Compositions and methods for treating neurological disorders

Abstract

The present disclosure relates to a method of treating a neurological disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to any embodiment described herein.The present disclosure relates to a method of treating Parkinson's disease and dementia with Lewy bodies 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 TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 163,546, filed March 19, 2021, the contents of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure provides a method of treating a neurological disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition according to any embodiment described herein.

[0003] Some embodiments disclose a method of treating a neurological disorder, the method comprising administering to a subject in need of said treatment a therapeutically effective amount of a compound selected from the group consisting of: A. A compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof, In the formula, Each of R1 and R2 is independently H, CC 16 alkyl, or CHOR', where R', and each R', if present in R, is independently H or C-C alkyl; Each of R3, R4, R5, and R6 is 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), 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', C(O)O(C1-C4 alkyl), OC(O)N(R'), C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl), where each R', when present in R3, R4, R5, and R6, is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl), 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 represent OH, amino, halo, C 1- C6 alkyl, C 1- C6 haloalkyl, C 1- C6 alkoxy, C 1-R3 and R4 join to form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R3 and R4 join to form -OC 1- C 1-2 forming a methylene-O-group, or R4 and R5 together with the C atom to which they are attached represent OH, amino, halo, C 1- C6 alkyl, C 1- C6 haloalkyl, C 1- C6 alkoxy, C 1- R4 and R5 are linked to form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R4 and R5 are linked to form -OC 1-2 forming a methylene-O-group, R7, R8, R9, R 10 , and R 11 Each of the 1- C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C 1- 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 alkoxyC1-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'), C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl), where R7, R8, R9, R 10 , and R 11 each R', if present, is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-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 attached, are OH, amino, halo, C, C 1-6 R7 and R8 are linked to form -OC, or 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 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl; 1-2 forming a methylene-O-group, or R8 and R9 together with the N or C atom to which they are attached represent OH, amino, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6R8 and R9 combine to 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 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R8 and R9 combine to form -OC 1-2 forming a methylene-O-group, each n is independently 0, 1, or 2; However, R7, R8, R9, R 10 , and R 11 is not all H, and However, the following compounds or pharma- ceutically acceptable salts thereof are excluded: [ka] or B. Compound of Formula IA [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R a , R b , R c , R d and R e each 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.

[0004] Some embodiments of the present disclosure are directed to a method of treating a neurological disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: [ka] TIFF2024510249000006.tif183141TIFF2024510249000007.tif91141

[0005] Some embodiments disclose a method of treating a neurological disorder, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to any embodiment described herein.

[0006] Some embodiments describe the use of a medicament according to any embodiment described herein in the manufacture of a medicament for the treatment of a neurological disease.

[0007] Some embodiments describe the use of a medicament according to any embodiment described herein in the manufacture of a medicament for the treatment of a neurological disease.

[0008] In some embodiments, the neurological disease is age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), excitatory synucleinopathy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) dementia, autosomal dominant Parkinson's disease, chemotherapy-induced neuropathy (CIPN), cognitively impaired (CIND), dementia, Creutzfeldt-Jakob disease (CJD), diffuse Lewy body disease (DLBD), also known as dementia with Lewy bodies (DLB), a disease or condition characterized by the presence of Lewy bodies, Down's syndrome, dyskinesia, epilepsy, frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), HIV dementia, Huntington's disease, incident LBD, hereditary LBD, Lewy body dysphagia, mild cognitive impairment (MCI), multiple sclerosis, multiple system atrophy (MSA), neuropathy (including, but not limited to, peripheral neuropathy), The present invention is selected from, but is not limited to, neurological disorders (including peripheral neuropathy, diabetic neuropathy, retinal neuropathy), oligodendroglial atrophy, Parkinson's disease (PD), preclinical Alzheimer's disease (PCAD), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, psychosis), pure autonomic dysfunction, seizures, Shy-Drager syndrome, striatal degeneration, synucleinopathy, traumatic brain injury (TBI), combined Alzheimer's and Parkinson's disease and / or MSA, vascular dementia, a disease, disorder or condition associated with abnormal expression, stability, activity and / or cellular processing of alpha-synuclein, a disease, disorder or condition characterized by the presence of Lewy bodies, and combinations thereof. [Brief description of the drawings]

[0009] [Figure 1A] Figure 1A shows representative images of neuronal cultures treated with α-seeded control (7.1 nM) and vehicle for 24 h. Cultures were immunostained for α-synuclein oligomers using the neurite marker microtubule-associated protein 2 (MAP2; green) and an α-synuclein oligomer-specific antibody (ASYO5 antibody, Agrisera; red). No α-synO is present in vehicle-treated cultures. [Figure 1B] Figure 1B shows representative images of neuronal cultures treated with synthetic α-synuclein oligomers (1 μM) for 24 h and immunostained for α-synuclein oligomers using the neurite marker microtubule-associated protein 2 (MAP2; green) and an α-synuclein, oligomer-specific antibody (ASYO5 antibody, Agrisera; red). [Figure 1C] Figure 1C shows representative images of neuronal cultures treated with the following substances: [ka] Cells were treated with synthetic α-synuclein oligomers (1 μM) and compound A (10 μM) for 24 hours, and then immunostained for neurite marker microtubule-associated protein 2 (MAP2; green) and α-synuclein oligomers using an α-synuclein oligomer-specific antibody (ASYO5 antibody, Agrisera; red). [Figure 1D] 1 is a graphical representation of the binding affinity of α-synuclein oligomers (α-SynO) to neuronal synapses following treatment with carrier (α-SynO) or treatment with Compound B. [ka] [Figure 1E] 1 is a graph showing the binding affinity of α-synuclein oligomers (α-SynO). This is a graph showing the binding affinity of oligomers (α-SynO) to neuronal synapses. [ka] [Figure 1F] Graphs of vesicle trafficking are shown for control cultures, cultures treated with α-synuclein oligomers (α-SynO) for 24 hours, or [ka] Cultures treated with carrier α-synuclein oligomers (α-SynO) and compound B. [Figure 1G]1 is a graphical representation of vesicular trafficking in untreated control cultures, cultures treated with α-synuclein oligomers (α-SynO) for 24 hours, or cultures treated with α-synuclein oligomers (α-SynO) and Compound A. [ka] . DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention is not limited to the specific process, composition, or methodology described herein, as variations may occur. The terms used herein are for the purpose of describing specific versions or embodiments only, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by prior invention.

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

[0012] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that embodiments of the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6"Alkyl" is specifically intended to individually 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, as well as, for example, 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, the reference to any element of the invention by the indefinite article "a" or "an" does not exclude the possibility that there is one or more of the element.

[0014] As used herein, the term "Abeta" or "Aβ" includes compositions that include soluble amyloid peptides, including components such as Aβ monomers, Aβ oligomers, or complexes of Aβ peptides (in monomeric, dimeric, or polymeric forms) with other soluble peptides or proteins, as well as other soluble Aβ assemblies, including any processed products of amyloid precursor protein. Soluble Aβ 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 thought to be neuroprotective, and self-association of Aβ monomers into soluble Aβ oligomers is necessary for neurotoxicity. However, certain Aβ mutant monomers (arctic mutations E22G) have been reported to be associated with familial Alzheimer's disease.

[0015] As used herein, the term "about" means plus or minus 10% of the numerical value with which it is used. Thus, about 50 mL means a range of 45 mL to 55 mL.

[0016] Unless otherwise indicated, the term "active ingredient" should be understood to refer to a compound according to any embodiment described herein.

[0017] "Administering" or "administration" and the like, when used in conjunction with the compounds of the present disclosure, refers to providing a 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 comprises administering the pharmaceutical composition of the present invention alone or in combination with another therapeutic agent. When the pharmaceutical composition of the present invention is administered in combination with another therapeutic agent, the pharmaceutical composition of the present invention and the other therapeutic agent can be administered at the same time or at different times.

[0018] The term "agonist" refers to a compound that produces a biological activity of a receptor, the presence of which is the same as that which occurs in the presence of a naturally occurring ligand for the receptor.

[0019] The term "alkanoyl" or "alkylcarbonyl" as used herein refers to an alkyl group attached to a carbonyl radical. Examples of alkanoyl include: [ka]

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

[0021] As used herein, "alkenyl" is intended to include a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds, which may occur at any stable point along the chain. For example, "C2-C6 alkenyl" or "C 2-6 "(Alkenyl)" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl 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-propenyl, and 4-methyl-3-pentenyl.

[0022] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. 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 "alkoxysilkoxy" refers to an alkoxy group bonded to an alkoxy group. Examples of alkoxy groups include -O-(CH2)2, -OCH3.

[0024] As used herein, "alkynyl" is intended to include a hydrocarbon chain of straight or branched configuration 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, the term "α-synuclein", "α-synuclein" or "αSyn" refers to a protein encoded by the SNCA gene in humans. α-synuclein is a neuronal protein that controls the trafficking of synaptic vesicles and the subsequent release of neurotransmitters. As used herein, the term "α-synuclein" is intended to include compositions that contain soluble α-synuclein peptides, including components such as α-synuclein monomers, α-synuclein oligomers, or complexes of α-synuclein peptides (in monomeric, dimeric, or polymeric forms) with other soluble peptides or proteins, as well as other soluble α-synuclein assemblies that include any processed form of α-synuclein. Soluble α-synuclein oligomers are known to be neurotoxic, and α-synuclein oligomers have been reported to be associated with familial Parkinson's disease and dementia with Lewy bodies (DLB).

[0026] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrate animals, such as wild animals, laboratory animals, domestic animals, farm animals and pets.

[0027] The term "antagonist" refers to an entity, such as a compound, antibody, or fragment, that results in a decrease in the degree of biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of the biological activity of a receptor. As used herein, the term "sigma-2 receptor antagonist" is used to describe a compound that acts as a "functional antagonist" at the sigma-2 receptor.

[0028] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, etc. In some embodiments, an aryl group has from 6 to about 20 carbon atoms. In some embodiments, an aryl group has from 5 to about 10 carbon atoms.

[0029] As used herein, "arylalkyl" refers to an aryl group linked to an alkyl radical. In preferred embodiments, the alkyl is C 1-6 It is an alkyl.

[0030] The term "aroyl" or "arylcarbonyl" as used herein refers to an aryl group attached to a carbonyl radical. Examples of aroyl include, but are not limited to, benzoyl.

[0031] As used herein, the term "brain permeability" refers to the ability of a drug, antibody or fragment to cross the blood-brain barrier. In some embodiments, animal pharmacokinetic (pK) studies, e.g., mouse pharmacokinetic / blood-brain barrier studies, can be used to determine or predict brain permeability. In some embodiments, various concentrations of a compound or pharmaceutical composition according to any embodiment described herein can be administered po, ​​e.g., at 3, 10, and 30 mg / kg, for 5 days, and various pK characteristics can be measured, e.g., in animal models. 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 of >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 penetration is defined as greater than about 0.1%, 1%, 5%, about 10%, and preferably greater than about 15% of the administered dose crossing the BBB after a given period of time. In certain embodiments, the dose is administered orally (po). In other embodiments, the dose is administered intravenously (iv) prior to measuring the pK properties.

[0032] As used herein, the term "contacting" refers to bringing together or binding molecules (or molecules having higher order structures, such as cells or cell membranes) 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, the contacting occurs in a solution where the bound or contacted molecules are mixed in a common solvent and allowed to freely associate. In some embodiments, the contacting can occur 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 can be a whole cell lysate, a nuclear lysate, a cytoplasmic lysate, and combinations thereof. In some embodiments, the cell-free lysate is a lysate obtained from nuclear extraction and isolation, where the nuclei of a cell population are removed from the cells and then lysed. In some embodiments, the nuclei are not lysed, but are still considered to be a cell-free environment. The molecules can be brought together by mixing, such as vortexing, shaking, etc.

[0033] The term "cyclic amino" or "cyclic amino group" as used herein refers to a heterocycloalkyl or heteroaryl group that contains a nitrogen radical and thus allows attachment through the nitrogen atom. This group is represented by the formula: [ka]

[0034] is any heterocyclic or heteroaromatic ring containing 0-3 additional heteroatoms selected from nitrogen, sulfur and oxygen.

[0035] The term "cycloalkanoyl" or "cycloalkylcarbonyl" as used herein is meant to represent a cycloalkyl group attached to a carbonyl radical. Examples of cycloalkanoyl include: [ka] These include, but are not limited to,

[0036] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon containing up to 20 ring-forming carbon atoms, including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, as well as spiro ring systems. Cycloalkyl groups can 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 a cycloalkyl group can be optionally substituted with oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to the 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 cyclized alkyl groups containing up to 20 ring-forming carbon atoms. Examples of cycloalkyl preferably include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0037] The term "cycloalkylalkyl" refers to a cycloalkyl group linked to an alkyl radical. In preferred embodiments, the alkyl group is 1-6 It is an alkyl.

[0038] As used herein, the term "drug-like properties" is used to describe the pharmacokinetic and stability properties of a compound upon administration, including brain penetrability, metabolic stability, and / or plasma stability.

[0039] As used herein, "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0040] As used herein, "haloalkoxy" represents a haloalkyl group, as defined herein, having the indicated number of carbon atoms attached through 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 exemplary haloalkoxy group is OCF3. As used herein, "trihalomethoxy" refers to a methoxy group having three halogen substituents. Examples of trihalomethoxy groups include, but are not limited to, -OCF3, -OCClF2, -OCCl3, and the like.

[0041] As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Exemplary haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, CH2CF3, and the like.

[0042] As used herein, a "heteroaryl" group refers to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has at least one or more heteroatom ring-forming atoms each independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl (aka pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl (aka pyrrolyl), oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, etc. In some embodiments, heteroaryl groups have from about 1 to about 20 carbon atoms as ring-forming atoms, and in further embodiments, from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, or from about 1 to about 2 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms, hi some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0043] As used herein, the term "heterocycloalkoxy" refers to an -O-heterocycloalkyl group. Examples of heterocycloalkoxy groups are: [ka] It is.

[0044] As used herein, "heterocycloalkyl" or "heterocyclyl" refers to non-aromatic heterocyclyl groups 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 replaced with a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., both fused and spiro systems). For example, "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolebenzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with oxo or sulfido. For example, a ring-forming S atom can be substituted with one or two oxos (i.e., forming S(O) or S(O)2). For example, a ring-forming C atom can be substituted with oxo (i.e., forming a carbonyl). Also included in the definition of heterocycloalkyl are moieties in which one or more aromatic rings are fused (i.e., have a common bond). Benzo derivatives of heterocycles such as pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, indoline, isoindoline, isoindoline-1-one-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3-yl groups. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted with oxo or sulfido. 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, a heterocycloalkyl group has 1-4 heteroatoms. In some embodiments, a heterocycloalkyl group contains 0-3 double bonds. In some embodiments, a heterocycloalkyl group contains 0-2 triple bonds.

[0045] The terms "hydroxyl" and "hydroxy" are used interchangeably to refer to an OH group.

[0046] The term "ameliorate" is used to convey that the present disclosure changes any of the characteristics and / or physical attributes of the tissue to which it is provided, applied or administered. The term "ameliorate" may also be used in conjunction with a disease state such that when a disease state is "ameliorated," a symptom or physical characteristic associated with the disease state is reduced, alleviated, eliminated, delayed or avoided.

[0047] The term "inhibit" includes blocking, abrogating, or restoring a particular result or process. In the context of prophylaxis or treatment by administration of the compounds of the present disclosure, "inhibit" includes protecting (partially or fully) against symptoms or delaying the onset of symptoms, alleviating symptoms, or protecting against, alleviating, or eliminating a disease, condition, or disorder.

[0048] As used herein, the term "metabolic stability" refers to the ability of a compound to withstand first-pass metabolism (degradation or conjugation in the intestine and liver of an orally administered drug). This can be assessed in vitro, for example, by exposing the compound to mouse or human liver microsomes. In some embodiments, good metabolic stability ... 1 / 2 In some embodiments, good metabolic stability refers to a metabolic rate of <300 uL / min / mg, preferably >5 min, >10 min, >15 min, >20 min, or >30 min. < 200 uL / min / mg, more preferably < Intrinsic clearance rate (Cl) of 100 uL / min / mgint )

[0049] The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms at the moiety where n is the number of ring-forming atoms. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

[0050] As used herein, the term "neuronal cell" can be used to refer to a single cell or a population of cells. In some embodiments, the neuronal cell is a primary neuronal cell. In some embodiments, the neuronal cell is an immortalized or transformed neuronal cell or a stem cell. A primary neuronal cell is a neuronal cell that cannot differentiate into other types of neuronal cells, such as glial cells. A stem cell is a cell that can differentiate into other types of neuronal cells, such as neurons and glial cells. In some embodiments, the assay utilizes a composition that includes at least one neuronal cell that does not include glial cells. In some embodiments, the composition includes less than about 30%, 25%, 20%, 15%, 10%, 5%, or 1% glial cells that are known to internalize and accumulate Abeta. The primary neuronal cell can be from any part of the animal's brain. In some embodiments, the neuronal cell is a hippocampal cell or a cortical cell. The presence of glial cells can be determined by any method. In some embodiments, glial cells can be detected by the presence of GFAP and neuronal cells can be detected by positive staining with an antibody against MAP2.

[0051] As used herein, the term "optionally substituted" means that the substitution is optional, and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety may be replaced with a selection from the indicated substituents, provided that the normal valence of the specified atom or moiety is not exceeded and that the substitution results in a stable compound. For example, when a methyl group (i.e., CH3) is optionally substituted, up to three hydrogen atoms on the carbon atom may be replaced with a substituent. Substituents include, but are not limited to, substituted or unsubstituted C3-C6 alkyl, alkyl, aryloxy, aryloxy, cycloalkanoyl, and the like. 10 Cycloalkyl, -OC(O)NCH(CH3)2, (N,N-dimethylamino)pyridinyl, (N,N-dimethylamino)sulfonyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonyl, methylsulfonylphenyl, morpholinylpyridinyl, optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10Heteroaryl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, CF3. Substituted alkyl groups refer, for example, to one or more hydrogen atoms on the alkyl group being replaced with a substituent selected from, but not limited to, halo, hydroxyl, alkoxy, heterocycloalkoxy, alkoxyalkoxy, C(O)OMe, and C(O)OEt. Substituted aryl groups refer, for example, to one or more hydrogen atoms on the aryl group being replaced with a substituent selected from, but not limited to, -SO2Me or a phenyl group. Substituted heteroaryl groups refer, for example, to one or more hydrogen atoms on the heteroaryl group being replaced with a substituent selected from, but not limited to, heterocycloalkyl, heteroaryl, N,N-dimethylamino. For example, a substituted heterocycloalkyl group indicates that one or more hydrogen atoms on the heterocycloalkyl group are replaced with a substituent selected from, but not limited to, heterocycloalkyl, heteroaryl, N,N-dimethylamino, hydroxyl, alkoxy, alkoxycarbonyl, alkyl, aryl, sulfonyl, dimethylaminosulfonyl, aroyl, cycloalkanoyl, alkanoyl, and -OC(O)NCH(CH). In certain embodiments, for example, two hydrogen atoms on the same carbon of a heterocyclyl or alkyl group are replaced with a group, for example, [ka] and forming a spiro compound selected from, but not limited to:

[0052] "Partial agonist" refers to a compound in which the biological activity of a receptor is of the same type, but to a lesser extent, as occurs in the presence of a naturally occurring ligand for that receptor.

[0053] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally regarded as safe and non-toxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of the present disclosure are physiologically acceptable, compatible with other ingredients, and typically do not produce allergic or similar unpleasant reactions (e.g., upset stomach, dizziness, etc.) when administered to a patient. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more particularly in humans.

[0054] As used herein, the phrase "pharmaceutically acceptable salt(s)" includes salts of the disclosed compounds that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds or compounds identified according to the disclosed methods. Pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the present disclosure may form pharma-ceutically acceptable salts with various amino acids. Suitable 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 suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0055] As used herein, the term "pharmaceutical 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 encompasses any of the agents approved by a regulatory agency of the U.S. Federal government or listed in the United States Pharmacopeia for use in animals, including humans.

[0056] The term "selectivity" or "selective" refers to the binding affinity (Ki ) is different from receptors other than sigma receptors. The compound has high selectivity for sigma receptors in synaptic neurons. The K i is the K for non-sigma receptors i In some embodiments, the compounds are selective sigma-2 receptor antagonists or sigma-1 receptor ligands, and have binding dissociation constants K i Value, or IC 50 have at least 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 100-fold, or 500-fold, or more, greater affinity for binding to sigma receptors compared to non-sigma receptors, as assessed by comparison of K values, or binding constants, at different receptors. i or IC 50 To assess the value, any known assay protocol can be used, for example, by monitoring the competitive displacement from the receptor of a radiolabeled compound with a known dissociation constant, such as by the method of Cheng and Prusoff (1973) (Biochem. Pharmacol. 22, 3099-3108), or specifically by the methods provided herein.

[0057] The term "plasma stability" as used herein 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 compound is incubated in plasma for various times. The percentage of parent compound (analyte) remaining at each time point reflects the plasma stability. Poor stability tends to result in low bioavailability. Good plasma stability can be defined as 50% or more of the analyte remaining after 30 minutes, 50% or more of the analyte remaining after 45 minutes, and preferably 50% or more of the analyte remaining after 60 minutes.

[0058] "Sigma-2 ligand" refers to a compound that binds to the sigma-2 receptor, and includes agonists, antagonists, partial agonists, inverse agonists, and simple competitors for other ligands of this receptor or protein.

[0059] The term "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 with respect to abeta effect oligomer-induced synaptic dysfunction resulting from sigma-2 receptor binding.

[0060] The terms "subject", "individual" or "patient" are used interchangeably and are intended to include humans and non-human animals as used herein. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, with mammals such as non-human primates, sheep, dogs, cats, cows, and horses being preferred. Preferred subjects include human patients. The method is particularly suitable for treating human patients with a disease or disorder as described herein.

[0061] As used herein, the term "therapeutic" refers to an agent utilized to treat, combat, ameliorate, prevent or ameliorate an unwanted condition or disease in a subject.

[0062] A "therapeutically effective amount" of a compound, a pharma- ceutically 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 or pathological process. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject sees or feels an effect, or the physician observes a change). A therapeutically effective amount of a compound according to any embodiment described herein may be, broadly defined, from 0.01 mg / kg to about 500 mg / kg, from about 0.01 to about 250 mg / kg, from about 0.01 to about 25 mg / kg, from about 0.05 mg / kg to about 20 mg / kg, from about 0.1 mg / kg to about 400 mg / kg, from about 0.1 mg / kg to about 200 mg / kg, from about 0.1 mg / kg to about 25 mg / kg, from about 0.1 to about 10 mg / kg, from about 0.2 to about 5 mg / kg, from about 1 mg / kg to about 300 mg / kg, from about 10 mg / kg to about 100 mg / kg, body weight. Benefits contemplated herein include both medical and / or prophylactic treatments, as appropriate. The specific dose of the compound administered according to the present disclosure to obtain therapeutic and / or prophylactic effects is determined by the specific circumstances surrounding the case, including, for example, the compound administered, the route of administration, co-administration of other active ingredients, the condition to be treated, the activity of the specific compound employed, the specific composition employed, the age, weight, general health, sex, and diet of the patient; the administration time, route of administration, and excretion rate of the specific compound employed, and the duration of treatment. The therapeutically effective dosage is determined by the physician in light of the aforementioned relevant circumstances and the exercise of sound medical judgment. The therapeutically effective amount of the compound according to any embodiment described herein is typically an amount that is 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 a compound according to any embodiment described herein administered to a human or other animal in a single or divided dose can be, 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,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 of body weight per day. A single dose pharmaceutical composition of any embodiment described herein may contain such amounts or multiples thereof to make up a daily dose. For example, a compound according to any embodiment described herein may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times, or four times per day. In some embodiments, a therapeutically effective amount of a compound according to any embodiment disclosed herein may range from about 0.01 to about 25 mg / kg / day. In some embodiments, the therapeutically effective amount is about 0.01 mg / kg body weight, about 0.1 mg / kg body weight, about 0.2 mg / kg body weight, about 0.3 mg / kg body weight, about 0.4 mg / kg body weight, about 0.5 mg / kg body weight, about 0.60 mg / kg body weight, about 0.70 mg / kg body weight, about 0.80 mg / kg body weight, about 0.90 mg / kg body weight, about 1 mg / kg body weight, about 2.5 mg / kg body weight, about 5 mg / kg body weight, about 7.5 mg / kg body weight, about 10 mg / kg body weight, about 12.5 mg / kg body weight, about 15 mg / kg body weight, about 17.5 mg / kg body weight, about 20 mg / kg body weight, about 22.5 mg / kg body weight, and and up to about 25 mg / kg body weight; and up to about 25 mg / kg body weight, about 22.5 mg / kg body weight, about 20 mg / kg body weight, about 17.5 mg / kg body weight, about 15 mg / kg body weight, about 12.5 mg / kg body weight, about 10 mg / kg body weight, about 7.5 mg / kg body weight, about 5 mg / kg body weight, about 2.5 mg / kg body weight, about 1 mg / kg body weight, about 0.9 mg / kg body weight, about 0.8 mg / kg body weight, about 0.7 mg / kg body weight, about 0.6 mg / kg body weight, about 0.5 mg / kg body weight, about 0.4 mg / kg body weight, about 0.3 mg / kg body weight, about 0.2 mg / kg body weight, about 0.1 mg / kg body weight, and about 0.01 mg / kg body weight. In some embodiments, the therapeutically effective amount is about 0.1 mg / kg / day to about 10 mg / kg / day, and in some embodiments, the therapeutically effective amount is about 0.2 mg / kg / day and about 5 mg / kg / day. In some embodiments, the treatment regimens according to the present disclosure are administered to patients in need of such treatment, typicallyThe present invention includes administering, in a single or multiple doses, about 1 mg to about 5000 mg, about 10 mg to about 2000 mg, about 10 mg to about 200 mg, about 20 mg to about 1000 mg, about 20 mg to about 500 mg, about 20 mg to about 400 mg, about 40 mg to about 800 mg, about 50 mg to about 500 mg, about 80 mg to about 1600 mg, and about 50 mg of a compound according to any embodiment disclosed herein, or a pharma- ceutically acceptable salt thereof, per day. In some embodiments, the therapeutically effective amount is a total daily dose of 50 mg to 500 mg. In some embodiments, the daily dose is about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about g, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 2 45mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, 300mg, about 305mg, about 310mg, About 315mg About 320mg, About 325mg, About 330mg, About 335mg, About 340mg, About 345mg, About 350mg, About 355mg, About 360mg, About 365mg, About 370mg, About 375mg, About 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg; about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450mg, about 455mg, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 495mg, about 490mg, about 485mg, about 480mg, about 475mg, about 470mg about 465mg, about 460mg, about 455mg, about 450mg, about 445mg, about 440mg, about 435mg, about 430mg, about 425mg,Approx. 420 mg, approx. 415 mg, approx. 410 mg, approx. 405 mg, approx. 400 mg, approx. 395 mg, approx. 390 mg, approx. 385 mg, approx. 380 mg, approx. g, approx. 325 mg, approx. 320 mg, approx. 315 mg, approx. 310 mg, approx. 305 mg, approx. 300 mg, approx. 295 mg, approx. 290 mg, approx. mg, about 225 mg, about 220 mg, about 215 mg, about 210 mg, about 205 mg, 200 mg, about 195 mg, about 190 mg, about 185 mg, about 180 mg, about 175 mg, about 170 mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg; about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, and about 50 mg of a compound according to any embodiment herein. In some embodiments, the total daily dose is about 50 mg to about 150 mg. In some embodiments, the total daily dose is about 50 mg to about 250 mg. In some embodiments, the total daily dose is about 50 mg to about 350 mg. In some embodiments, the total daily dose is about 50 mg to about 450 mg. In some embodiments, the total daily dose is about 50 mg. It will be understood that the pharmaceutical formulations of the present disclosure do not necessarily contain the entire amount of the compound effective for treating the disorder, since such an effective amount may be reached by administration of multiple divided doses of such pharmaceutical formulations. The compound may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times or four times per day.

[0063] "Tissue" refers to an association of similarly specialized cells that are united to perform a particular function.

[0064] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to protect against or delay (e.g., attenuate or postpone onset) an undesirable physiological condition, disorder, or disease (partially or fully), or to obtain a beneficial or desired clinical result, such as partial or total restoration or inhibition of decline of a parameter, value, function, or outcome that was or becomes abnormal. For purposes of this disclosure, beneficial or desired clinical results include alleviation of symptoms; reduction in the extent or momentum or rate of onset of a condition, disorder or disease; stabilization of the condition (i.e., not worsening), stabilization of the condition, disorder or disease state (i.e., not worsening), delay in onset or slowing of progression of the condition, disorder or disease, improvement in the condition, disorder or disease state, and remission (whether partial or total), whether it leads to immediate relief of actual clinical symptoms, or enhancement or amelioration of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without undue side effects. Treatment also includes extending survival compared to expected survival in the absence of treatment. Five million people worldwide suffer from Parkinson's disease. Although the symptoms of Parkinson's disease are debilitating and negatively impact a patient's quality of life, there is as yet no disease-modifying therapy to treat Parkinson's disease. Sigma 2 modulators prevent neurological dysfunction caused by alpha-synuclein oligomers.

[0065] Alpha-synuclein (α-syn) pathology, i.e. Lewy bodies consisting of α-syn aggregates, was identified very early as a cardinal feature of Parkinson's disease. Since then, human genetic evidence has been accumulating showing that both familial and sporadic forms of Parkinson's disease are associated with SCNA, the gene encoding α-syn. More recently, accumulating evidence is indicating that soluble oligomeric forms of α-syn, α-syn oligomers (α-synOs), are toxic species present in Parkinson's disease and may contribute to neurodegeneration by various mechanisms, including inhibiting intracellular trafficking, blocking normal autophagy, and inducing synaptic dysfunction and loss. α-synOs can interact with synapses and spread through synapses to anatomically connected areas, and its spread correlates with the Braak staging of Parkinson's disease and with Lewy bodies and synaptic pathology in neurons. Most α-syn targeting approaches in the clinic neglect to target oligomeric species, and thus therapeutic approaches that effectively target α-synOs are urgently needed. Screening assays identified compounds disclosed herein that can inhibit recombinant α-synO-induced impaired lipid vesicle trafficking and chaperone-mediated autophagy (increased expression of LAMP-2A). These compounds were identified as sigma-2 receptor modulators. After confirming concentration-dependent activity in the trafficking assay, these compounds were tested in a more physiologically relevant trafficking assay using Parkinson's disease brain-derived α-synOs, and the sigma-2 modulators indeed restored trafficking to normal. The sigma-2 receptor complex is composed of transmembrane protein 97 (TMEM97) and progesterone receptor membrane component 1 (PGRMC1). Molecular interactions between the sigma-2 receptor components PGRMC1 and TMEM97, α-synOs, and proteins regulating vesicle tracking and autophagy, such as LC3B, may form the basis of these observations.Importantly, these data show for the first time that small molecule selective sigma-2 receptor modulators can block at least some of the toxic effects of α-synOs on neuronal cells.In vitro proof-of-concept studies demonstrating that sigma-2 receptor modulators alleviate α-synO-induced neurotoxicity through multiple mechanisms support their potential as a treatment for Parkinson's disease.

[0066] How to use Various embodiments are directed to a method of treating a neurological disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0067] In some embodiments, the neurological disease is selected from the group consisting of age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), excitatory synucleinopathy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) dementia, autosomal dominant Parkinson's disease, chemotherapy-induced neuropathy (CIPN), dementia without cognitive impairment (CIND), dementia, Creutzfeldt-Jakob disease (CJD), diffuse Lewy body disease (DLBD), also known as dementia with Lewy bodies (DLB), a disorder or condition characterized by the presence of Lewy bodies, Down's syndrome, dyskinesia, epilepsy, frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), HIV dementia, Huntington's disease, incident LBD, hereditary LBD, Lewy body dysphagia, mild cognitive impairment (MCI), multiple sclerosis, multiple system atrophy (MSA), neurological disorders. The present invention relates to a disease, disorder or condition associated with alpha-synucleinopathy, including, but not limited to, peripheral neuropathy, neuropathy (including peripheral neuropathy, diabetic neuropathy, retinal neuropathy), oligodendroglial atrophy, Parkinson's disease (PD), preclinical Alzheimer's disease (PCAD), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, psychosis), pure autonomic failure, seizures, Shy-Drager syndrome, striatal degeneration, synucleinopathies, traumatic brain injury (TBI), combined Alzheimer's and Parkinson's disease and / or MSA, vascular dementia, a disease, disorder or condition associated with aberrant expression, stability, activity and / or cellular processing of alpha-synuclein, a disease, disorder or condition characterized by the presence of Lewy bodies, and combinations thereof.

[0068] Various embodiments are directed to a method of treating a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0069] Some embodiments are directed to a method of treating Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0070] Some embodiments are directed to a method of treating Huntington's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0071] Some embodiments are directed to a method of treating diffuse Lewy body disease (DLBD), also known as dementia with Lewy bodies (DLB), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0072] Some embodiments are directed to a method of preventing cell death in neuronal cells, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0073] In some embodiments, the compound according to any embodiment described herein can be protective against cell dysfunction in neurological disease.In some embodiments, the compound according to any embodiment described herein can prevent cell dysfunction associated with neurological disease.In some embodiments, the compound according to any embodiment described herein can prevent cell dysfunction associated with neurological disease, where cell dysfunction can be caused by exposure to oligomer abeta, oxidative stress, and the activity of complement C3. In some embodiments, the neurological disease is selected from age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), excitatory synucleinopathy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) dementia, autosomal dominant Parkinson's disease, chemotherapy-induced neuropathy (CIPN), cognitively impaired (CIND), dementia, Creutzfeldt-Jakob disease (CJD), diffuse Lewy body disease (DLBD), also known as dementia with Lewy bodies (DLB), a disease or condition characterized by the presence of Lewy bodies, Down's syndrome, dyskinesia, epilepsy, frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), HIV dementia, Huntington's disease, incident LBD, hereditary LBD, Lewy body dysphagia, mild cognitive impairment (MCI), multiple sclerosis, multiple system atrophy (MSA), neuropathy (peripheral nerve disorders), neurological disorders (including peripheral neuropathy, diabetic neuropathy, retinal neuropathy), oligodendroglial atrophy, Parkinson's disease (PD), preclinical Alzheimer's disease (PCAD), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorders, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, psychosis), pure autonomic failure, seizures, Shy-Drager syndrome, striatal degeneration, synucleinopathies, traumatic brain injury (TBI), combined Alzheimer's and Parkinson's disease and / or MSA, vascular dementia, diseases, disorders or conditions associated with aberrant expression, stability, activity and / or cellular processing of alpha-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, and combinations thereof.

[0074] In some embodiments, oxidative stress leads to cell damage. In some embodiments, cell damage is selected from the group consisting of cytotoxicity, lipid peroxidation, carbonyl formation, formation of reactive oxygen species, alteration of mitochondrial membrane potential, alteration of mitochondrial mass, alteration of mitochondrial function, alteration of autophagic flux, loss of lysosomal integrity, alteration of lysosomal activity, defective photoreceptor extracellular segment (POS) transport, accumulation of toxic macromolecules, axonal injury, cellular senescence, apoptosis, and cell death.

[0075] Some embodiments are directed to a method of preventing cytotoxicity comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0076] Some embodiments are directed to a method of preventing alterations in lysosomal activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0077] Some embodiments are directed to a method of preventing alteration of autophagic flux comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0078] Some embodiments are directed to a method of preventing cell death comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0079] Some embodiments are directed to a method of preventing apoptosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0080] Some embodiments are directed to a method of preventing complement C3 dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0081] In some embodiments, the dysfunction of complement C3 results in cell damage, in some embodiments, the cell damage is selected from the group consisting of cell death, defective transepithelial electrical resistance (TEER), and defective RPE barrier.

[0082] Some embodiments are directed to a method of preventing inflammation comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0083] Some embodiments are directed to a method of slowing the progression of a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0084] Some embodiments are directed to a method of preventing a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0085] Some embodiments are directed to a method of slowing the progression of symptoms associated with a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0086] Compounds used in the present invention In some embodiments, the compound for use in the present invention is a compound selected from the group consisting of: A. A compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony Each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR'; wherein R1, and each R', if present in R2, is independently H or C1-C6 alkyl; Each of R3, R4, R5, and R6 is 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), 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 independently selected from the group consisting of R', C(O)O(C1-C4 alkyl), OC(O)N(R'), C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl); wherein each R', when present in R3, R4, R5, and R6, is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, wherein 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 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl 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 join to form -O-CC 1-2 forming a 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, heteroaryl, or heterocycloalkyl 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, R5 are linked to form -OC 1-2 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from those which form methylene-O- groups; R7, R8, R9, R 10 , and R 11each of which 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 alkoxyC1-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'), C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl); where R7, R8, R9, R 10 , and R 11 If present, each R' is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-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 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R7, R8 are linked to form -OC 1-2 Forming a methylene-O-group; or R8 and R9 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R8, R9 join to form -OC 1-2 forming a methylene-O-group; each n is independently 0, 1, or 2; However, R7, R8, R9, R 10 , and R 11 is not all H; and However, the following compounds or pharma- ceutically acceptable salts thereof are excluded: [ka] B. Compound of Formula IA [ka] or a pharma- ceutically acceptable salt thereof, where R a , R b , R c , R d and R e each 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.

[0087] Compounds of Formula I In some embodiments, the compounds for use in the present invention are selected from compounds of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR', where each R', when present in R1 and R2, is independently H or CC 16 is alkyl; Each of R3, R4, R5, and R6 is 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), 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', C(O)O(C1-C4 alkyl), OC(O)N(R'), C(O)(C1-C4 alkyl), and C(O)NH(CC 14wherein each R', when present in R3, R4, R5, and R6, is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, 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 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl 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 to form -OC 1- C2 Forms a 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, heteroaryl, or heterocycloalkyl 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, R5 are linked to form -OC 1-2 forming a methylene-O-group; R7, R8, R9, R 10 , and R 11each of which 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 alkoxyC1-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'), C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl), where R7, R8, R9, R 10 , and R 11 When present, each R' is H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, CC 16 Independently selected from the group consisting of alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl); or R7 and R8 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R7, R8 are linked to form -OC 1-2Forming a methylene-O-group; or R8 and R9 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R8, R9 are linked to form -OC 1-2 forming a methylene-O-group; each n is independently 0, 1, or 2; However, R7, R8, R9, R 10 , and R 11 is not all H, and However, the following compounds or pharma- ceutically acceptable salts thereof are excluded: [ka]

[0088] In some embodiments, the compound for use in the present invention is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from H or CH3; R3, R4, R5, and R6 are each independently selected from H, CC 16 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) nR', where n=0, 1, or 2, each R' is 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 or R4 and R5 together with the C atom to which they are attached form a cycloalkyl or aryl; 3-7 cycloalkyl, or 5- or 6-membered aryl, or R3 and R4 are linked together to form -OC 1-2 Form a methylene-O- group, or R4 and R5 are linked to form -OC 1-2 forming a methylene-O- group, and R7, R8, R9, R 10 , and R 11 are each 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), OC(O)N(R')2, and C(O)NH(C 1-4 where n=0, 1, or 2 and each R' is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, or C 1-6 It is an alkoxy.

[0089] In some embodiments, the compound for use in the present invention is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R 10 , R 11are each H; R3 and R4 are each independently H, F, Cl, S(O), n R', C(O)R', n=2, R' is selected from CH3, piperazin-1-yl, piperidin-1-yl, morpholinyl, R8 is selected from OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, or OC(CH3)3, and R9 is OH.

[0090] In some embodiments, the compound for use in the present invention is a compound of formula I, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: [ka] TIFF2024510249000024.tif164141

[0091] In a further embodiment, the compound for use in the invention is a compound of formula II, or a pharma- ceutically acceptable salt thereof: [ka] Here, R3, R4, R 5, and R6 are each independently H, Cl, F, OH, CH3, C 1-6 Alkyl, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, OC 1-6 Heterocycloalkyl, CO2R', CONR'2, NC(O)R', NS(O) selected from alkyl, aryl, heteroaryl. 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 alkyl), where n=0, 1, or 2, and R′ is, independently at each occurrence, H, C1-C6 alkyl, C1-C6 haloalkyl; or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6 Alkoxy, NH(C 1-4 alkyl), or NH(C 1-4 alkyl)2, where the optionally substituted groups are selected from C1-C6 alkyl or C2-C7 acyl; or R3, R4 together with the C atom to which they are attached form a 6-membered aryl, or R3, R4 together with them form -OC 1-2 forming a methylene-O- group; or R4, R5 together with the C atom to which they are attached form a 6-membered aryl; or R4, R5 together with the C atom to which they are attached form -OC 1-2 forming a methylene-O-group; and R8 and R9 are each independently H, Cl, F, OH, CH3, C 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 alkyl); or R8 and R9 together with the N or C atom to which they are attached represent OH, amino, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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; R 9 and R 10 are each independently selected from a bond, C, N, S, and O; or R8 and R9 are linked to form -OC 1-2It forms a methylene-O- group.

[0092] In a further embodiment, the compound for use in the present invention is a compound of formula II, or a pharma- ceutically 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.

[0093] In another embodiment, the compound for use in the present invention is a compound of Formula II, or a pharma- ceutically acceptable salt thereof, wherein R, R 10 , R 11 R3 and R4 are each independently H, F, Cl, S(O), n R', C(O)R', where n=2, R' is selected from CH3, or optionally substituted piperazin-1-yl, piperidin-1-yl, or morpholinyl, the optionally substituted groups being 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.

[0094] In a further embodiment, the compound for use in the invention is a compound of Formula II, or a pharma- ceutically acceptable salt thereof, wherein R3 and R4 are each independently H, F, Cl, S(O), n R', C(O)R', n=2, 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, and R9 is OH.

[0095] In a further embodiment, the compound for use in the present invention, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of: [ka] TIFF2024510249000027.tif181141TIFF2024510249000028.tif188141TIFF2024510249000029.tif190141

[0096] In a further embodiment, the compound for use in the present invention, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of: [ka] .

[0097] In a further embodiment, the compound for use in the present invention, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of: [ka]

[0098] In some embodiments, the compounds for use in the present invention include [ka] or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the compound for use in the present invention is: [ka]

[0100] In some embodiments, the compounds for use in the present invention, or pharma- ceutically acceptable salts thereof, are represented by the formula I, which includes R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , and R 11 each of which is as defined herein, provided that R1, R3, R6, R7, R 10 and R 11is each H; R2 is CH3; R8 is OCH3 or Cl, and R9 is OH or Cl, and R4 is not Cl or CF3, and R5 is not Cl or CF. 3

[0101] In some embodiments, the compound for use in the present invention is a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof, wherein R3, R4, R5, R6, R8, and R9 are as described herein.

[0102] In another embodiment, the compound used in the present invention is a compound of formula III [ka] or a pharma- ceutically acceptable salt thereof, wherein R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 is as provided herein, and each -- is independently selected from a single bond, a double bond, or a triple bond.

[0103] In some embodiments, the compound for use in the present invention is a compound according to formula III selected from the group consisting of: [ka] or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, compounds for use in the present invention include racemic mixtures or enantiomers of compounds of formula I, where R3, R4, R5, R6, R8, and R9 are as described herein.

[0105] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R are OH, C 1-6 Alkoxy and hydroxy C 1-6 alkoxy.

[0106] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R and R are OH and NH(C 1-4 alkyl).

[0107] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R are H, halo, C, 1-6 Haloalkyl, and C 1-6 haloalkoxy.

[0108] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R are each independently OH, halo, C 1-6 Alkoxy, and C 1-6 haloalkoxy; R1 and R2 are each independently selected from C 1-6 It is an alkyl.

[0109] In some embodiments, compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are each methyl.

[0110] In some embodiments, the compound for use in the present invention comprises a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein one of R1 and R2 is methyl and the other is H.

[0111] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R and R are each independently selected from OH and C. 1-6 alkoxy, and R1 and R2 are each independently methyl.

[0112] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R are independently selected from H, halo, and C. 1-6 haloalkyl, and R1, R2 are each methyl.

[0113] In some embodiments, compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, where R 8 and R 9 are each independently H, halo, or C 1-6 haloalkyl.

[0114] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R and R 11 are H, respectively.

[0115] In some embodiments, the compounds for use in the present invention include compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R, R 5, and R6 are each independently H, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy.

[0116] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R, and R are each independently H, halo, C, 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6alkoxy.

[0117] In some embodiments, the compounds for use in the present invention include compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R, R, R 5, and R6 are each independently H, halo, S(O) n R', C(O)OR', C(O)N(R')2, and C(O)R'; where n=2 and R' is each independently H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, or aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl optionally substituted with C1-C6 alkyl or C2-C7 acyl.

[0118] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R3, R4, and R5 are each independently H, halo, S(O), n R', and C(O)R'; where n=2 and R' is independently CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholinyl-4-yl.

[0119] In some embodiments, the compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R3, R4, and R5 are each independently H, halo, S(O), n R', and C(O)R'; where n=2 and R' are each independently CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholinyl-4-yl; R8 and R9 are each independently OH, halo, C 1-6 Alkoxy, and C 1-6 haloalkoxy, and R1 and R2 are each methyl.

[0120] In some embodiments, the compounds for use in the present invention include compounds of formula I, or pharma- ceutically acceptable salts thereof, in which R3 and R4, or R4 and R5, together with the C atom to which they are attached, form a 6-membered cycloalkyl, or heterocycloalkyl, aryl or heteroaryl ring.

[0121] In some embodiments, compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, wherein R3 and R4, or R4 and R5, are O and joined together to form -OC. 1-2 It forms a methylene-O- group.

[0122] In some embodiments, compounds for use in the present invention include compounds of Formula I, or a pharma- ceutically acceptable salt thereof, where R 2 and R 3 H, OH, halo, C 1-6 Alkoxy and C 1-6 haloalkyl.

[0123] In some embodiments, the compounds for use in the present invention include compounds of Formula II, or a pharma- ceutically acceptable salt thereof, wherein R3 and R4 are independently H, Cl, F, -OMe, -CF3, S(O) n R', and C(O)R'; where n=2 and R' are each independently H, CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholinyl-4-yl; R8 and R9 are each independently OH and C 1-6 alkoxy.

[0124] In some embodiments, the compounds for use in the present invention include compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 and R 3 is independently selected from H, OH, Cl, F, -OMe, and -CF3, 7 and R8 H and C 1-6 alkyl, 9 is H, where R 5 and R 6 H and C 1-6 haloalkyl.

[0125] In some embodiments, a compound of any of Formulae I-III according to any embodiment described herein can include a provisos removing one or more of the following compounds: [ka]

[0126] Compound of Formula IA In some embodiments, the compounds for use in the present invention have formula IA [ka] or a pharma- ceutically acceptable salt thereof: During the ceremony, R a , R b , R c , R d and R e each 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.

[0127] In some embodiments, the compounds for use in the present invention include a substituent R a , R b , R c , R d and R eis independently selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino.

[0128] In some embodiments, the compounds for use in the present invention include a substituent R a , R b , R c , R d and R e each is independently selected from the group consisting of H, Cl, F, and CF3.

[0129] In some embodiments, the compounds for use in the present invention include a substituent R a , R b , R d and R e is independently H, and R c is selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0130] In some embodiments, the compounds for use in the present invention include a substituent R a , R b , R d and R e is independently H, and R c is selected from the group consisting of H, hydroxyl, Cl, F, methyl, -OCH3, -OC(CH3)3, O-CH(CH3)2, CF3, SO2CH3, and morpholino.

[0131] In some embodiments, the compounds for use in the present invention include a substituent R a , R b , R d and R e each is independently H; and R c is selected from the group consisting of H, Cl, F and CF3.

[0132] In various embodiments, the compounds for use in the present invention comprise a compound of formula IA, wherein R 2A is any heterocycloalkyl or heteroaryl containing a nitrogen in the ring that is attached to the aliphatic chain of formula IA through a nitrogen atom. In some embodiments, for example, R 2A is an optionally substituted cyclic amino group selected from: [ka] and the like, where each nitrogen-containing heterocycloalkyl or heteroaryl can be optionally substituted with one or more substituents selected from hydroxyl, halo, CF, alkoxy, aryloxy, optionally substituted C-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10 Heteroaryl, substituted or unsubstituted C3-C 10 It may be optionally substituted with one or more substituents selected from cycloalkyl or heterocycloalkyl.

[0133] In various embodiments, the compounds for use in the present invention comprise a compound of formula IA, where R 2A is selected from the group consisting of optionally substituted aziridinyl, optionally substituted pyrrolidinyl, optionally substituted imidizolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted oxopiperazinyl, and optionally substituted morpholinyl.

[0134] In some embodiments, the compounds for use in the present invention include compounds of formula IA, where R 2A, substituted cyclic amino, one or more of the hydrogen atoms in the cyclic amino group are substituted with a group selected from alkanoyl, alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, aryloyl, cycloalkanoyl, -OC(O)NCH(CH3), (N,N-dimethylamino)pyridinyl, (N,N-dimethylamino)sulfonyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, 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: [ka] Forms spiro compounds.

[0135] In some embodiments, the compounds for use in the present invention comprise a compound of formula IA, where R 2A is 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 2A is a substituted pyrrolidinyl substituted with one substituent selected from the group consisting of alkoxyalkyl, alkoxycarbonyl, alkyl, hydroxyl, and hydroxyalkyl. In some embodiments, R 2A is a substituted pyrrolidinyl substituted with a single substituent selected from the group consisting of hydroxyl, hydroxymethyl, methoxymethyl, methoxycarbonyl, and methyl.

[0136] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A, piperidinyl or a substituted piperidinyl substituted with one or more substituents selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, aryloxy, -OC(O)NCH(CH), halo, heterocyclyl, (N,N-dimethylamino)pyridinyl, alkyl, aryloxy, -OC(O)NCH(CH), (N,N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF. In some embodiments, R 2A is 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(CH), (NN-dimethylamino)phenyl, N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF. In some embodiments, R 2A is 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(CH), (NN-dimethylamino)phenyl, N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF. In some instances, R 2Ais piperidinyl or a substituted piperidinyl substituted with a single substituent selected from the group consisting of methyl, isopropyl, isobutyl, CF, isobutyl, CF3, hydroxymethyl, hydroxyethyl, (isopropyloxy)ethyl, -(CH2)2O(CH2)2OCH3, -(CH2)3OCH3, -C(O)OMe, -C(O)OEt, hydroxyl, methoxy, isopropyloxy, phenyloxy, F, ethoxy, and phenyl. [ka]

[0137] In some embodiments, R 2A is piperidinyl or a substituted piperidinyl substituted at the 4-position of the piperidinyl with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, O)NCH(CH), (N,N-dimethylamino)pyridinyl, halo, heterocyclyl, (heterocyclyl)alkoxyalkyl, hydroxyl, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF. In some embodiments, R 2A is piperidinyl or a substituted piperidinyl substituted at the 4-position of the piperidinyl with a single substituent selected from the group consisting of methyl, isopropyl, isobutyl, CF, hydroxymethyl, hydroxyethyl, (isopropyloxy)ethyl, -(CH), O(CH), OCH, -(CH), OCH, -C(O)OMe, -C(O)OEt, hydroxyl, methoxy, isopropyloxy, phenyloxy, F, ethoxy, and phenyl. [ka]

[0138] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A In some embodiments, R is piperidinyl or a substituted piperidinyl substituted with two substituents on the same carbon of the piperidinyl, independently selected from the group consisting of alkoxyalkyl, alkyl, -OC(O)NCH(CH), hydroxyl, and phenyl. 2A is an alkoxyalkyl, alkyl, -OC(O)NCH(CH) 32 In some embodiments, R is piperidinyl or a substituted piperidinyl substituted with two substituents at the 4-position of the piperidinyl, each of which is independently selected from the group consisting of phenyl, hydroxyl, and phenyl. 2A are hydroxyl and methyl; hydroxyl and ethyl; hydroxyl and -(CH2)2OCH 3; , hydroxyl and phenyl; piperidinyl or substituted piperidinyl substituted with two substituents at the 4-position selected from the group consisting of methyl and phenyl, methyl and -OC(O)NCH(CH3)2, and butyl and -OC(O)NCH(CH3)2. In some embodiments, the two hydrogen atoms on the same carbon of piperidinyl are substituted with a compound selected from [ka] In some embodiments, the two hydrogen atoms at the 4-position of the piperidinyl are replaced with a compound selected from the following: [ka] Forms spiro compounds.

[0139] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2Ais piperazinyl or a substituted piperazinyl substituted with one or more substituents selected from the group consisting of alkanoyl, alkoxycarbonyl, aryloyl, cycloalkanoyl, (N,N-dimethylamino)sulfonyl, heterocyclyl, methylsulfonyl, and phenyl. In some embodiments, R 2A is a substituted piperazinyl substituted with a single substituent selected from the group consisting of alkanoyl, alkoxycarbonyl, aryloyl, cycloalkanoyl, (N,N-dimethylamino)sulfonyl, heterocyclyl, methylsulfonyl, and phenyl. 2A is a substituted piperazinyl substituted with a single substituent selected from the group consisting of -C(O)OC(CH3)3, -C(O)OCH2CH(CH3)2, -C(O)OCH2CH3, -C(O)OCH3, phenyl, -C(O)CH3, -C(O)Ph, -SO2Me, -SON(CH3) 2、 [ka] In some embodiments, R 2A is a substituted piperazinyl substituted with a single substituent at the 4-position selected from the group consisting of -C(O)OC(CH3)3, -C(O)OCH2CH(CH3)2, -C(O)OCH2CH3, -C(O)OCH3, phenyl, -C(O)CH3, -C(O)Ph, -SO2Me, -SON(CH3)2 [ka] .

[0140] In certain embodiments, the compounds for use in the present invention consist of a compound of formula IA, wherein R 2A wherein R is a substituted piperdinyl; [ka] In the formula, R 3A is hydrogen or CC 18 is alkyl, R 4Ais hydrogen, hydroxyl, halogen, CF3, alkoxy, aryloxy, 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 a heterocycloalkyl.

[0141] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A teeth [ka] In the formula, R 5A and R 6A each independently is hydrogen, hydroxyl, sulfonyl, dialkylamino, optionally substituted C-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10 Heteroaryl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In some embodiments, R 5A is hydrogen, dialkylamino, or C3-C 10 In some embodiments, R 5A is hydrogen, dialkylamino, pyrrolidinyl, or morpholinyl. 6A is sulfonyl. In some embodiments, R 6A is methylsulfonyl.

[0142] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A teeth; [ka] TIFF2024510249000050.tif196163, In the formula, R 3a is hydrogen and CC 18 alkyl, n A is an integer selected from 0, 1 and 2.

[0143] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A is as follows. [ka]

[0144] In some embodiments, the compounds for use in the present invention include R 2A In some embodiments, R is an optionally substituted morpholinyl. 2A is morpholinyl.

[0145] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R is: 2A or an optionally substituted formula, [ka] In the formula, R 7 is hydrogen, hydroxyl, sulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, acyl, benzoyl, cycloalkylcarbonyl, optionally substituted C-C 10 Alkyl, optionally substituted C5-C 10 ArylOptionally Substituted C3-C 10 Heteroaryl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In some embodiments, R 7A is sulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, acyl, benzoyl, cycloalkylcarbonyl, C5-C10 Aryl or optionally substituted C3-C 10 It is a heterocycloalkyl.

[0146] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A is as follows. [ka]

[0147] In various embodiments, the compounds for use in the present invention include R 2A and optionally substituted pyrrolidinyl of formula IA: [ka] In the formula, R 8A is hydrogen, hydroxyl, sulfonyl, optionally substituted C1-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10 Heteroaryl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In some embodiments, R 8A is hydrogen, hydroxyl or an optionally substituted C-C 10 It is an alkyl.

[0148] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A : [ka]

[0149] In some embodiments, the compounds for use in the present invention comprise a compound of formula IA, where R 2Ais an optionally substituted bicyclic ring or an optionally substituted fused ring. For example, in some embodiments, R 2A is selected from the group consisting of: [ka] Here, R 9A is hydrogen, hydroxyl, sulfonyl, 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 a heterocycloalkyl.

[0150] In some embodiments, the compounds for use in the present invention consist of a compound of formula IA, where R 2A is [ka] In the formula, R 11a , R 11b , R 11c , and R 11d each independently represents hydrogen, hydroxy, sulfonyl, optionally substituted C-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10 Heteroaryl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In certain embodiments, R 2A is as follows [ka] TIFF2024510249000059.tif117139

[0151] In some embodiments, the compounds for use in the invention are compounds of formula IA, where each R a , R b , R c , R d and R e is R a , R b , R c , R d and R e R 1A is R 1A and R 2A is R 2A The present invention is selected from any of the embodiments disclosed herein.

[0152] In some embodiments, the compound for use in the present invention is a compound selected from the group consisting of: [ka] TIFF2024510249000061.tif178141TIFF2024510249000062.tif175141TIFF2024510249000063.t if170141TIFF2024510249000064.tif184141TIFF2024510249000065.tif178141TIFF2024510249 000066.tif172141TIFF2024510249000067.tif178141TIFF2024510249000068.tif180141TIFF20 24510249000069.tif178141TIFF2024510249000070.tif168141TIFF2024510249000071.tif20914 1TIFF2024510249000072.tif176141TIFF2024510249000073.tif175141TIFF2024510249000074. tif172141TIFF2024510249000075.tif170141TIFF2024510249000076.tif184141TIFF2024510249 000077.tif170141TIFF2024510249000078.tif171141TIFF2024510249000079.tif195141TIFF20 24510249000080.tif173141TIFF2024510249000081.tif208141TIFF2024510249000082.tif53116

[0153] In some embodiments, the compound for use in the present invention is a compound selected from the group consisting of: [ka]

[0154] In some embodiments, the compound for use in the present invention is a compound of formula IIA or a pharma- ceutically acceptable salt thereof: [ka]

[0155] Substituent R of formula IIA f , R g , R h , R i and R j are each independently selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0156] Substituent R of formula IIA 10A is an optionally substituted cyclic amino group, m A is an integer between 0 and 3.

[0157] In some embodiments, the substituent R of formula IIA f , R g , R h , R i and R j Each of is independently selected from the group consisting of H, hydroxyl, and alkoxy. f , R g , R h , R i and R j Each of is independently selected from the group consisting of H, hydroxyl, and methoxy. f , R g , and R j is H, and each of R g , and R h Each of is independently selected from hydroxyl, or methoxy.

[0158] In some embodiments, R of formula IIA 10Ais optionally substituted aziridinyl, optionally substituted pyrrolidinyl, optionally substituted imidizolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted oxopiperazinyl, or optionally substituted morpholinyl, and any of the individual substituted or unsubstituted piperdinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted bicyclic ring, or substituted or unsubstituted fused ring as described above in connection with Formula I.

[0159] In some embodiments, R of formula IIA 10A is an optionally substituted fused ring, such as: [ka] and In the formula, R 11e , R 11f , R 11g , and R 11h each independently represents hydrogen, hydroxy, sulfonyl, optionally substituted C-C 10 Alkyl, optionally substituted C5-C 10 Aryl, optionally substituted C-C 10 Heteroaryl, optionally substituted C-C 10 Cycloalkyl or optionally substituted C-C 10 In certain embodiments, R 10A m A When is 2, [ka] isn't it.

[0160] In some embodiments, R 10A Formula IIA is [ka] TIFF2024510249000088.tif187141

[0161] In some embodiments, the compound for use in the invention is a compound of formula IIa: [ka]

[0162] Substituent R of formula IIa k and R l each is independently selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino.

[0163] Substituent R of formula IIa 12A is selected from the group consisting of aryloxy, alkenyloxy, alkoxy, aminoalkyl, N,N-dimethylaminoalkyl, pyrrolidinyl, N-methylpyrrolidinyl, N-acylpyrrolidinyl, carboxyaminoalkyl, hydroxyalkyl, -O(CH2)2OC(O)CH3. [ka] TIFF2024510249000091.tif69139

[0164] In some embodiments, the substituent R of formula IIa k and R l Each of R is independently selected from the group consisting of H, hydroxyl, and methoxy. lA is methoxy and R k is hydroxyl.

[0165] In some embodiments, the substituent R of formula IIa 12A is selected from the group consisting of 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]

[0166] In some embodiments, the compound for use in the present invention is a compound selected from the group consisting of: [ka] TIFF2024510249000094.tif137141TIFF2024510249000095.tif49135

[0167] In some embodiments, the compound for use in the present invention is a compound selected from the group consisting of: [ka] TIFF2024510249000097.tif178141TIFF2024510249000098.tif179141TIFF2024510249 000099.tif204141TIFF2024510249000100.tif63116TIFF2024510249000101.tif58126

[0168] Additional embodiments include salts, solvates, stereoisomers, prodrugs, and active metabolites of the compounds according to any of the embodiments described herein.

[0169] Additional embodiments include salts, solvates, stereoisomers, prodrugs, and active metabolites of the compounds according to any of the embodiments described herein.

[0170] Some embodiments are directed to the free base form of the compound according to any embodiment described herein.Other embodiments include salts of such compounds, including, for example, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable addition salts of free bases.Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nitric acid, phosphoric acid, sulfuric acid, or hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, and salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic acid, maleic acid, succinic acid, or citric acid. Non-limiting examples of such salts include napadisilate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Additional salt forms of the above compounds include salts of amino acids such as arginates, gluconates, galacturonates, and the like (see, eg, Berge et al., "Pharmaceutical Salts," J. Pharma. Sci. 1977;66:1).

[0171] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, procaine, and the like. The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid.

[0172] Various embodiments include total and partial salts, i.e., salts having 1, 2 or 3 equivalents, preferably 2 equivalents, of base per mole of acid of the compound or salt according to any embodiment described herein, and 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. Typically, pharma- ceutically 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 precipitate from the solution and be recovered by filtration or can be recovered by evaporation of the solvent. For example, an aqueous solution of an acid, such as hydrochloric acid, can be added to an aqueous suspension of the compound according to any embodiment described herein, and the resulting mixture can be evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, the compound according to any embodiment described herein can be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid can be added in the same solvent or another suitable solvent. The resulting acid addition salt can then be precipitated directly or by the addition of a less polar solvent, such as diisopropyl ether or hexane, and isolated by filtration.

[0173] Many organic compounds can form complexes with solvents in which they are reacted, precipitated, or crystallized. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Various embodiments include solvates of the compounds according to any embodiment described herein. In some embodiments, salts of these compounds may form solvates.

[0174] Further embodiments include N-oxides of the compounds according to any of the embodiments described herein. The N-oxides include an otherwise unsubstituted sp 2 Heterocycles containing an N atom are included. Examples of such N-oxides include pyridyl N-oxide, pyrimidyl N-oxide, pyrazinyl N-oxide and pyrazolyl N-oxide.

[0175] Compounds according to any embodiment described herein may have one or more chiral centers and, depending on the nature 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 individual enantiomers or as mixtures of enantiomers. A mixture containing equal proportions of enantiomers is called a "racemic mixture." A mixture containing unequal portions of enantiomers is described as having an "enantiomeric excess" (ee) of either the R or S compound. The excess of one enantiomer in a mixture is often expressed in % enantiomeric excess. The ratio of enantiomers may also be defined by "optical purity," which is the degree to which a mixture of enantiomers rotates plane-polarized light compared to individual optically pure R and S compounds. A compound may also be a substantially pure (+) or (-) enantiomer of a compound described herein. In some embodiments, the composition may comprise 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 comprise a substantially pure enantiomer that is at least 99.5% of one enantiomer.

[0176] The above description encompasses all individual isomers of the compounds according to any embodiment described herein, and the description or naming of a particular compound in the specification and claims is intended to include both the individual enantiomers and mixtures thereof. Methods for the determination of stereochemistry and the separation or stereosynthesis of stereoisomers are well known in the art. Diastereomers differ in both physical properties and chemical reactivity. Mixtures of diastereomers can be separated into enantiomeric pairs based on solubility, fractional crystallization, or chromatographic properties, e.g., thin layer chromatography, column chromatography, or HPLC. Purification of a complex mixture of diastereomers into enantiomers usually requires two steps. In the first step, the mixture of diastereomers is resolved into the enantiomeric pair, as described above. In the second step, the enantiomeric pair is further purified to a composition enriched in one or the other enantiomer, or more preferably, to a composition consisting of the pure enantiomer. Separation of enantiomers usually requires reaction or molecular interaction with a chiral agent, e.g., a solvent or column matrix. For example, resolution can be achieved by converting a mixture of enantiomers, e.g., a racemic mixture, into a mixture of diastereomers by reacting it with a pure enantiomer of a second agent, i.e., a resolating agent. The two resulting diastereomeric products can then be separated. The separated diastereomers are reconverted to the pure enantiomers by reversing the initial chemical change.

[0177] Separation of enantiomers can also be achieved by differences in non-covalent binding to chiral substances. Non-covalent binding of enantiomers to chromatographic adsorbents leads to the formation of diastereomeric complexes, which lead to differences in their partitioning between mobile and bound states in the chromatographic system. Thus, the two enantiomers move at different rates through a chromatographic system such as a column, allowing for their separation.

[0178] Further embodiments include prodrugs of compounds according to any of the embodiments described herein, i.e., compounds that release active compounds according to any of the embodiments described herein in vivo when administered to a mammalian subject. Prodrugs are pharmacologically active compounds that are converted to pharmacologically active agents by metabolic conversion, or more typically inactive compounds. Prodrugs of compounds according to any of the embodiments described herein are prepared by modifying functional groups present in the compounds according to any of the embodiments described herein such that the modifications can be cleaved in vivo to release the parent compound. In vivo, the prodrugs readily undergo chemical changes under physiological conditions (e.g., hydrolyzed or acted upon by naturally occurring enzymes), resulting in the release of the pharmacologically active agent. Prodrugs include compounds according to any of the embodiments described herein in which a hydroxyl group, amino group, or carboxy group is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, amino group, or carboxy group, respectively. Examples of prodrugs include, but are not limited to, esters of compounds according to any embodiment described herein (e.g., acetate derivatives, formates, and benzoates), or any other derivatives that are converted to active parent drug when returned to physiological pH or by enzymatic action. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the art (e.g., see Bundgaard.Design of Prodrugs.Elsevier, 1985).

[0179] In some embodiments, one or more hydrogen atoms of the compound according to any embodiment described herein are replaced with deuterium.It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological profile of its hydrogen counterpart while positively affecting its metabolic outcome.By selectively replacing one or more hydrogen atoms in the compound according to any embodiment described herein with deuterium, the safety, tolerability and efficacy of the compound can be improved compared to its all-hydrogen counterpart.

[0180] Methods for incorporating deuterium into compounds are well established. Using metabolic studies established in the art, compounds according to any embodiment described herein can be tested to identify sites at which deuterium isotopes are preferentially placed, where the deuterium isotopes are not metabolized. Furthermore, these studies identify metabolic sites where deuterium atoms will be placed.

[0181] Pharmaceutical compositions for use in the present invention Some embodiments describe pharmaceutical compositions comprising a compound according to any of the embodiments described herein, its pharma- ceutically acceptable salt, its solvate, its stereoisomer, its prodrug, or its active metabolite; and a pharma- ceutically acceptable carrier or diluent.The pharmaceutical compositions can be prepared by methods well known in the pharmaceutical art, and can be administered by various routes, depending on whether local or systemic treatment is desired and the site to be treated.

[0182] While it is possible for a compound as described in any embodiment herein to be administered as a bulk substance, it is preferable to present the compound in a pharmaceutical formulation, e.g., where the active agent is in admixture with a pharma- ceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0183] In particular, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any embodiment described herein, and optionally a pharma- ceutically acceptable carrier.

[0184] combination For the pharmaceutical compositions and methods of the present disclosure, the compounds according to any of the embodiments described herein may be used in combination with other therapeutic and / or active agents.

[0185] In some embodiments, a compound according to any embodiment described herein may be combined with one or more therapeutic agents useful in the treatment of neurological disorders, including, but not limited to, donepezil, memantine, and anti-abeta antibodies.

[0186] Thus, in a further aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound according to any embodiment described herein or a pharma- ceutically acceptable derivative thereof; a second active agent; and, optionally, a pharma- ceutically acceptable carrier.

[0187] It will be understood that if combined in the same formulation, the two or more compounds must be stable with each other and compatible with the other components of the formulation, If formulated separately, they may be provided in any convenient formulation, in such a manner as is known in the art for such compounds.

[0188] Preservatives, stabilizers, dyes and flavorings can be provided in any pharmaceutical composition described herein.Examples of preservatives include sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid.Antioxidants and suspending agents can also be used.

[0189] For combinations involving biologics such as monoclonal antibodies or fragments, suitable excipients are generally employed for parenteral administration, e.g., intravenous administration, to prevent aggregation and stabilize the antibody or fragment in a low endotoxin solution. See, e.g., Formulation and Delivery Issues of Monoclonal Antibody Therapeutics, Daugherty et al., Current Trends in Monoclonal Antibody Development and Manufacturing, Part 4, 2010, Springer, New York pp 103-129.

[0190] The compounds according to any of the embodiments described herein can be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) formulations of the compounds can be prepared by processes known in the art, for example, see WO02 / 00196 (SmithKlineBeecham).

[0191] A compound according to any embodiment described herein, or a pharma- ceutically acceptable salt, solvate, stereoisomer, prodrug, or active metabolite thereof, can be formulated for any route of administration.

[0192] Route of Administration and Unit Dosage Form Routes for administration (delivery) include oral (e.g., as a tablet, capsule, or ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), parenteral (e.g., including but not limited to, intraperitoneal, intramuscular, intravenous, intraspinal, intraventricular, intrathecal or other depot administration), or gastrointestinal.

[0193] Thus, the pharmaceutical composition according to any embodiment described herein includes those that are specifically formulated for the mode of administration.In certain embodiments, the pharmaceutical composition of the present disclosure is formulated in a form suitable for oral delivery.In some embodiments, the compound is an orally bioavailable compound suitable for oral delivery.In other embodiments, the pharmaceutical composition of the present disclosure is formulated in a form suitable for parenteral delivery.

[0194] The compounds according to any embodiment described herein may be formulated for administration in any convenient way for use in human or veterinary medicine, and thus the present disclosure includes within its scope pharmaceutical compositions comprising compounds according to any embodiment described herein adapted for use in human or veterinary medicine. Such pharmaceutical compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Carriers acceptable for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985). The choice of pharmaceutical carrier may be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may include, in addition to the carrier, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s).

[0195] Different delivery systems may require different pharmaceutical compositions / formulations. It is understood that not all compounds need to be administered by the same route. Similarly, when a pharmaceutical composition contains multiple active ingredients, those ingredients may be administered by different routes. As an example, the pharmaceutical composition of the present disclosure may be formulated to be delivered via a topical ocular route, for example, as a subconjunctival intraocular injection or an intravitreal intraocular injection, in which case the pharmaceutical composition is formulated for delivery for injection into the eye. Alternatively, the formulation may be designed to be delivered systemically, in which case the pharmaceutical composition is formulated for delivery by, for example, an intravenous or oral route. Alternatively, the formulation may be designed to be delivered by multiple routes.

[0196] The combination of the compound according to any of the embodiments described herein and the antibody or antibody fragment molecule can be formulated and administered by any of a number of routes, and is administered at a therapeutically effective concentration for the desired indication or purpose. To achieve this goal, the antibody can be formulated with various acceptable excipients known in the art. Typically, the antibody is 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, JP Harm Sci 97(8):3051-3066, incorporated herein by reference, describes various high concentration antibody self-buffering formulations. For example, monoclonal antibodies in self-buffered formulations may be, for example, 50 mg / mL mAb, 5.25% sorbitol, pH 5.0; or 60 mg / mL mAb, 5% sorbitol, 0.01% polysorbate 20, pH 5.2; or conventional buffered formulations, such as 50 mg / mL mAb1, 5.25% sorbitol, 25 or 50 mM acetate, glutamate or succinate, pH 5.0; or 60 mg / mL in 10 mM acetate or glutamate, 5.25% sorbitol, 0.01% polysorbate 20, pH 5.2; other lower concentration formulations may also be employed as known in the art.

[0197] Some compounds of the disclosure cross the blood-brain barrier and can therefore be administered in a variety of ways, for example, systemically (e.g., iv, SC, oral, mucosal, transdermal routes) or locally (e.g., intracranially).

[0198] When the compound according to any embodiment described herein is delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during the passage of the gastrointestinal tract; for example, it should be resistant to proteolysis, stable at acidic pH, and resistant to the cleansing effect of bile. For example, the compound according to any embodiment described herein prepared for oral administration can 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 of the following can be used separately or in combination; for example, a solution or dispersion of, for example, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, shellac or other suitable enteric coating layer polymer. In some embodiments, the aqueous enteric coating layer is a methacrylic acid copolymer.

[0199] Where appropriate, the pharmaceutical compositions according to any of the embodiments described herein may be administered by inhalation, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or eggs, alone or mixed with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or may be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For buccal or sublingual administration, the pharmaceutical compositions according to any of the embodiments described herein may be administered in the form of tablets or lozenges, which may be formulated in a conventional manner.

[0200] When the pharmaceutical composition according to any embodiment described herein is administered parenterally, such administration includes, but is not limited to, administering the compound of the present disclosure intravenously, intraarterially, intrathecally, intracranially, intramuscularly, or subcutaneously; and / or using infusion techniques. Antibodies or fragments are typically administered parenterally, for example, intravenously.

[0201] Pharmaceutical compositions according to any of the embodiments 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, as appropriate, adapted for the preparation of such a sterile solution or dispersion suitable for injection or infusion. The formulation may also be optionally encapsulated in liposomes. In either case, the final formulation must be sterile, liquid, and stable under the conditions of manufacture and storage. To improve storage stability, such formulations may also contain a preservative to prevent the growth of microorganisms. Prevention of the action of microorganisms can be achieved by the addition of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, or ascorbic acid. In many cases, isotonic substances, for example, sugars, buffers, and sodium chloride, are recommended to ensure an osmotic pressure similar to that of body fluids, especially blood. The absorption of such injectable mixtures can be prolonged by the incorporation of absorption-delaying agents, such as aluminum monostearate or gelatin.

[0202] Dispersion can be prepared in liquid carrier or intermediate, such as glycerin, liquid polyethylene glycol, triacetin oil, and mixtures thereof.Liquid carrier or intermediate can be, for example, a solvent or liquid dispersion medium, including water, ethanol, polyol (e.g., glycerol, propylene glycol, etc.), vegetable oil, non-toxic glycerin ester, and suitable mixtures thereof.Proper fluidity can be maintained by forming liposomes, administering appropriate particle size in case of dispersion, or adding surfactant.

[0203] For parenteral administration, the compounds according to any of the embodiments described herein are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably pH 3-9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0204] Sterile injectable solution can be prepared by mixing the compound according to any embodiment described herein with suitable solvent and one or more of the above-mentioned carriers, then aseptically filtering.For the sterile powder suitable for use in preparing sterile injectable solution, the preferred preparation method includes vacuum drying and freeze-drying, which provide the powder mixture of compound and desired excipients for the subsequent preparation of sterile solution.

[0205] The compounds according to any of the embodiments described herein may be formulated for use in human or veterinary medicine by injection (e.g., intravenous bolus injection or infusion, or intramuscular, subcutaneous, or intrathecal routes), and may be presented in unit dose form, ampoules, or other unit dose containers, or in multi-dose containers, optionally with the addition of preservatives. The pharmaceutical compositions for injection may be in the form of a suspension, solution, or emulsion in an oily or aqueous carrier, and may contain compounding agents such as suspending agents, stabilizing agents, solubilizing agents, and / or dispersing agents. Alternatively, the active ingredient may be in the form of a sterile powder for reconstitution with a suitable carrier, e.g., sterile pyrogen-free water, before use.

[0206] The compounds according to any of the embodiments described herein can be administered in the form of tablets, capsules, troches, wafers, elixirs, solutions, or suspensions for immediate, delayed, modified, sustained, pulsed, or controlled release applications.

[0207] The compounds according to any embodiment described herein may also be presented for human or veterinary use in a form suitable for oral or buccal administration, such as in the form of a solution, gel, syrup, or suspension, or in a dry powder for reconstitution with water or other suitable carrier before use.Solid pharmaceutical compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powders, pastes, granules, powders, premixes, etc. 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 contain one or more pharma- ceutically acceptable carriers and excipients, which may be in solid or liquid form.

[0208] 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), disintegrants such as sodium starch glycolate, croscarmellose sodium, certain complex silicates, granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, acacia, etc.

[0209] Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate or talc may be included.

[0210] The pharmaceutical composition according to any embodiment described herein can be orally administered in the form of immediate or controlled release tablets, microparticles, mini tablets, capsules, sachets, and oral solutions or suspensions, or powders for their preparation.Oral formulations can optionally contain a variety of standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, glidants, lubricants, dyes, disintegrants, flavorings, sweeteners, surfactants, release agents, anti-adherents and coating agents.Some excipients have multiple roles in pharmaceutical compositions, for example, they can act as both binders and disintegrants.

[0211] Examples of pharma- ceutically 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, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicate, and cross-linked polyvinylpyrrolidone.

[0212] Examples of pharma- ceutically 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, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pregelatinized starch, tragacanth, xanthine resin, alginate, magnesium aluminum silicate, polyethylene glycol, or bentonite.

[0213] Examples of pharma- ceutically 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 microcrystalline cellulose), calcium dihydro- or anhydro-phosphate, calcium carbonate, and calcium sulfate.

[0214] Examples of pharma- ceutically acceptable lubricants useful in the 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.

[0215] Examples of pharma- ceutically acceptable odorants suitable for the oral pharmaceutical composition according to any embodiment described herein include, but are not limited to, synthetic aromas and natural aroma oils, such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas.Their use depends on many factors, the most important of which is the organic acceptability of the people who take the pharmaceutical composition.

[0216] Examples of pharma- ceutically acceptable dyes suitable for oral pharmaceutical compositions according to any embodiment described herein include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene, and extracts of grapefruit peel.

[0217] Examples of useful pharma- ceutically acceptable coatings for oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, and acrylate-methacrylate copolymers, which are typically used to facilitate swallowing, modify release characteristics, improve appearance, and / or mask the taste of the pharmaceutical composition.

[0218] Suitable examples of pharma- ceutically 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.

[0219] Suitable examples of pharma- ceutically acceptable buffering agents include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate, magnesium hydroxide, and the like.

[0220] Suitable examples of pharma- ceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.

[0221] Similar types of solid compositions can also be employed as gelatin capsule fillers.Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols.For aqueous suspensions and / or elixirs, the drug can be combined with various sweeteners or flavorings, colorants or dyes, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0222] As indicated, the compounds according to any embodiment described herein can be administered intranasally or by inhalation, conveniently in the form of a dry powder inhaler or aerosol spray presentation from a pressurized container, pump, spray or nebulizer, for example, using a hydrofluoroalkane such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA), carbon dioxide or other suitable gas, delivered using a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol and a propellant as a solvent, and may further contain a lubricant, for example, sorbitan trioleate.

[0223] Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of a compound according to any of the embodiments described herein and a suitable powder base such as lactose or starch.

[0224] For topical administration by inhalation, the compounds according to any of the embodiments described herein can be delivered via a nebulizer for human or veterinary use.

[0225] The pharmaceutical composition of the present disclosure may contain 0.01 to 99% by weight of the active substance per volume. For example, for topical administration, the pharmaceutical composition generally contains 0.01 to 10%, more preferably 0.01 to 1% of the active substance.

[0226] The compounds according to any of the embodiments described herein can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles, etc. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0227] The pharmaceutical composition or unit dosage form according to any embodiment described herein may be administered according to a dosage and administration regimen defined by routine testing in light of the guidelines given above to obtain optimal activity while minimizing toxicity or side effects for a particular patient. The dosage of the compound or unit dosage form may vary according to various factors, such as the underlying disease state, the individual's condition, weight, sex and age, and the mode of administration. The exact amount administered to a patient will vary according to the state and severity of the disorder and the physical condition of the patient. A measurable improvement in any symptom or parameter may be determined by one of skill in the art or may be reported by the patient to a physician. It will be understood that a clinically or statistically significant attenuation or improvement in any symptom or parameter is within the scope of this disclosure. A clinically significant attenuation or improvement means perceptible by the patient and / or physician.

[0228] In some embodiments, the amount of compound administered may range from about 0.01 to about 25 mg / kg / day. Generally, a dosage between 0.01 to 25 mg / kg of body weight per day is administered to a patient, e.g., a human. In some embodiments, a therapeutically effective amount is about 0.01 mg / kg body weight, about 0.1 mg / kg body weight, about 0.2 mg / kg body weight, about 0.3 mg / kg body weight, about 0.4 mg / kg body weight, about 0.5 mg / kg body weight, about 0.60 mg / kg body weight, about 0.70 mg / kg body weight, about 0.80 mg / kg body weight, about 0.90 mg / kg body weight, about 1 mg / kg body weight, about 2.5 mg / kg body weight, about 5 mg / kg body weight, about 7.5 mg / kg body weight, about 10 mg / kg body weight, about 12.5 mg / kg body weight, about 15 mg / kg body weight, about 17.5 mg / kg body weight, about 20 mg / kg body weight, about 22.5 mg / kg body weight, and about 26.5 mg / kg body weight. and up to about 25 mg / kg body weight; and up to about 25 mg / kg body weight, about 22.5 mg / kg body weight, about 20 mg / kg body weight, about 17.5 mg / kg body weight, about 15 mg / kg body weight, about 12.5 mg / kg body weight, about 10 mg / kg body weight, about 7.5 mg / kg body weight, about 5 mg / kg body weight, about 2.5 mg / kg body weight, about 1 mg / kg body weight, about 0.9 mg / kg body weight, about 0.8 mg / kg body weight, about 0.7 mg / kg body weight, about 0.6 mg / kg body weight, about 0.5 mg / kg body weight, about 0.4 mg / kg body weight, about 0.3 mg / kg body weight, about 0.2 mg / kg body weight, about 0.1 mg / kg body weight, and about 0.01 mg / kg body weight. In some embodiments, the therapeutically effective amount is between about 0.1 mg / kg / day and about 10 mg / kg / day; in some embodiments, the therapeutically effective amount is between about 0.2 and about 5 mg / kg / day. It will be understood that the pharmaceutical formulations of the present disclosure do not necessarily contain the entire amount of the compound effective for treating the disorder, since such effective amounts may be reached by administration of multiple divided doses of such pharmaceutical formulations. The compound may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times, or four times per day.

[0229] In some embodiments of the present disclosure, the compounds according to any embodiment described herein are formulated into a capsule or tablet, typically containing about 10 to about 200 mg of the compound. In some embodiments, the capsule or tablet contains about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, and about 200 mg. As upper limits, about 200 mg, about 195 mg, about 190 mg, about 185 mg, about 180 mg, about 175 mg, about 170 mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg; about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, and about 10 mg of a compound according to any embodiment herein.

[0230] In some embodiments, the compound according to any embodiment herein is administered to a patient at a total daily dose of 50 mg to 500 mg. In some embodiments, the daily dose is between about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or between about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, or between about 220 mg, about 225 mg, or between about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 395 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg, about 510 mg, about 52 5mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg , about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg;About 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 490 mg, about 485 mg, about 480 mg, about 475 mg, about 470 mg, about 465 mg, about 460 mg, about 455 mg, with an upper limit of about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 485 mg, about 480 mg, about 475 mg, about 470 mg, about 465 mg, about 460 mg, about 455 mg , about 450 mg, about 445 mg, about 440 mg, about 435 mg, about 430 mg, about 425 mg, about 420 mg, about 415 mg, about 410 mg, about 405 mg, about 400 mg, about 395 mg, about 390 mg, about 38 5mg, about 380mg, about 375mg, about 370mg, about 365mg, about 360mg, about 355mg, about 350mg, about 345mg, about 340mg, about 335mg, about 330mg, about 325mg, about 320mg, Approximately 315mg, approximately 310mg, approximately 305mg, approximately 300mg, approximately 295mg, approximately 290mg, approximately 285mg, approximately 280mg, approximately 275mg, approximately 265mg, approximately 260mg, approximately 255mg, approximately 250mg, approximately 245 mg, about 240mg, about 235mg, about 230mg, about 225mg, about 220mgabout 215mg, about 210mg, about 205mg200mg, about 195mg, about 190mg, about 185mg, about 180mg, about 175 mg, about 170 mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 120 mg, about 115 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg; about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, and about 50 mg of a compound according to any embodiment herein. In some embodiments, the total daily dose is about 50 mg to about 150 mg. In some embodiments, the total daily dose is about 50 mg to about 250 mg. In some embodiments, the total daily dose is about 50 mg to about 350 mg. In some embodiments, the total daily dose is about 50 mg to about 450 mg. In some embodiments, the total daily dose is about 50 mg. ;

[0231] A pharmaceutical composition for parenteral administration contains from about 0.01% to about 100% by weight of an active compound according to any embodiment described herein, based on 100% by weight of the total pharmaceutical composition.

[0232] Generally, a transdermal dosage form contains from about 0.01% to about 100% by weight of an active compound according to any embodiment described herein, based on 100% total weight of the dosage form.

[0233] Pharmaceutical composition or unit dosage form can be administered once a day or the total daily dosage can be administered in divided doses.In addition, for the treatment of disorders, it may be desirable to administer another compound in combination or sequentially.For this purpose, the combined active principle is formulated into a simple dosage unit.

[0234] Provided herein is embodiment A, a method of treating a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of compounds of formula I: [ka]

[0235] or a pharma- ceutically acceptable salt thereof: wherein each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR', where each R', when present in R1 and R2, is independently H or C1-C6 alkyl, and 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), O CF3, 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, selected from the group consisting of 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)nR', S(O)nR'2, S(O)nR', 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', when present in R3, R4, R5, and R6, is H, CH3, CH2CH3 , C3-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-C6 alkoxy, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, 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 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl, which groups are 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 together form a -O-C1-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, heteroaryl, or heterocycloalkyl, which groups are selected from the group consisting of 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 together are selected from the group consisting of -O-C1-2 each of R7, R8, R9, R10 and R11 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, and C1-C6 alkoxyC1- 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)nNR'2, S(O)nR', C(O)O(C1-C4 alkyl), OC(O)N(R')2, C(O)(C1-C4 alkyl), and C(O)NH(C1-C4 alkyl);wherein each R', when present in R7, R8, R9, R10, and R11, is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-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 attached form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group, which is selected from the group consisting of OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl. or a group in which R7 and R8 are linked together to form an -O-C1-2 methylene-O- group; or R8 and R9, 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 which is selected from the group consisting of OH, amino, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or a group in which R8 and R9 are linked together to form an -O-C1-2 methylene-O- group, each n is independently 0, 1 or 2, with the proviso that R7, R8, R9, R10 and R11 are not all H, and with the proviso that the following compound, or a pharma- ceutically acceptable salt thereof, is excluded: [ka]

[0236] Provided herein is embodiment B, 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 selected from the group consisting of compounds of formula IA: [ka] or a pharma- ceutically acceptable salt thereof: wherein: each of Ra, Rb, Rc, Rd and Re 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; R1A is selected from the group consisting of hydrogen, alkyl, phenyl, or -CH=C(CH3)2; and R2A is an optionally substituted cyclic amino group.

[0237] In embodiment C, the method of embodiment A, wherein the compound is a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0238] In embodiment D, the method of any one of embodiments A to C, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0239] In embodiment E, 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, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

[0240] In embodiment F, the method of any one of embodiments A to E, wherein the pharma- ceutically acceptable salt is a fumarate salt.

[0241] In embodiment G, the method of any one of embodiments A to F, wherein the compound is [ka]

[0242] In embodiment H, the method of embodiment B, wherein the compound is a compound of formula IA or a pharma- ceutically acceptable salt thereof.

[0243] In embodiment I, the method of any one of embodiments A or H, further comprising: 2A , optionally substituted piperidinyl.

[0244] In embodiment J, the method of any one of embodiments A, H, or I, further comprising: 2A s is selected from the group consisting of: [ka]

[0245] In embodiment K, the method of any one of embodiments A, H, I, or J, wherein the compound is selected from the group consisting of: [ka] or a pharma- ceutically acceptable salt thereof.

[0246] Provided herein is embodiment L, a method of treating a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, the compound being selected from the group consisting of: [ka] TIFF2024510249000110.tif110120TIFF2024510249000111.tif174141TIFF2024510249000112.tif45130

[0247] In embodiment M, a method of treating a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of embodiments A-L and a pharma- ceutical acceptable excipient.

[0248] Provided herein is embodiment N, a method of treating a neurological disease comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of: [ka] or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0249] In embodiment O, the method of embodiment N, 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, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

[0250] The method of embodiment N, wherein in embodiment P, the pharma- ceutically acceptable salt is a fumarate salt.

[0251] In embodiment Q, the method of embodiment P, wherein the compound is [ka] A pharma- ceutically acceptable salt thereof.

[0252] Provided herein is a method for the manufacture of a medicament for treating a neurological disorder, comprising the steps of: [ka] or a pharma- ceutically acceptable salt thereof.

[0253] Provided herein is a method for the manufacture of a pharmaceutical agent for a neurological disease, comprising the steps of: [ka] or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0254] In embodiment T, the use of a compound or composition according to any of embodiments R or S, wherein the compound is a pharma- ceutically acceptable salt thereof.

[0255] In embodiment U, the use of any one of embodiments R-T, 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, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0256] In embodiment V, the use of embodiment U, wherein the pharma- ceutically acceptable salt is a fumarate salt.

[0257] In embodiment W, the use of any of embodiments R or S, wherein the compound is [ka]

[0258] In embodiment X, the use of any of embodiments R or S, wherein the compound is [ka]

[0259] In embodiment Y, the use of any of embodiments R or S, wherein the compound is [ka] .

[0260] In embodiment Z, the method of any one of embodiments A to Y, wherein the neurological disease is selected from age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), excitatory synucleinopathy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) dementia, autosomal dominant Parkinson's disease, chemotherapy-induced neuropathy (CIPN), cognitively intact (CIND), dementia, Creutzfeldt-Jakob disease (CJD), diffuse Lewy body disease (DLBD), also known as dementia with Lewy bodies (DLB), a disease or condition characterized by the presence of Lewy bodies, Down's syndrome, dyskinesia, epilepsy, frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), HIV dementia, Huntington's disease, incident LBD, hereditary LBD, Lewy body dysphagia, mild cognitive impairment (MCI), multiple sclerosis, multiple system atrophy. Neuropathy (MSA), neuropathy (including, but not limited to, peripheral neuropathy, diabetic neuropathy, retinal neuropathy), oligodendroglial atrophy, Parkinson's disease (PD), preclinical Alzheimer's disease (PCAD), psychiatric disorders (including, but not limited to, schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, psychosis, and psychoses), pure autonomic failure, seizures, Shy-Drager syndrome, striatal degeneration, synucleinopathies, traumatic brain injury (TBI), co-occurring Alzheimer's disease and Parkinson's disease and / or MSA, vascular dementia, diseases, disorders or conditions associated with abnormal expression, stability, activity and / or cellular processing of alpha-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, and combinations thereof.

[0261] In embodiment AA, the use of a compound or composition according to any one of embodiments A to Z in the manufacture of a medicament for the treatment of a neurological disorder.

[0262] In embodiment BB, the use of embodiments A-AA, wherein the compound is administered orally. EXAMPLES

[0263] Compounds according to any embodiment described herein can be prepared, for example, by the general and specific methods outlined in WO2013 / 029057, WO2015 / 116923 and WO2018 / 213281, each of which is incorporated by reference in its entirety and which methods constitute further aspects of the present disclosure. Throughout the examples, the following sigma 2 receptor modulators were used: [ka] . Example 1: Substitution of α-synuclein oligomers Experimental Design:

[0264] Rat neuronal cultures were treated with carrier (α-seeded control (7.1 nM) without α-synuclein oligomers (α-synOs)) or synthetic α-synOs for 24 h. Cultures were immunostained for neurite marker microtubule-associated protein 2 (MAP2; green) and α-synuclein, oligomer-specific antibody (ASYO5 antibody, Agrisera; red).

[0265] Analysis and Results Compound A and Compound B inhibit a-synO binding to neuronal synapses and rescue the a-synO-induced transport impairment in a concentration-dependent manner. Untreated carrier control cultures without added α-synO lack α-synO immunoreactivity (Figure 1A). Neurons treated with 1 μM α-synO show punctate binding of a-synO along neurites in the presence (Figure 1C), but not in the absence (Figure 1B), of Compound A (10 μM). Compound B (Figure 1D) and Compound A (Figure I-E) concentration-dependently block a-synO binding to neuronal synapses and concentration-dependently rescue the a-synO-induced transport impairment. α-synOs (final concentration 1.0 μM) caused significant deficits in vesicle transport (filled circles) compared to untreated carrier controls (squares). Compound B showed Emax=92% and EC50=0.31 μM (Figure 1F), and Compound A showed Emax=87% and EC50=650 nM (Figure 1G), which improved this α-synO defect in a concentration-dependent manner. Figure 1D, 1E, 1F, 1G: *p<0.05, ***p<0.01, ***p<0.01, ***p<0.001, one-way ANOVA with Dunnett's post-hoc test for drug concentration vs. control. EXAMPLES

[0266] Experimental Design: Compounds A and B show efficacy in animal models of Parkinson's disease, including models that overexpress α-synuclein and models that mimic the spread of α-synuclein throughout the brain. One such overexpression model is the rat AAV1 / 2A53T-α-synuclein model (Koprich, JB, Johnston, TH, Huot, P., Reyes, MG, Espinosa, M., Brotchie, JM., "Progressive neurodegeneration or endogenous compensation in an animal model of Parkinson's disease produced by decreasing doses of alpha-synuclein," PLoSOne, 6:1-9 (2011), which is incorporated by reference initia), in which induction of α-synuclein overexpression is accompanied by loss of nigral dopaminergic cells, decreased dopamine transporter levels, decreased dopamine levels, and motor deficits.In another example, preformed α-synuclein fibrils are injected into the brain to model the propagation of Parkinson's disease pathology in the brain (Duffy, MF, Collier, TJ, Patterson, JR, Kemp, CJ, Fischer D.L., Stoll, AC, Sortwell, CE, "Quality over quantity: Benefits of using α-synuclein preformed fibrils to model idiopathic Parkinson's disease," FrontNeurosci, 12:1-10 (2018) and Patterson, JR,, Duffy, MF, Kemp, CJ, Howe, JW, Collier, TJ, Stoll, AC, Miller, KM, Pate L, P., Levine, N., Moore, DJ, Luk, KC, Fleming, SM, Kanaan, NM, Paumier, KL, ElAgnaf, OMA, Sortwell, CE, "Timecourse and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in therapeutic model of synucleinopathy triggered by intrastriatal alpha-synuclein preformed fibrils," Neurobiol Dis, 130 (2019), which are incorporated by reference in their entireties. Models using injections of preformed alpha-synuclein fibrils recapitulate several aspects of idiopathic Parkinson's disease, including increased alpha-synuclein oligomer concentrations, increased pSer129 levels, and decreased striatal dopamine and dopamine transporter expression in a manner that propagates outward from the injection site.

[0267] result Treatment of both Parkinson's disease models with either Compound A or Compound B reduces some or all of the damage characteristic of Parkinson's disease and / or slows the propagation of such damage throughout the brain.

Claims

1. A compound for use in the treatment of a neurological disorder selected from the group consisting of chemotherapy-induced neuropathy (CIPN), frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), neuropathy (including but not limited to peripheral neuropathy, diabetic neuropathy, and retinal neuropathy), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, and psychosis), and combinations thereof, comprising: A. A compound of formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof: During the ceremony: R １ and R ２ each independently represents H, C 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), 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-C ３７ 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); where R 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 piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C independently selected from the group consisting of haloalkyl, optionally substituted aryl, alkylaryl, piperazin-1-yl, １ -C ６ Alkoxy, NH(C １ -C ４ alkyl), and N(C １ -C ４ Alkyl) ２ wherein the optionally substituted group is 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, heteroaryl, or heterocycloalkyl, 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 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 form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C, C １－６ 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 , R ５ are linked together to form -O-C １－２ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from those which form 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), 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 When present, each R' 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 １４ Alkyl) ２ and 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, which may be selected from the group consisting of OH, amino, halo, C １ -C ６ 1, 2, 3, 4, OH, amino, halo, C independently selected from alkyl, C haloalkyl, C alkoxy １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ７ , 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 form a 4-, 5-, 6-, 7- or 8-membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group, which may be substituted with OH, amino, halo, C １ -C ６ Alkyl, C １ -C ６ 1, 2, 3, 4, OH, amino, halo, C １ -C ６ Alkyl, C １ -C １－６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or R ８ , 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 are not all H; and however, With the exception of the following compounds or pharma- ceutically acceptable salts thereof: 【Chemistry 2】 B. A compound of formula IA, 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof: During the ceremony, R ａ , R ｂ , R ｃ , R ｄ and R ｅ each independently represents 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; A compound selected from the group consisting of:

2. 2. The compound for use according to claim 1, wherein said compound is a compound of formula I or a pharma- ceutically acceptable salt thereof.

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

4. 4. The compound for use according to any one of claims 1 to 3, 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, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.

5. The compound for use according to any one of claims 1 to 4, wherein the pharma- ceutically acceptable salt is a fumarate salt.

6. A compound for use according to any one of claims 1 to 5, wherein the compound is 【Chemistry 5】 A compound.

7. 2. The compound for use according to claim 1, wherein said compound is a compound of formula IA or a pharma- ceutically acceptable salt thereof.

8. 8. The compound for use according to claim 1 or 7, wherein R ２Ａ is an optionally substituted piperidinyl.

9. 9. The compound for use according to claim 1, 7 or 8, wherein R 2A is 【Chemistry 6】 A compound selected from the group consisting of:

10. 10. A compound for use according to any one of claims 1, 7, 8 or 9, wherein the compound is 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

11. A compound for use in the treatment of a neurological disorder selected from the group consisting of chemotherapy-induced neuropathy (CIPN), frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), neuropathy (including but not limited to peripheral neuropathy, diabetic neuropathy, and retinal neuropathy), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, and psychosis), and combinations thereof, wherein the compound is selected from the group consisting of: 【Chemistry 8】 【change】 【change】 A compound selected from the group consisting of:

12. A pharmaceutical composition for use in the treatment of a neurological disorder selected from the group consisting of chemotherapy-induced neuropathy (CIPN), frontotemporal dementia (FTD), HIV-associated neurocognitive disorder (HAND), neuropathy (including but not limited to peripheral neuropathy, diabetic neuropathy, and retinal neuropathy), psychiatric disorders (including but not limited to schizophrenia, bipolar disorder, depression, mania, anxiety disorder, post-traumatic stress disorder, delirium, eating disorders, autism, REM sleep behavior disorder, hallucinations, attention deficit hyperactivity disorder, and psychosis), and combinations thereof, comprising a compound according to any one of claims 1 to 10 and a pharmacologic acceptable excipient.

13. The pharmaceutical composition for use according to claim 12, wherein the compound is: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

14. 14. The pharmaceutical composition for use according to 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, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.

15. 14. A pharmaceutical composition for use according to claim 13, wherein the pharma- ceutically acceptable salt is a fumarate salt.

16. 15. The pharmaceutical composition for use according to claim 14, wherein the compound is 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

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