -C ６ Alkyl, C １ -C ６ Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C １ -C ６ Alkoxy, NH(C １ -C ４ alkyl), and N(C １ -C ４ Alkyl) ２ wherein the optionally substituted groups are independently selected from the group consisting of C １ -C ６ Alkyl or C ２ -C ７ acyl, Or, R ３ and R ４ together with the C atom to which they are attached, they are OH, amino, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ forming a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R ３ and R ４ are linked together to form -O-C １－ C ２ forming a methylene O-group, Or, R ４ and R ５ together with the C atom to which they are attached, they are OH, amino, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ forming a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloaryl, or heteroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R ４ and R ５ are linked together to form -O-C １－２ forming a methylene O-group, R ７ , R ８ , R ９ , R １０ , and R １１ Each of １ -C ６ Alkyl, OH, OCH ３ , OCH(CH ３ ) ２ , O.C.H. ２ CH (CH ３ ) ２ , O.C. (CH ３ ) ３ , O(C １ -C ６ alkyl), OCF ３ , O.C.H. ２ CH ２ OH, O(C １ -C ６ alkyl)OH, O(C １ -C ６ haloalkyl), O(CO)R', F, Cl, Br, I, CF ３ , C.N., N.O. ２ , N.H. ２ , C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, aryl, heteroaryl, C ３ -C ７ Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO ２ R', C(O)R', NH(C １ -C ４ Alkyl), N(C １ -C ４ Alkyl) ２ , NH(C ３ -C ７ cycloalkyl), NHC(O)(C １ -C ４ alkyl), CONR' ２ , NC(O)R', NS(O) ｎ R', S(O) ｎ N.R. ２ , S(O) ｎ R', C(O)O(C １ -C ４ alkyl), OC(O)N(R') ２ , C(O)(C １ -C ４ alkyl), and C(O)NH(C １ -C ４ alkyl), where R ７ , R ８ , R ９ , R １０ , and R １１ Each R' when present is H, CH ３ , C.H. ２ CH ３ , C ３ -C ６ Alkyl, C １ -C ６ haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C １ -C ６ Alkoxy, NH(C １ -C ４ alkyl), and N(C １ -C ４ Alkyl) ２ are independently selected from the group consisting of Or, R ７ and R ８ together with the N or C atom to which they are attached, OH, amino, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ forming a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R ７ and R ８ are linked together to form -O-C １－２ forming a methylene-O- group, Or, R ８ and R ９ together with the N or C atom to which they are attached, OH, amino, halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ forming a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R ８ and R ９ are linked together to form -O-C １－２ forming a methylene O-group, each n is independently 0, 1, or 2; However, R ７ , R ８ , R ９ , R １０ , and R １１ is not all H, and However, the following compounds: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, excluding a compound of formula I as above or a pharma- ceutically acceptable salt thereof; or B. A compound of formula IA or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 Here, R ａ , R ｂ , R ｃ , R ｄ , and R ｅ Each of the groups is H, hydroxyl, Cl, F, methyl, —OCH ３ , -OC(CH ３ ) ３ , O-CH(CH ３ ) ２ , C.F. ３ , S.O. ２ CH ３ and morpholino, R １Ａ is hydrogen, alkyl, phenyl, or -CH=C(CH ３ ) ２ and R ２Ａ is an optionally substituted cyclic amino group, or a pharma- ceutically acceptable salt thereof; A compound selected from the group consisting of:

2. 2. The compound of claim 1, wherein the compound is a compound of formula I or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of claim 1, wherein the compound is 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of claim 1, wherein the pharma- ceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentiate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

5. 2. The compound of claim 1, wherein the pharma- ceutically acceptable salt is the fumarate salt.

6. 2. The compound of claim 1, wherein the compound is 【Chemistry 5】 A compound.

7. 2. The compound of claim 1, wherein the compound is a compound of formula IA or a pharma- ceutically acceptable salt thereof.

8. In the compound according to claim 1, the R ２Ａ is optionally substituted piperidinyl.

9. In the compound according to claim 1, the R ２Ａ but, 【Chemistry 6】 A compound selected from the group consisting of:

10. 2. The compound of claim 1, wherein the compound is 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

11. A compound comprising: 【Chemistry 8】 【change】 【change】 A compound selected from the group consisting of:

12. A composition for use in treating dry age-related macular degeneration, comprising: A. A compound of formula I, or a pharma- ceutically acceptable salt thereof, 【Chemistry 9】 wherein each of R 1 and R 2 is independently selected from H, C 1 -C 6 alkyl, or CH 2 OR′, where each R′, when present in R 1 and R 2 , is independently H or C 1 -C 6 alkyl; Each of R 3 , R 4 , R 5 , and R 6 is H, C 1 -C 6 alkyl, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCF 3 , OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R', C(O)R', NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR' 2 , NC(O)R', NS(O) n R', S(O) n NR' 2 , S(O) n R', C(O)O(C 1 -C 4 alkyl), OC(O)N(R') 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); where each R', when present in R 3 , R 4 , R 5 , and R 6 , is selected from the group consisting of H, CH 3 , CH 2 CH 3 . , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 , wherein the optionally substituted groups are selected from C 1 -C 6 alkyl or C 2 -C 7 acyl; or R 3 and R 4 together with the C atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heterocycloaryl or heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 3 and R 4 join together to form a -O-C 1 -C 2 methyleneO- group; or R 4 and R 5 together with the C atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heterocycloaryl or heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 and R 5 join together to form an -O-C 1-2 methyleneO- group; Each of R 7 , R 8 , R 9 , R 10 , and R 11 is H, C 1 -C 6 alkyl, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCF 3 , OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), O(CO)R′, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R', C(O)R', NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR' 2 , NC(O)R', NS(O) n R', S(O) n NR' 2 , S(O) n R', C(O)O(C 1 -C 4 alkyl), OC(O)N(R') 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl), where R 7 , R 8 , R 9 , R 10 , and R 11, each R' when present is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 ; or R 7 and R 8 together with the N or C atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R 7 and R 8 join together to form an —O—C 1-2 methylene-O— group; or R 8 and R 9 together with the N or C atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or R 8 and R 9 join together to form an —O—C 1-2 methyleneO— group; each n is independently 0, 1, or 2; With the proviso that R 7 , R 8 , R 9 , R 10 and R 11 are not all H; and However, the following compounds: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof, excluding a compound of formula I as above or a pharma- ceutically acceptable salt thereof; or B. A compound of formula IA or a pharma- ceutically acceptable salt thereof: 【Chemistry 11】 wherein each of R a , R b , R c , R d , and R e is independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, —OCH 3 , —OC(CH 3 ) 3 , O—CH(CH 3 ) 2 , CF 3 , SO 2 CH 3 , and morpholino; R 1A is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH 3 ) 2 , and R 2A is an optionally substituted cyclic amino group, or a pharma- ceutically acceptable salt thereof; A composition comprising a compound selected from the group consisting of: and a pharma- ceutically acceptable excipient.

13. A composition for use in treating dry age-related macular degeneration, comprising: 【Chemistry 12】 A composition comprising a compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

14. 14. The composition of claim 13, wherein the pharma- ceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentiate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

15. 14. The composition of claim 13, wherein the pharma- ceutically acceptable salt is a fumarate salt.

16. 16. A composition for use according to claim 15, wherein the compound is 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof.

17. In the manufacture of a pharmaceutical for treating dry age-related macular degeneration, 【Chemistry 14】 20. The use of a compound selected from:

18. In the manufacture of a pharmaceutical for treating dry age-related macular degeneration, 【Chemistry 15】 23. The use of a composition comprising a compound selected from the group consisting of:

19. 19. The use according to claim 17 or 18, wherein the compound is a pharma- ceutically acceptable salt.

20. 19. The use according to claim 17 or 18, wherein the pharma- ceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentiate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

21. 21. The use according to claim 20, wherein the pharma- ceutically acceptable salt is the fumarate salt.

22. 19. The use according to claim 17 or 18, wherein the compound is 【Chemistry 16】 That is, use.

23. 19. The use according to claim 17 or 18, wherein the compound is 【Chemistry 17】 That is, use.

24. 19. The use according to claim 17 or 18, wherein the compound is 【Chemistry 18】 That is, use.

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