Dystonin-binding compounds for dendritic spine generation

Abstract

In some embodiments, a method of promoting dendritic spine generation in a patient is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound that binds to fascin at least at binding site 2 or binding site 3.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 723381, filed August 27, 2018, U.S. Provisional Application No. 62 / 726904, filed September 4, 2018, and U.S. Provisional Application No. 62 / 785435, filed December 27, 2018, pursuant to 35 U.S. SC §119(e), which are incorporated herein by reference in their entirety. Technical Field

[0003] This article provides methods for promoting dendritic spine formation and for treating neuronal diseases or conditions. Background Technology

[0004] Neurological disorders are diseases of the brain, spinal cord, and peripheral nervous system. In terms of epidemiology and individual morbidity, the greatest social cost is borne by neurodegenerative conditions that result in damage or loss of neurons and synaptic connections between them. The most prominent of these are Alzheimer's disease and Parkinson's disease. Other neurodegenerative conditions include age-related conditions (e.g., Parkinson's dementia, vascular dementia, amyotrophic lateral sclerosis), genetic syndromes (e.g., Down syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic encephalopathy), and conditions typically considered purely psychotic in nature, such as schizophrenia and depression.

[0005] Researchers have categorized hundreds of neurological disorders, such as brain tumors, epilepsy, Alzheimer's disease, Parkinson's disease, and stroke, as well as age-related conditions like dementia. Some of these conditions are caused by the progressive loss of synapses (the junctions between two distinct neurons) and eventually the loss of the neurons themselves (neurodegenesis). Unfortunately, neurodegenerative diseases are almost entirely resistant to treatment. Neurons in the brain communicate with each other by sending neurotransmitters (chemical substances) to synapses, which in turn alter the electrical potential of the receiving neurons. The part of the neuron that releases neurotransmitters is the axon (the presynaptic side of the synapse), and the part of the synapse affected by neurotransmitters is called the dendritic spine (the postsynaptic side of the synapse). Variations in the number, location, and even shape of synaptic junctions are fundamental to memory, learning, thinking, and personality. The part of the brain called the hippocampus is closely involved in memory formation and suffers significant loss of synapses and neurons in neurodegenerative diseases. The development of novel methods to restore spine density in the hippocampus may have significant implications for the treatment of many neurodegenerative and developmental cognitive disorders.

[0006] Dendritic complexity, synapse formation, and proper neuronal development and function are endogenously regulated by growth factors, such as brain-derived neurotrophic factor (BDNF). While some small molecules have recently been reported to exhibit neurotrophic-like activity, it has not yet been demonstrated that these molecules promote dendritic spine formation. Novel cellular targets identifying small molecules could lead to treatments for many neurodegenerative and psychodevelopmental disorders, and also have the potential to improve memory and learning. Therefore, small molecules that promote spine formation have potential use in improving cognitive deficits in neurodegenerative diseases such as Alzheimer's disease, and could also serve as general cognitive enhancers. However, pharmaceutically acceptable compounds with this activity are needed. Summary of the Invention

[0007] This article provides methods for promoting dendritic spine formation and for treating neuronal diseases or conditions.

[0008] In some embodiments, a method is provided to promote dendritic spine formation or to treat a patient’s neuronal disease or condition, the method comprising contacting myofascitis with an agent that inhibits the activity of myofascitis.

[0009] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis at least at binding site 2 or binding site 3.

[0010] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis at least at binding site 2.

[0011] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis at at least binding site 3.

[0012] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering a therapeutically effective amount of a compound of formula I to the patient in need:

[0013]

[0014] Or its pharmaceutically acceptable salt;

[0015] Where A 1 A 2 A 3 A 4 A 5 and A 6 Independently select CH and CR 3 A group consisting of N and N, with the condition that A1 A 2 A 3 A 4 A 5 and A 6 No more than four of them are N;

[0016] R 1 The group selected is composed of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, the 5-membered heteroaryl, or the 6-membered heteroaryl is optionally surrounded by one to three R... 6 replace;

[0017] L 2 Choose from the following groups: covalent bonds, -NR 8 -、-C(O)NR 8 -、-NR 8 -、-C(O)NR 8 -、-NR 8 C(O)-、-C(O)CR 8 2-、-CR 8 2C(O)-、-NR 8 CR 8 2- and -CR 8 2NR 8 -;

[0018] R 2 For H, C 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally surrounded by 1 to 4 R... 4 Replace, where each R 4 Choose independently from the following groups: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, phenyl groups (optionally C-terminated) 1-6 Alkyl, halogen, C 1-6 (halogenated alkyl or -OH substituted), -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 7 -NR10 CO2R 7 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0019] Each R 3 Choose independently from the following groups: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 7 -NR 10 CO2R 7 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0020] q is 1, 2, or 3;

[0021] Each R 6 Independently select from the following groups: cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -CH2OH;

[0022] R 7 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0023] R 8 It is hydrogen or C 1-6 alkyl;

[0024] Each R 10 Independently hydrogen or C 1-6 Alkyl, or two R 10It forms 4- to 6-membered rings together with one or more atoms it is attached to; and

[0025] R 11 For hydrogen or R 3 .

[0026] In some embodiments, a method for treating depression is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound is the compound described in U.S. Patent Publication No. 2015 / 0299191. In some embodiments, the compound is the compound described in U.S. Patent Publication No. 2014 / 0080843.

[0028] In some embodiments, the compound is the compound described in International Patent Publication No. WO 2013 / 013240. In some embodiments, the compound is the compound described in U.S. Patent Publication No. 2014 / 0024705.

[0029] In some embodiments, a method for treating or preventing neuronal diseases or conditions is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis at least at binding site 2.

[0030] In some embodiments, a method for treating or preventing neuronal diseases or conditions is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis at least at binding site 3.

[0031] In some embodiments, a method for treating or preventing neuronal diseases or conditions is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound described herein, such as a compound selected from compounds of formula I provided herein or pharmaceutically acceptable salts thereof, compounds of formula II provided herein or pharmaceutically acceptable salts thereof, compounds selected from compounds of formula IV provided herein or pharmaceutically acceptable salts thereof, compounds selected from compounds of formula V provided herein or pharmaceutically acceptable salts thereof, compounds selected from compounds of formula VII provided herein or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11 or pharmaceutically acceptable salts thereof.

[0032] In some embodiments, the neuronal disease or condition is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, Fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or condition is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, Fragile X syndrome, depression, and traumatic brain injury.

[0033] In some embodiments, the neuronal disease or condition is an emotional disorder, such as depression.

[0034] In some embodiments, this document provides a method for promoting dendritic spine formation in a patient, the method comprising administering to a patient in need a therapeutically effective amount of the agent described herein, for example, a compound selected from compounds of formula II, IV, V, VII, VIII, IX, X or XI or pharmaceutically acceptable salts thereof, or compound 1, compound 8, compound 9, compound 10 or compound 11 or pharmaceutically acceptable salts thereof.

[0035] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering to a patient in need a therapeutically effective amount of N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide (compound 1) having the following structure:

[0036]

[0037] Or its pharmaceutically acceptable salt.

[0038] In some embodiments, a compound is provided that inhibits myofascitis, wherein the compound does not bind to myofascitis at binding site 1.

[0039] In some embodiments, a method for promoting dendritic spine formation in a patient is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound that binds to myofascitis, provided that the compound is not a compound of formula III:

[0040]

[0041] Where Y is –NR 33 -、O or –S-;R 31 Independently halogen, -CX 31 -CHX 31 -CH2X 31 -OCX 31 3. -OCHX 31 2. -OCH2X 31-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -HNC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 32 Independently halogen, -CX 32 3. -CHX 32 2. -CH2X 32 -OCX 32 3. -OCHX 32 2. -OCH2X 32 -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X 31 and X 32 Each of z1 and z2 is an independent halogen; each of z1 and z2 is an independent integer from 0 to 4; z3 is an integer from 1 to 12; and R 33 It is hydrogen or substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, with respect to formula III, Y is –NR. 33 -or –S-. Attached Figure Description

[0042] Figure 1 Three known actin binding sites of myofascitis are shown in one embodiment.

[0043] Figures 2A-2D Front, bottom, top, and back views of myofascitis are provided based on the available crystal structures in one embodiment.

[0044] Figures 3A-3C A docking complex of human muscle fasciculus 1 with comparative compounds 2, 3 and 4 is shown in one embodiment.

[0045] Figure 4A 2D interaction diagram of the comparative compound 2 and human muscle fasciculus 1 complex in one embodiment is shown.

[0046] Figure 5 The pre-binding structure of myofascitis superimposed on the myofascitis structure bound by compound 1 is shown, wherein binding site 1 is shown in the examples and binding site 2 is shown in the examples.

[0047] Figure 6 The results of synaptic growth of Comparative Compound 2, Comparative Compound 7, and Compound 1 compared with the caustic control are shown in one embodiment. Detailed Implementation

[0048] Typically, the compositions and methods described herein provide the administration of a compound that binds to myotrigin at binding site 2 or binding site 3 to promote dendritic spine formation. In some embodiments, the compositions and methods may be used to treat neuronal diseases or conditions. Typically, the active ingredient or main ingredient will comprise an agent, such as a compound described herein, or a pharmaceutically acceptable salt of a compound. The active ingredient or main ingredient may also comprise one or more additional pharmaceutically active materials.

[0049] I. Definition

[0050] The following description illustrates exemplary embodiments of the present technology. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0051] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless otherwise indicated in the context in which they are used.

[0052] The term "myotrigin" refers to a 54-58 kDa protein that is a cross-linked actin protein. The term "myotrigin" may refer to the amino acid sequence of human myotrigin 1. The term "myotrigin" includes the nucleotide sequence or protein in its wild-type form and any mutants thereof. In some embodiments, "myotrigin" is wild-type myotrigin. In some embodiments, "myotrigin" is one or more mutant forms. In some embodiments, myotrigin is human myotrigin 1. In some embodiments, myotrigin is encoded in a nucleotide sequence corresponding to reference number GI:347360903. In some embodiments, myotrigin is encoded in a nucleotide sequence of RefSeq M_003088. In some embodiments, the myotrigin corresponds to the amino acid sequence of RefSeq NP_003079.1.

[0053] The term "dendritic spine formation," etc., in its usual and conventional sense refers to the development (e.g., growth and / or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote dendritic spine formation without affecting spine morphology. Promotion is relative to the absence of application of the compound.

[0054] As used herein, the term "dendritic" refers to the branching extension of a neuronal cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axons of neighboring neurons. The terms "dendritic spine" or "dendritic spike" refer to protoplasmic projections on a neuronal cell (e.g., neurons on dendrites). In some embodiments, a dendritic spine can be described as having a membranous neck that can be capped with a small head (e.g., a head). Dendritic spines are classified according to their shape: headless, thin, short and thick, mushroom-shaped, or branching. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuronal cell. For example, the dendritic spine density can be given as the number of dendritic spines per micrometer.

[0055] The term "dendritic spine formation," etc., in its usual and conventional sense refers to a process that results in an increase in the number or development of dendritic spines. The term "dendritic spine morphology," etc., in its usual and conventional sense refers to the physical characteristics (e.g., shape and structure) of dendritic spines. Improvement in dendritic spine morphology is a morphological change (e.g., an increase in length or width) that leads to enhanced functionality (e.g., an increase in the number of contacts between neurons or a reduction in the space between adjacent neurons (e.g., synaptic clefts)). Exemplary methods for this characterization, as known in the art and disclosed herein, include measuring the dimensions (i.e., length and width) of the dendritic spines. Therefore, the term "improved dendritic spine morphology" generally refers to an increase in the length, width, or both of the dendritic spines.

[0056] "Binding" refers to at least two different species (e.g., chemical compounds comprising biomolecules or cells) coming close enough to react or interact, resulting in the formation of a complex. For example, the binding of two different species (e.g., proteins and compounds described herein) may lead to the formation of a complex, wherein the species interact through non-covalent or covalent bonds. In some embodiments, the resulting complex is formed when two different species (e.g., proteins and compounds described herein) interact through non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).

[0057] As defined herein, the terms “activation,” “activate,” “activating,” etc., relating to protein-activator (e.g., agonist) interactions mean positively influencing (e.g., increasing) the activity or function of a protein relative to the activity or function of the protein in the absence of an activator (e.g., the compounds described herein).

[0058] "Control" or "controlled experiment" is used in its general sense and refers to an experiment in which the subjects or reagents are treated as in a parallel experiment, except that the experimental procedures, reagents, or variables are omitted. In some instances, controls are used as a standard for comparison in evaluating the effects of an experiment.

[0059] "Contact" is used in its ordinary, general sense and refers to a process that brings at least two different species (e.g., chemical compounds comprising biomolecules or cells) close enough to react. The term "contact" can include allowing two molecular species to react or physically touch, wherein said two species can be compounds, biomolecules, proteins, or enzymes as described herein. In some embodiments, contact includes allowing the compounds described herein to interact with proteins (e.g., myofascitis) or enzymes. In some embodiments, contact may include binding to proteins.

[0060] As defined herein, the terms “inhibition,” “inhibit,” and “inhibiting” will be given their conventional meanings to those skilled in the art. Regarding protein-inhibitor (e.g., antagonist) interactions, the terms “inhibition,” “inhibit,” and “inhibiting” mean a negative impact (e.g., a reduction) on the functional activity of a protein relative to the absence of an inhibitor.

[0061] A dash ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH2 is connected by a carbon atom. A dash before or at the end of a chemical group is for convenience; a chemical group may be depicted with one or more dashes or without one or more dashes without losing its general meaning. A wavy line drawn through a line in the structure indicates the connection point of a group. Directionality does not indicate or imply the order in which chemical groups are written or named unless required by chemistry or structure.

[0062] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0063] This document refers to the value or parameter “about” as including (and describing) embodiments relating to said value or parameter itself. In some embodiments, the term “about” includes an indicated amount ±10%. In other embodiments, the term “about” includes an indicated amount ±5%. In some other embodiments, the term “about” includes an indicated amount ±1%. Similarly, the term “about X” includes a description of “X”. Likewise, unless the context clearly specifies otherwise, the singular forms “a” and “said” include multiple references. Thus, for example, a reference to “compound” includes multiple such compounds, and a reference to “determination” includes a reference to one or more determinations and their equivalents known to those skilled in the art.

[0064] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, with 1 to 8 carbon atoms (i.e., C464). 1-8 Alkyl groups, with 1 to 6 carbon atoms (i.e., C646). 1-6 Alkyl group or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specified number of carbons is named by chemical name or identified by molecular formula, it may encompass all positional isomers having said number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2). In some embodiments, the term "lower alkyl" refers to C 1-6 alkyl.

[0065] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having the following characteristics: 2 to 20 carbon atoms (i.e., C64 ... 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0066] "Alkyne" refers to an alkyl group containing at least one carbon-carbon triple bond and having the following alkyl groups: 2 to 20 carbon atoms (i.e., C64 ... 2-20alkynyl group), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C4 group) 2-4 (Alkynyl). The term "alkynyl" also includes those groups that have one triple bond and one double bond.

[0067] "Alkoxy" refers to "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0068] "Haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, as defined above.

[0069] "alkyl thio" refers to the group "alkyl-S-".

[0070] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined above. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0071] "Amino" refers to the substituent group -C(O)NR y R z The "C-amino group" and the substituent group -NR y C(O)R z The "N-amino group" of both, of which R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0072] "Amino" refers to the -NR group. y R z , where R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0073] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C4 group) 6-10Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not encompass heteroaryl groups as defined below or overlap with heteroaryl groups in any way. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0074] "Aryl group" refers to an aryl group that is side-attached to an alkyl group. Examples of aryl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0075] "Carbamoyl" refers to the substituent group –OC(O)NR y R z The “O-carbamoyl” and the term -NR y C(O)OR z The “N-carbamoyl”, where R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0076] "Carboxyl group" refers to -C(O)OH.

[0077] "Carboxy ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined above.

[0078] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group having a single or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12C ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C1646) 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, as well as partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0079] "Imine" refers to the group -C(NR)R, wherein each R is an alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of which may be optionally substituted as defined above.

[0080] "Halogen" or "halogen group" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, in cases where residues are substituted with more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihalogenated and trihalogenated alkyl groups refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which can be, but do not have to be, the same halogen. Examples of halogenated alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0081] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatom groups. The term "heteroalkyl" encompasses unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl groups comprise 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0082] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls comprise 5 to 20 ring atoms (i.e., 5-membered to 20-membered heteroaryls) or 5 to 10 ring atoms (i.e., 5-membered to 10-membered heteroaryls); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryls include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]phenylthio, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be linked through any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connectivity of the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass aryl groups as defined above or does not overlap with aryl groups.

[0083] "Heterocyclic group" and "heterocyclic alkyl group" refer to a saturated or unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The terms "heterocyclic group" and "heterocyclic alkyl group" encompass heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused β-heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group regardless of its connection (i.e., it can be bonded by carbon atoms or heteroatoms). Further, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which ring can be fused with an aryl ring or a heteroaryl ring, regardless of the connection of the rest of the molecule. As used herein, a heterocyclic group has 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclic groups), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclic groups), or 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclic groups); or has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomium, wherein the ring heteroatomium is independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazineyl, oxobutyryl, dioxopentyl, azirheyryl, and morpholinyl. As used herein, the term "bridging heterocyclic group" refers to a four- to ten-membered ring portion of a heterocyclic group connected at two non-adjacent atoms, wherein one or more (e.g., one or two) four- to ten-membered ring portions have at least one heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridging heterocyclic groups comprise bicyclic or tricyclic ring systems. Also as used herein, the term "spiroheterocyclic" refers to a ring system in which a ternary to decacyclic heterocyclic group has one or more additional rings, wherein the one or more additional rings are ternary to decacyclic alkyl or ternary to decacyclic heterocyclic groups, and wherein the individual atoms of the one or more additional rings are also ternary to decacyclic atoms. Examples of spiroheterocyclic rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothienophyllo, [2,3-c]pyridyl, indole, and isoyindole, wherein the heterocyclic group can be linked by any ring of the fused system.

[0084] "Oxygenation" refers to the group (=O) or (O).

[0085] "Sulfoyl" refers to the group -S(O)2R, where R is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0086] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0087] "alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0088] "Thiocyanate" refers to the group –SCN.

[0089] "Thio" or "thion" refers to the group (=S) or (S).

[0090] As used herein, the term "saccharide" refers to sugar, such as monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Monosaccharides include, but are not limited to, glucose, ribose, and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides are sugars consisting of 2 to 10 sugars preferably linked together by α-bonds. Examples of oligosaccharides include maltose, lactose, sucrose, etc. Polysaccharides include, but are not limited to, cellulose, hemicellulose, lignocellulose, or starch. Sugars or sugars can contain any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, sialic acid (including its aldol and pyranose forms), and its D and L isomers.

[0091] Certain commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" can also be referred to as "alkylene" or "alkylenyl," "arylene" or "arylenyl," respectively. Similarly, unless otherwise explicitly stated, when a combination of groups is referred to herein as a moiety, such as an aralkyl group, the last group mentioned contains the atoms through which the moiety is connected to the remainder of the molecule.

[0092] The terms “optional” or “optionally” mean that the event or situation subsequently described may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. Similarly, the term “optionally substituted” means that any one or more hydrogen atoms on a specified atom or group may be substituted with or may not be substituted with hydrogen atoms.

[0093] The protecting group can be any known in the art, for example, as described in Peter GMWuts and Theodora W. Greene, Greene's Protective Groups in Organic Synthesis (Wiley-Interscience, 2007). In some embodiments, the oxygen protecting group can be selected from benzyl ethers, silyl ethers, esters, carbonates, cyclic acetals, and ketals.

[0094] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imine tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between tautomers, those skilled in the art should understand that the compound includes all tautomers.

[0095] Any formula or structure given herein is intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, differing in that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure or their counterions include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, as well as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Compounds labeled with various isotopes are possible under this disclosure, for example, those doped with radioactive isotopes, such as... 3 H, 13 C and 14 Those containing C. Compounds labeled with this type of isotope can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for use in patients undergoing radiotherapy.

[0096] This disclosure also includes compounds and their counterions that are “deuterated analogs”, wherein one to n hydrogen atoms bonded to carbon atoms are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. When administered to mammals, particularly humans, such compounds exhibit increased metabolic tolerance and can therefore be used to increase the half-life of the compounds. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol.Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0097] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life and reduced dose requirement and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the protocols or examples and the preparation described below. It should be understood that, in this context, deuterium is considered a substituent in the compound.

[0098] The concentration of this heavier isotope, specifically deuterium, can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” said position is understood to have hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0099] The compounds described herein may exist in the form of salts, such as pharmaceutically acceptable salts. The compounds are capable of forming salts, such as acid salts and / or base salts. Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means a compound, salt, composition, dosage form, or other material that can be used to prepare pharmaceutical compositions suitable for veterinary or human use. Salts of the compounds described herein may be prepared according to procedures described herein and those known in the art.

[0100] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts containing inorganic acids and salts containing organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be prepared according to conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts only. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkyl)3), and di(substituted alkenyl)amines (i.e., HN(substituted alkyl)3). Suitable amines include, for example, amines containing substituted alkenyl groups (e.g., N-substituted alkenyl groups), tri(substituted alkenyl)amines (i.e., N-substituted alkenyl)3, mono-, di-, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixtures thereof. Specific examples of suitable amines include, for example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc. Methods for preparing salts also include mixing compounds by redox reactions with active metals or by, for example, ion exchange, due to the different solubilities of the salts.

[0101] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are substituted by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amino, aryl, -N3, carbamoyl, carboxyl, carboxyl ester, -CN, haloyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, -OH, imino, oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., a substituted aryl having a substituted alkyl group, the substituted alkyl group itself being further substituted by a substituted aryl group substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of series substitutions in the compounds described herein is three. For example, the series of substitutions of two other substituted aryl groups to a substituted aryl group is limited to (substituted aryl group) substituted aryl group. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituents in that group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents comprising hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is substituted. In other embodiments, the substituents may be further substituted with halogens, alkyl groups, haloalkyl groups, alkoxy groups, hydroxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, or heteroaryl groups, each of which is substituted.

[0102] A solvate is a solid form of a compound in which solvent molecules are incorporated. Solvates are formed through the interaction of a solvent and a compound. A hydrate is a solvate in which water is the solvent. Solvates of salts of the compounds described herein are also provided.

[0103] As used herein, "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Complementary active ingredients may also be incorporated into the composition.

[0104] "Treatment" or "treating" is a method used to obtain a beneficial or desired outcome, including clinical outcomes. A beneficial or desired clinical outcome may include one or more of the following: a) treating a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e. causing the remission of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another medicine, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0105] "Prevention" or "preventing" refers to any treatment administered to prevent the development of clinical symptoms of a disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing a disease or condition or who have a family history of the disease or condition.

[0106] "Subject" refers to a mammal (including humans) that is or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human therapeutic and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. When the subject is a human, the subject may be referred to as a "patient".

[0107] The term "therapeutic effective amount" or "effective amount" for compounds or pharmaceutically acceptable salts thereof described herein refers to an amount sufficient, when administered to a subject, to achieve therapeutic benefits such as symptom improvement or slowed disease progression. For example, a therapeutic effective amount could be an amount sufficient to reduce symptoms of neuronal disease. Therapeutic effective amounts can vary depending on the subject and the disease or symptom being treated, the subject's weight and age, the severity of the disease or symptom, and the method of administration, and can be readily determined by those skilled in the art.

[0108] The methods described herein can be applied to cell populations either in vivo or in vitro. “In vivo” means within a living individual, such as in an animal or human. In this context, the methods described herein can be used therapeutically in an individual. “In vitro” means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples containing liquid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro for a given indication, cell type, individual, and other parameters to determine the optimal schedule and / or dosage of the compounds of this disclosure. Information gathered from this use can be used for experimental purposes or in clinical settings to establish in vivo treatment protocols. Other in vitro uses of the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine safe or tolerable doses in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

[0109] Table of amino acids and abbreviations

[0110]

[0111]

[0112] compound

[0113] This document provides agents that promote dendritic spine formation. Such agents can be used to treat neuronal diseases and conditions. The agents may be compounds provided herein. These compounds may be those described in U.S. Patent Publication No. 2015 / 0299191. These compounds may be compounds of Formula I:

[0114]

[0115] Or its pharmaceutically acceptable salt;

[0116] Where A 1 A 2 A 3 A 4 A 5 and A 6 Independently select CH and CR 3 A group consisting of N and N, with the condition that A 1 A 2 A 3 A 4 A 5 and A6 No more than four of them are N;

[0117] R 1 The group selected is composed of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, the 5-membered heteroaryl, or the 6-membered heteroaryl is optionally surrounded by one to three R... 6 replace;

[0118] L 2 Choose from the following groups: covalent bonds, -NR 8 -、-C(O)NR 8 -、-NR 8 -、-C(O)NR 8 -、-NR 8 C(O)-、-C(O)CR 8 2-、-CR 8 2C(O)-、-NR 8 CR 8 2- and -CR 8 2NR 8 -;

[0119] R 2 For H, C 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally surrounded by 1 to 4 R... 4 Replace, where each R 4 Choose independently from the following groups: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, phenyl groups (optionally C-terminated) 1-6 Alkyl, halogen, C 1-6 (halogenated alkyl or -OH substituted), -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 7 -NR 10 CO2R 7 -SOR 7 -SO2R 7 -SO2NR10 R 10 and -NR 10 SO2R 7 ;

[0120] Each R 3 Choose independently from the following groups: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 7 -NR 10 CO2R 7 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0121] q is 1, 2, or 3;

[0122] Each R 6 Independently select from the following groups: cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -CH2OH;

[0123] R 7 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0124] R 8 It is hydrogen or C 1-6 alkyl;

[0125] Each R 10 Independently hydrogen or C 1-6 Alkyl, or two R 10 It forms 4- to 6-membered rings together with one or more atoms it is attached to; and

[0126] R 11 For hydrogen or R 3 .

[0127] The compound may be one described in International Patent Publication No. WO 2013 / 013240. The compound may be a compound of Formula II:

[0128]

[0129] Or its pharmaceutically acceptable salt;

[0130] Where n and m are each independently 0, 1, 2, 3 or 4;

[0131] X 1 -O-, -NR 7a -、-CR 9a R 9b -、-C(O)-NR 7a -、-NR 7a -C(O)-、-NR 8a -S(O)2- or -S(O)2-NR 8a -;

[0132] X 2 For -NR 8a -、-CR 9a R 9b -, -S-, -O-, -S(O)-, -S(O)2-, -C(O)-NR 8a -、-NR 8a -C(O)-、-NR 8a -S(O)2- or -S(O)2-NR-;

[0133] R 1a Halogenated, C 1-6 Alkyl or C 1-6 Alkoxy;

[0134] Each R 2a and R 2b Independently hydrogen or C 1-6 alkyl;

[0135] Each R 4a and R 4b Independently hydrogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy;

[0136] Each R 5a and R 5b Independently hydrogen, halogen, amino, amine, C 1-6 Alkyl or C 1-6 Alkoxy;

[0137] Each R 6a and R6b Independently hydrogen, halogen, amino, amine, C 1-6 Alkyl or C 1-6 Alkoxy;

[0138] R 7a For hydrogen, C 1-6 Alkyl, acyl, aryl, or aralkyl;

[0139] R 8a For hydrogen, C 1-6 Alkyl, acyl, aryl, or aralkyl; and

[0140] Each R 9a and R 9b Independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, amino, aryl, or heteroaryl.

[0141] The compound may be one described in U.S. Patent Publication No. 2014 / 0024705. The compound may be a compound of formula IV:

[0142]

[0143] Or its pharmaceutically acceptable salt;

[0144] in:

[0145] It can be a single bond or a double bond;

[0146] R 21 Hydrogen or optionally substituted C 1-6 alkyl;

[0147] R 22 The oxygen protecting group, hydrogen, or optionally substituted C 1-6 alkyl;

[0148] R 23 and R 25 For each independently and arbitrarily substituted C 1-6 Alkyl; and

[0149] R 24 It is hydrogen or -TY;

[0150] -T- represents C that has been optionally substituted. 1-8 A double-bonded, saturated or unsaturated, straight-chain or branched hydrocarbon chain, wherein one or more methylene units are optionally and independently bound by —NR 26 —、—N(R 26 )C(O)—、—C(O)N(R 26 )—、—N(R 26SO2—、—SO2N(R) 26 )—, —O—, —C(O)—, —OC(O)—, —OC(O)O—, —C(O)O—, -OC(O)N(R 26 —, —S—, —SO— or —SO2— are substitutes;

[0151] Each R 26 Independently hydrogen or optionally substituted groups, wherein the optionally substituted groups are selected from the group consisting of: C 1-20 Alkyl, C 1-20 Heteroalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 12-membered heterocyclic; and

[0152] —Y represents hydrogen or an acyl group.

[0153] The compound may be a compound described in U.S. Patent Publication No. 2014 / 0080843. The compound may be a compound of formula V:

[0154]

[0155] in

[0156] L 5 Choose from the following groups: -(C(R) 58 )2) q -、-(C(R 58 )2) q -C(O)-(C(R 58 )2) r -、-(C(R 58 )2) q -C(O)N(R 58 )-(C(R 58 )2) r -、-(C(R 58 )2) q -N(R 58 )C(O)-(C(R 58 )2) r -、-(C(R 58 )2) q -N(R 58 )S(O)2-(C(R 58 )2) r -(CH2) q -S(O)2N(R 58 )-(CH2) r -、-S-、-O- and -NR 58 -;

[0157] Each R51 The C group is independently selected from the halogen group and the halogen group optionally replaced by 1-3 halogen groups. 1-6 The group consisting of alkyl groups; or two adjacent R groups on a phenyl ring. 51 Forming a 5- or 6-membered cycloalkyl or heterocyclic group fused with a phenyl ring;

[0158] Each R 58 Independently hydrogen or C 1-6 alkyl;

[0159] q is 0 or 1;

[0160] r is 0 or 1; and

[0161] u5 is 1, 2, or 3;

[0162] Or its pharmaceutically acceptable salt.

[0163] In some embodiments, the compound may be a compound described in U.S. Patent Publication No. 2014 / 0080843. In some embodiments, the compound is a compound of formula Ia or formula Ib.

[0164]

[0165] Q in equation Ia or equation Ib 1 and Q 2 It is independently a phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl and is fused together in formula Ia;

[0166] Q in equation Ib 3 It is a 6-membered unsaturated ring, where (1)Y 1 With Y 2 The bond between them is a double bond, and Y and Y 2 The bond between them is a single bond, or (2)Y 1 With Y 2 The bond between them is a single bond, and Y 3 With Y 2 The bond between them is a double bond, and Q is a double bond. 3 With Q 2 They are fused together in formula Ib;

[0167] In equation Ia or equation Ib, s is 0 or 1;

[0168] In equation Ia or equation Ib, t is 1 or 2;

[0169] Y in formula Ia or formula Ib 1 Y 3 and Y 4 Independently C or N; Y in equation Ia or equation Ib 2 Y 4and Y 6 Independently CH, CR 3 Or N; the condition is Y in equation Ia or equation Ib. 1 Y 2 Y 3 Y 4 Y 5 and Y 6 No more than four of them are N;

[0170] R in equation Ia or equation Ib 1 It is a phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl, wherein the phenyl, the 5-membered heteroaryl, or the 6-membered heteroaryl is optionally surrounded by one to three Rs of formula Ia or formula Ib. 6 replace;

[0171] R and R in equation Ia or Ib 4 One of them is absent or is hydrogen, a halogen or a lower alkyl group (preferably methyl or ethyl), and R and R 4 The other one is L 2 -R 5 or L 3 -R 3 ; or R does not exist, and R 4 For —(CH2) j —R 11a R in equation Ia or equation Ib 11a Choose from the following groups: —OH, —OR 7 —SH, —SR 7 —NR 10 R 10 , cyano, nitro, -COH, -COR 7 —CO2H, —CO2R 7 —CONR 10 R 10 —OCOR 7 —OCO2R 7 —OCONR 10 R 10 —NR 10 COR 10 —NR 10 CO2R 10 —SOR 7 SO2R 7 —SO2NR 10 R 10 and —NR 10 SO2R 7 ;

[0172] X in formula Ia or formula Ib 1 Choose freely OR8 NHR 8 and SR 8 The group formed;

[0173] X in formula Ia or formula Ib 2 Choose freely O, NR 8 Groups consisting of S and below;

[0174] L in formula Ia or formula Ib 1 Choose from the following groups: —(C(R) 8 )2) j —、—(C(R 8 )2) q —C(O)—(C(R 8 )2) r —、—(C(R 8 )2) q —C(O)N(R 8 )—(C(R 8 )2) r —、—(C(R 8 )2) q —N(R 8 )C(O)—(C(R 8 )2) r —、—(C(R 8 )2) q —N(R 8 )S(O)2—(C(R 8 )2) r —、—(CH2) q —S(O)2N(R 8 )—(CH2) r —、—S—、—O— and —NR 8 —;

[0175] In equation Ia or equation Ib, j is 1, 2 or 3;

[0176] In equation Ia or equation Ib, q is 0 or 1;

[0177] In equation Ia or equation Ib, r is 0 or 1;

[0178] L in formula Ia or formula Ib 2 Choose from the following groups: covalent bonds, —C(O)N(R) 8 )—、—N(R 8 )C(O)—、—N(R 8 S(O)2— and —S(O)2N(R) 8 —;

[0179] L in formula Ia or formula Ib3 It can be either ═NC(O)— or ═NS(O)2—;

[0180] Each R in equation Ia or equation Ib 3 Independently selected from the group consisting of lower alkyl groups (preferably methyl or ethyl) and halogen groups;

[0181] R in equation Ia or equation Ib 5 It is a phenyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl; wherein the phenyl, the 5-membered heteroaryl, or the 6-membered heteroaryl is optionally surrounded by 1 to 4 R... 2 Replacement, where each R in formula Ia or formula Ib 2 Independently selected from the group consisting of: lower alkyl, lower haloalkyl, -OH, -OR 7 —SH, —SR 7 —NR 10 R 10 Halogenated, cyano, nitro, -COH, -COR 7 —CO2H, —CO2R 7 —CONR 10 R 10 —OCOR 7 —OCO2R 7 —OCONR 10 R 10 —NR 10 COR 10 —NR 10 CO2R 10 —S(O)R 7 SO2R 7 —SO2NR 10 R 10 and —NR 10 SO2R 7 ;

[0182] Each R in equation Ia or equation Ib 6 The group consisting independently of a halogenated group and a lower alkyl group (preferably methyl or ethyl) optionally substituted with 1-3 halogenated groups; or two adjacent R groups on the phenyl ring. 6 Forming a 5- or 6-membered cycloalkyl or heterocycloalkyl group fused with a phenyl ring;

[0183] R in equation Ia or equation Ib 7 It is a lower alkyl group (preferably methyl or ethyl);

[0184] R in equation Ia or equation Ib 8 It is hydrogen or a lower alkyl group (preferably methyl or ethyl); and

[0185] Each R in equation Ia or equation Ib 10 Independently hydrogen or a lower alkyl group (preferably methyl or ethyl), or two R 10 Together with one or more atoms it is attached to, it forms a 4- to 6-membered ring.

[0186] In some embodiments, compounds according to formula VII are provided:

[0187]

[0188] Wherein: the nitro group is ortho or meta; R in formula VII is methyl or ethyl; and X in formula VII is O or S; or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, compounds according to formula VIII are provided:

[0190]

[0191] Where: R 81 for

[0192] in Indicates a connection point; or its pharmaceutically acceptable salt.

[0193] In some embodiments, compounds according to Formula IX are provided:

[0194]

[0195] Where R 91 It is methyl or 3-pyrrolidine, and ring IX is...

[0196] in Indicates a connection point; or its pharmaceutically acceptable salt.

[0197] In some embodiments, compounds according to formula X are provided:

[0198]

[0199] Where R 101 For H, in Indicates a connection point; or its pharmaceutically acceptable salt.

[0200] In some embodiments, compounds according to formula XI are provided:

[0201]

[0202] Where E is N, or E is the subject Replaced C, and R 111 For H, in Indicates a connection point; or its pharmaceutically acceptable salt.

[0203] In some embodiments, the compound is selected from:

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222] as well as Or its pharmaceutically acceptable salt.

[0223] In some embodiments, the compound is selected from:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] as well as

[0232] Or its pharmaceutically acceptable salt.

[0233] In some embodiments, the compound is selected from:

[0234]

[0235]

[0236] as well as

[0237]

[0238] as well as Or its pharmaceutically acceptable salt.

[0239] In some embodiments, the compound is selected from

[0240]

[0241]

[0242]

[0243] and Or its pharmaceutically acceptable salt.

[0244] In some embodiments, the compound is

[0245]

[0246] Or its pharmaceutically acceptable salt.

[0247] In some embodiments, the compound is N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide, having the following structure:

[0248] (“Compound 1”) or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the compound is not comparative compound 2, comparative compound 3, or comparative compound 4:

[0250] Comparative compound 2

[0251] Comparative compound 3

[0252]

[0253] Comparative compound 4. In some embodiments, comparative compound 2, comparative compound 3, or comparative compound 4 are present in their pharmaceutically acceptable salt form.

[0254] In some embodiments, the compound is compound 5 or compound 6:

[0255]

[0256] Or its pharmaceutically acceptable salt.

[0257] In some embodiments, the compound is selected from:

[0258]

[0259] as well as

[0260] In some embodiments, the compound is migrastatin (compound 8) or isomigrastatin (compound 9):

[0261]

[0262] In some embodiments, compound 8 or compound 9 is present in its pharmaceutically acceptable salt form.

[0263] In some embodiments, the compound is compound 10:

[0264]

[0265] In some embodiments, compound 10 is present in its pharmaceutically acceptable salt form.

[0266] In some embodiments, the compound is compound 11:

[0267]

[0268] Or its pharmaceutically acceptable salt.

[0269] In some embodiments, the compound is BDP-00010834 or BDP-00013544 as disclosed below: “Abstract LB-228: Identifying small molecule inhibitors of Fascin 1 using fragment-based drug discovery”, Cancer Research 77(13 Supplement):LB-228-LB-228, July 2017; DOI:10.1158 / 1538-7445.AM2017-LB-228.

[0270] In some embodiments, the agent is a myofascitis antibody that binds to myofascitis at least at binding site 2 or binding site 3.

[0271] In some embodiments, the compound is not a compound of formula III:

[0272]

[0273] Where Y is –NR 33 -or –S-;R 31 Independently halogen, -CX 31 -CHX 31 -CH2X 31 -OCX 31 3. -OCHX 31 2. -OCH2X 31 -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -HNC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 32 Independently halogen, -CX 32 3. -CHX 32 2. -CH2X 32 -OCX 32 3. -OCHX 32 2. -OCH2X 32-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X 31 and X 32 Each of z1 and z2 is an independent halogen; each of z1 and z2 is an independent integer from 0 to 4; z3 is an integer from 1 to 12; and R 33 It is hydrogen or substituted or unsubstituted C 1-6 alkyl.

[0274] The compounds described herein can be prepared according to methods known to those skilled in the art. If available, the compounds can be commercially purchased from, for example, Sigma Aldrich or other chemical suppliers.

[0275] Synthesis can be performed using known procedures or variations thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bahen Chemical Co. (Torrance, California, USA), and Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other compounds can be prepared by procedures or variations thereof described in the following standard reference texts: *Fieser and Fieser's Reagents for Organic Synthesis*, Volumes 1-15 (John Wiley, and Sons, 1991), *Rodd's Chemistry of Carbon Compounds*, Volumes 1-5 and *Supplementals* (Elsevier Science Publishers, 1989), *Organic Reactions*, Volumes 1-40 (John Wiley, and Sons, 1991), *March's Advanced Organic Chemistry* (John Wiley, and Sons, 5th Edition, 2001), and *Larock's Comprehensive Organic Transformations* (VCH Publishers Inc., 1989).

[0276] Treatment methods and uses

[0277] Myofascitis

[0278] This article describes a method for regenerating dendritic spines that are detrimental to neurodegenerative conditions by targeting cytoskeletal proteins with agents such as compounds described herein. Unexpectedly, inhibition of the cytoskeletal protein myofascitis 1 (FSCN1) was observed to lead to a rapid upregulation of dendritic spines in vivo and in vitro. Dendritic spines contain filamentous actin (F-actin), cytoskeletal polymers that endow cells with structure and give them subcellular specialization. The elongation of F-actin filaments and changes in their organization are considered important for the formation, maturation, and plasticity of dendritic spines. Prior to this disclosure, the ability of myofascitis 1 to bundle F-actin filaments into parallel arrays was believed to be essential for the formation of various cellular processes, such as invasive pseudopodia, filopodia, and possibly dendritic spines. Myofascitis 1 is believed to promote processes related to cell migration and cancer metastasis through such methods. Small molecule inhibitors of myofascitis 1 that block its ability to bind F-actin have been observed to reduce F-actin-rich cell processes. Therefore, previous work suggested that myofascitis inhibitors would also block the formation of dendritic spines, which are F-actin-rich cell processes. However, contrary to expectation, this disclosure demonstrates the opposite: structurally different inhibitors of myofascitis 1, as well as myofascitis 1 gene knockdown, may lead to a rapid increase in dendritic spine density. Not wishing to be bound by theory, it is believed that dendritic spines require the formation of highly branched assemblages of F-actin, and that the formation of such assemblages can be prevented or significantly reduced by binding myofascitis 1 into parallel arrays.

[0279] In some embodiments, a method is provided for binding myotrigin at site 2 or site 3, the method comprising contacting the myotrigin with an effective amount of a compound described herein, such as a compound of formula I provided herein, a pharmaceutically acceptable salt thereof, or a compound of formula II provided herein or a pharmaceutically acceptable salt thereof, a compound selected from a compound of formula IV provided herein or a pharmaceutically acceptable salt thereof, a compound selected from a compound of formula V provided herein or a pharmaceutically acceptable salt thereof, a compound selected from a compound of formula VII provided herein or a pharmaceutically acceptable salt thereof, or compound 1, compound 8, compound 9, compound 10, compound 11 or a pharmaceutically acceptable salt thereof. In some embodiments, the method inhibits myotrigin. It is believed that compounds of formula I, II, IV, V, VII, VIII, IX, X or XI provided herein or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10 or 11 or pharmaceutically acceptable salts thereof, promote dendritic spine formation by inhibiting myotrigin.

[0280] Myofascitis is an important actin cross-linking agent that does not share amino acid sequence homology with other actin-binding proteins. Three forms of myofascitis have been found in vertebrates: myofascitis 1, widely found in the nervous system and elsewhere; myofascitis 2, found in retinal photoreceptor cells; and myofascitis 3, found only in the testes. In some embodiments, myofascitis is human myofascitis 1. Myofascitis has a molecular weight of 55 kDa and functions as a monomeric entity, cross-linking actin filaments into straight, tight, and rigid bundles, thus imparting mechanical stiffness to the actin bundles. It is believed that myofascitis holds parallel actin filaments together to form filamentous pseudopodia with a diameter of approximately 60-200 nm. The structure of myofascitis and its actin binding sites are as follows... Figure 1 As shown in the document.

[0281] During neuronal development, long bundles of f-actin are believed to push the neuronal membrane outward to form structures such as axons, dendrites, filopodia, and lamellar pseudopodia. Myotrombins are considered to be involved in the cytoskeleton remodeling of newly formed dendritic processes. Therefore, myotrombin-bundled actin is generally considered necessary for the formation and elongation of axons and dendrites. Surprisingly, the results of this invention indicate that inhibiting the activity of myotrombins in the formation of actin bundles promotes the formation of dendritic spines and the protrusion of the dendritic cell membrane.

[0282] It is believed that myofascitis proteins have at least three binding sites: binding site 1, binding site 2, and binding site 3. Therefore, refer to Figure 1 Myofascitis appears to have three binding sites for actin. Binding site 2 was not observed in the early pre-binding (ligand-free) crystal structure of myofascitis, likely due to protein structure shift during ligand binding. The compound disclosed in International Patent Publication No. WO 2017 / 120198 is believed to bind myofascitis at binding site 1.

[0283] It has been observed that when compound 1 binds, it opens actin binding site 2 and closes actin binding site 1, thereby preventing at least partial entanglement of actin filaments. Compound 1 has been found to bind myotrigin at binding site 2, such as... Figure 5 As shown in the figure. Furthermore, it has been found that compound 1 can increase the spike density compared to the control. Figure 6 Specifically, compound 1 was found to increase thorn density more than control compounds 1 and 7. Figure 6 Therefore, a novel molecular pathway to increase dendritic spine density was envisioned by inhibiting myofascitis through binding at least at two binding sites.

[0284] In some embodiments, myofascitis binding site 1 is defined at least in part by the following: V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492 and / or Y493. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10 or 11, or pharmaceutically acceptable salts thereof, do not bind to any myofascitis selected from the following myofascitis residues: V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492 and / or Y493. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, do not bind to myotrigin binding sites 1 and 2. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, do not bind to myotrigin binding sites 1 and 3. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10 or 11, or pharmaceutically acceptable salts thereof, do not bind to myofascitis binding sites 1, 2 and 3.

[0285] It is believed that myotrigin binding site 2 is at least partially defined by the following: F14, L16, L48, Q50, L62, W101, L103, E215, and / or S218. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11 thereof, or pharmaceutically acceptable salts thereof, bind to at least one myotrigin residue selected from: F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, bind to two, three, four, five, six, seven, or eight myotrigin residues selected from the group consisting of: F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, bind to at least one group I myotrigin residue selected from F14 and L16. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, bind to at least one group II myotrigin residue selected from L48, Q50, and L62. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, bind to at least one group III myotrigin residue selected from W101 and L103. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10 or 11 thereof, or pharmaceutically acceptable salts thereof, bind to at least one group IV myofascitis residue selected from E215 and S218.In some embodiments, myofascitis binding site 2 is defined at least in part by the following: F14, L16, L48, A58, V60, L62, I93, A95, W101, L103, V134, T213, L214, E215, F216 and / or R217.

[0286] In some embodiments, myofascitis binding site 3 is defined at least in part by the following: Q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and / or K379. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11 thereof, or pharmaceutically acceptable salts thereof, bind to at least one myofascitis protein residue selected from: Q291, R308, H310, T311, G312, K313, Y314, L31 7. T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379. In some embodiments, the pharmaceutical agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11 thereof, or pharmaceutically acceptable salts thereof, bind to two, three, four, five, six, seven, or eight myofascitis residues selected from the following: Q291, R308, H310, T311, G312, K313, ... Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379.

[0287] In some embodiments, the binding site of an agent, such as the compound described herein, can be determined by site-directed mutagenesis. For example, amino acid residues in mutant myotrigin can be altered relative to wild-type myotrigin. For instance, if an agent that substitutes an amino acid residue at binding site 1, binding site 2, or binding site 3 with a non-natural residue (e.g., an alanine residue) reduces the binding affinity between wild-type and mutant myotrigin, the reduction is attributable to a loss of affinity at the substitution site. Site-directed mutagenesis can be performed according to known methods, such as the Kunkel method, cassette mutagenesis, PCR site-directed mutagenesis, or CRISPR.

[0288] In some embodiments, the pharmaceutical agents described herein and K d It binds to the following myofascitises: at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 20 μM, at least about 50 μM, at least about 100 μM, or at least about 500 μM, as determined by isothermal titration calorimetry.

[0289] The various small molecule compounds disclosed herein can bind to myofascitis binding site 2 or myofascitis binding site 3. Variants and other compounds can also be identified using methods known in the art. For example, antibodies that bind to amino acid residues within myofascitis binding site 2 or 3, which act as epitopes of the antibody, can be identified.

[0290] Methods for preparing antibodies are well known in the art and are described herein. For example, antibodies targeting specific epitopes on proteins can be prepared by administering the protein or epitope fragment to an animal. Antibodies can be humanized, primate-derived, deimmunized, or chimeric antibodies can be prepared. These types of antibodies are derived from non-human antibodies, typically hamster or primate antibodies, that retain or substantially retain the antigen-binding properties of the parent antibody but have low immunogenicity in humans.

[0291] The binding specificity of the antigen-binding peptides disclosed herein can be determined by in vitro assays, such as immunoprecipitation, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA).

[0292] Humanized antibodies are antibody molecules derived from antibodies of non-human species that bind to a desired antigen having one or more complementarity-determining regions (CDRs) from the non-human species and a framework region from human immunoglobulin molecules. Fully human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be prepared using a variety of methods known in the art, including phage display methods using antibody libraries derived from human immunoglobulin sequences. Human antibodies can also be produced using transgenic mice that cannot express functional endogenous immunoglobulins but can express human immunoglobulin genes.

[0293] Neuronal diseases and symptoms and their treatment

[0294] A common feature of neurodegenerative diseases involving cognitive components is the loss of synapses that utilize glutamate as a neurotransmitter (“glutamatergic synapses”), believed to be the most numerous type of synapse in humans and other mammals. Importantly, approximately 90% of glutamatergic synapses involve postsynaptic dendritic spines. The majority of synapses lost in neurodegenerative diseases are those where the axon contacts the dendritic spines, known as “axonal synapses.” Under normal conditions, variations in the density, shape, and protein composition of dendritic spines affect the strength of synaptic transmission and are the basis for several forms of synaptic changes (i.e., “plasticity”) involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes. These changes in axonal synapses are believed to be important for memory encoding functions in structures such as the hippocampus. Therefore, early and progressive loss of dendritic spines in the hippocampus and other regions is believed to be a driving force behind memory loss and cognitive decline in Alzheimer's disease and other dementias. The development of novel methods for regenerating spine density may have significant implications for the treatment of many neurodegenerative and developmental cognitive disorders.

[0295] Dendritic spines are specialized processes responsible for receiving synaptic input and providing crucial functions in communication between neurons. The morphology and overall density of dendritic spines are correlated with synaptic function and are strongly involved in memory and learning. Cellular changes in brain cells may contribute to the pathogenesis of neuronal diseases. For example, abnormal levels of dendritic spine density in the brain (e.g., reduced density) may contribute to the development of neuronal diseases. Therefore, alterations or dysregulation of dendritic spines are believed to affect synaptic function and play a significant role in various neurological and psychiatric disorders such as autism, Fragile X syndrome, Parkinson's disease (PD), and Alzheimer's disease (AD). For example, in AD, there is increasing evidence that the deficits begin before neuronal loss due to alterations in hippocampal synaptic function caused by amyloid-β (Aβ) protein. Therefore, therapeutic strategies targeting initial synaptic loss rather than late-stage disease interventions could provide better prognoses for AD treatment. Furthermore, since most cognitive disorders trigger morphological and functional abnormalities in dendritic spines, it will be desirable to use small molecules to directly target them to alter or mitigate these spine changes. For example, Fragile X syndrome is characterized by an excessive number of immature spinous vertebrae.

[0296] In some embodiments, the agents described herein, such as compounds of formula I, II, IV, V, VII, VIII, IX, X, or XI, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, may be used to treat mood disorders. Mood disorders are major mental illnesses in which a patient's overall mood state or mood is distorted or inconsistent with the environment and interferes with the patient's ability to perform daily living functions. Subjects may be sad, empty, or irritable, or may experience alternating periods of negative feelings with excessive happiness (mania).

[0297] In some embodiments, the mood disorder may be depression. Depression, sometimes referred to as major depressive disorder or clinical depression, is a common but serious mood disorder. Those suffering from depression may experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. In addition to mood problems caused by depression, individuals may also experience physical symptoms such as chronic pain or digestive problems. To be diagnosed with depression, symptoms should generally have been present for at least two weeks. Depression can be diagnosed by those skilled in the art, for example, according to the guidelines of the Diagnostic and Statistical Manual of Mental Disorders (“DSM”). The DSM outlines the following criteria for diagnosing depression. Currently, according to the DSM-5 diagnostic criteria, for a diagnosis of depression, an individual must experience five or more symptoms during the same two-week period, and at least one of the symptoms must be (1) depressed mood or (2) loss of interest or pleasure. The symptoms identified in the DSM include:

[0298] 1. I experience depressive moods almost every day, most of the time.

[0299] 2. On most days, almost every day, there is a noticeable decrease in interest or enjoyment in all or almost all activities.

[0300] 3. Significant weight loss or gain when not dieting, or a decrease or increase in appetite almost every day.

[0301] 4. Slowed thinking and reduced physical movement (observable to others, not just a subjective feeling of unease or slowing down).

[0302] 5. I feel tired or lose energy almost every day.

[0303] 6. Feelings of worthlessness, excessive or inappropriate guilt occur almost daily.

[0304] 7. Decreased ability to think or concentrate almost every day, or indecisiveness.

[0305] 8. Frequently think about death, frequently have suicidal thoughts but no specific plan or attempt suicide, or have a specific plan for suicide.

[0306] To be diagnosed with depression, these symptoms should cause clinically significant distress or impairment in an individual’s functioning socially, professionally, or otherwise important. The DSM also provides diagnostic markers for depression: (1) having mixed features – this marker allows for the presence of manic symptoms as part of the diagnosis of depression in patients who do not meet all the criteria for a manic episode; (2) having anxiety distress – the presence of anxiety in a patient may affect prognosis, treatment options, and the patient’s response to it.

[0307] Depression has many contributing factors. Contributing factors can include stressors such as physical abuse, psychological abuse, one or more traumatic events, interpersonal conflict, loss of a loved one, social isolation, illness, substance abuse, or use of certain medications. Subjects may have a genetic predisposition to depression. Subjects may have experienced physical trauma affecting the brain, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). In some cases, depression is idiopathic. Categories of depression include major depressive disorder – prolonged and sustained periods of extreme sadness; bipolar disorder – also known as manic-depressive disorder or bipolar affective disorder, which includes alternating periods of depression and mania; seasonal affective disorder (SAD) – a form of depression that is most commonly associated with less daylight hours in the far north and south latitudes from late autumn to early spring; thymic disorder – a condition that causes mood swings that are less extreme than bipolar disorder; premenstrual anxiety disorder – mood changes and irritability that occur during the premenstrual phase of a woman's menstrual cycle and disappear with the onset of menstruation; persistent depressive disorder (psychotic depression) – long-term (chronic) but low-grade depression; disruptive mood disorder – a chronic, severe, and persistent irritability disorder in children, which typically includes frequent outbursts of temper inconsistent with the child's developmental age; medically related depression – persistent depressive mood and significant loss of enjoyment of most or all activities, which is directly related to the physical effects of another medical condition; and substance use or drug-induced depression – depressive symptoms that appear during or shortly after substance use or withdrawal or exposure to a drug.

[0308] In some embodiments, a method is provided for treating a mood disorder in a patient in need, the method comprising administering to the patient a commercially available compound described herein. In some embodiments, the mood disorder is depression. In some embodiments, the patient may be refractory to treatment with an antidepressant. The antidepressant may be an antidepressant described herein.

[0309] In another embodiment, compositions and methods for alleviating, reducing, or reversing symptoms of mood disorders are provided. The symptoms may be those described herein or known to those skilled in the art, such as any symptoms described in the DSM.

[0310] Symptoms of depression can include anxiety; loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness, or feelings of low mood, worthlessness, helplessness, or despair; fatigue, tiredness, or lack of energy; low self-esteem, self-criticism, and / or feelings of inadequacy; difficulty concentrating, remembering details, and / or making decisions; persistent irritability, hostility, and / or excessive anger; decreased activity, efficiency, and / or productivity; avoidance of social activities; feelings of guilt and / or worry about the past; loss of appetite or overeating; suicidal thoughts; decreased libido and / or loss of interest in sex; sleep disturbances, insomnia, early morning awakening, or excessive sleep; restlessness, loss of interest in pleasurable activities; overeating or loss of appetite; unexplained pain, unexplained aches, unexplained headaches, persistent cramps, persistent digestive problems; suicidal thoughts and behaviors.

[0311] This document provides methods for promoting dendritic spine formation. In some embodiments, the method includes administering to a subject an effective amount of an agent that binds to myotrigin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof, as described in the embodiments herein. Dendritic spine formation can be observed as an increase in the average number of spines per neuron or the length per neuronal unit, which may be referred to as an increase in dendritic spine density. Dendritic spine formation can be observed as an improvement in dendritic spine morphology. For example, an improvement in dendritic spine morphology can be observed as an increase in the average size of the spine head. Dendritic spine formation can be observed as an improvement in dendritic spine size, spine plasticity, spine mobility, spine density, and / or synaptic function. Dendritic spine formation can be observed as a local spatial average increase in membrane potential. Dendritic spine formation can be observed as Ca 2+An increase in postsynaptic concentration (e.g., mean volume) of dendritic spines can be observed. An increase in the average proportion of mature to immature spines can be observed in dendritic spine formation. In some embodiments, agents that bind to myotrigin at least at binding site 2 or binding site 3, or compounds of formulas I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, increase dendritic spine density relative to those observed at the time of initiation of treatment. In some embodiments, agents that bind to myotrigin at least at binding site 2 or binding site 3, or compounds of formulas I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or pharmaceutically acceptable salts thereof, or compounds 1, 8, 9, 10, or 11, or pharmaceutically acceptable salts thereof, increase dendritic spine density relative to those observed at the time of initiation of treatment. In some embodiments, the increase in dendritic spine density leads to a reduction in symptoms of neuronal disease or condition in the subject or patient. In some embodiments, the increased dendritic spine density was explained by anatomical observation. In some embodiments, an increased dendritic spine density was observed in primary hippocampal neurons.

[0312] In some embodiments, the mean dendritic spine density increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 10%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two numbers, relative to treatment with an agent that binds to myotrigin at at least binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the dendritic spine density is increased by about 50% to about 500% relative to the time elapsed by treatment with an agent that binds to myotrigin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or a compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the dendritic spine density is increased by about 100% to about 300% relative to the time elapsed by treatment with an agent that binds to myotrigin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or a compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the dendritic spine density is increased by about 200% to about 300% over time relative to treatment with an agent that binds to myotrigin at least at binding site 2 or binding site 3, or with compounds of formula I, II, IV, V, VII, VIII, IX, X or XI as provided herein, or with a pharmaceutically acceptable salt thereof, or with compounds 1, 8, 9, 10 or 11, or with a pharmaceutically acceptable salt thereof. In some embodiments, the duration of treatment with an agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10 or 11, or a pharmaceutically acceptable salt thereof, is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days or 365 days.

[0313] In some embodiments, the method increases spine density by promoting the formation of new spines. In some embodiments, relative to a control (e.g., spine density in the absence of the compound), the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two of these numbers, including the endpoints. In some embodiments, relative to a control (e.g., spine density in the absence of the compound), the method increases the average spine density by about 50% to about 500%. In some embodiments, relative to a control (e.g., spine density in the absence of the compound), the method increases the spine density by about 100% to about 300%. In some embodiments, the method increases the spine density by about 200% to about 300% relative to a control (e.g., spine density in the absence of the compound).

[0314] In some embodiments, the method increases spike density by increasing neuron length. In some embodiments, the method increases the average neuron length relative to treatment induced by an agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof, by about 100 nm, 300 nm, 500 nm, 700 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 7 μm, 10 μm, 15 μm, 20 μm, 25 μm, or any two of these numbers, including the endpoints. In some embodiments, the method increases the average neuron length by about 500 nm to about 25 μm relative to a control (e.g., neuron length in the absence of the compound). In some embodiments, the method increases the neuron length by about 10% to about 300% relative to a control (e.g., neuron length in the absence of the compound). In some embodiments, the method increases neuron length by about 200% to about 300% relative to a control (e.g., neuron length in the absence of the compound).

[0315] In some embodiments, the method increases the average number of spikes per neuron relative to the time elapsed by treatment with an agent that binds to myotrigin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the average number of spikes per unit length of neuron is increased by at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000, or any range between any two numbers, including the endpoints. In some embodiments, the time is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0316] In some embodiments, the compound can be used to treat neuronal diseases or conditions. A neuronal disease is a disease or condition in which the function of a subject's nervous system becomes impaired. A neuronal disease or condition can be a neurological disease or condition. A neuronal disease or condition can be associated with a neurodegenerative disease or condition.

[0317] In one aspect, a method of treating a neuronal disease in a patient in need is provided, the method comprising administering to the patient a marketable agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is Fragile X syndrome. In some embodiments, the disease or condition is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the neuronal disease is traumatic brain injury. In some embodiments, the patient with the neuronal disease suffered a traumatic brain injury before, during, or after the onset of the neuronal disease. In some embodiments, the neuronal disease includes neuronal damage. Neuronal damage may include atrophy or other reduction in the effective function of neurons. For example, Alzheimer's disease is known to manifest as neuronal damage, particularly of cortical neurons, such as hippocampal neurons and neurons near the hippocampus. Synaptic loss may be associated with the loss of dendritic spines and neurodegeneration.

[0318] In some embodiments, neuronal disease is associated with abnormal dendritic spine morphology, spine size, spine plasticity, spinal motility, spine density, and / or abnormal synaptic function. In some embodiments, neuronal disease is associated with abnormal (e.g., reduced) levels of dendritic spine density.

[0319] In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's disease with dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is stroke. In some embodiments, the neuronal disease is post-traumatic stress disorder (PTSD). In some embodiments, the neuronal disease is traumatic brain disease (TBD). In some embodiments, the neuronal disease is chronic traumatic encephalopathy (CTE). In some embodiments, the neuronal disease is schizophrenia. In some embodiments, the neuronal disease is dementia (e.g., common dementia). In some embodiments, the neuronal disease is attention deficit hyperactivity disorder (ADHD). In some embodiments, the neuronal disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neuronal disease is frontotemporal degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS). In some embodiments, the neuronal disease is memory loss. In some embodiments, the neuronal disease includes memory loss. In some embodiments, the neuronal disease is age-related memory loss. In some embodiments, the neuronal disease includes age-related memory loss. In some embodiments, the neuronal disease is hypertensive encephalopathy. In some embodiments, the neuronal disease is chronic stress. In some embodiments, the neuronal disease includes chronic stress. In some embodiments, the neuronal disease is FTLD-TDP type A. In some embodiments, the neuronal disease is FTLD-TDP type B. In some embodiments, the neuronal disease is FTLD-TDP type C. In some embodiments, the neuronal disease is FTLD-TDP type D.

[0320] Examples of neuronal diseases that can be treated with the compounds or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, depression, perinatal asphyxia, Parkinson's dementia ("PD dementia"), amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren), spongiform encephalopathy (e.g., bovine spongiform encephalopathy (mad cow disease), Kuru disease, Creutzfeldt-Jakob disease), fatal familial insomnia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Fragile X syndrome, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, and Huntington's disease. Diseases, HIV-related dementia, Kennedy's disease, Krabbe's disease,Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, spirochetal neuropathy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, amyotrophic lateral sclerosis, prions, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute spinal cord degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabess disease. Dorsalis, drug-induced Parkinson's disease, progressive supranuclear paralysis, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial type 1 (PARK1), Parkinson's disease 3, autosomal dominant Lewy body (PARK3), Parkinson's disease 4, autosomal dominant Lewy body (PARK4), Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive juvenile (PARK2), Parkinson's disease 7, autosomal recessive early-onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), or mitochondrial Parkinson's disease. In some embodiments, the neuronal disease is Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, stroke, post-traumatic stress disorder (PTSD), traumatic brain disease (TBD), chronic traumatic encephalopathy (CTE), schizophrenia, dementia (e.g., common dementia), attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS), memory loss (e.g., age-related memory loss), hypertensive encephalopathy, or chronic stress.

[0321] In some embodiments, the neuronal disease is Alzheimer's disease (AD). Alzheimer's disease is characterized by symptoms of memory loss in the early stages of the disease. Apoε4 carriers have a greater risk of developing AD. APOε4 is believed to be less effective than other isoforms in clearing Aε and may therefore be associated with greater amyloid burden, tau phosphorylation, synaptic toxicity, and reduced synaptic density. Having experienced traumatic brain injury (TBI) is another risk factor for AD, and studies have shown that those who have experienced TBI have a significantly increased risk of developing AD. Cognitive decline has been associated with progressive synaptic loss. As the disease progresses, symptoms include confusion, long-term memory loss, incoherent speech, vocabulary loss, aggression, irritability, and / or mood swings. In later stages of the disease, there is loss of physical function. Patients with Alzheimer's disease (AD) exhibit a number of characteristic neuropathies, such as increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. Without wishing to be bound by any theory, it is believed that both the cause and effect of these neuropathies are the accumulation of harmful forms of amyloid-β (Aβ) peptides in the brain. AD-related conditions include Alzheimer's disease type 2 (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-related memory impairment (AAMI). In some embodiments, a method of treating or preventing Alzheimer's disease is provided, the method comprising administering to a patient in need a therapeutically effective amount of an agent or a compound described herein, such as compound 1, that binds at least to myotrigin at binding site 2 or binding site 3. In some embodiments, the patient is an Apoε2 or Apoε3 carrier. In some embodiments, the patient already has TBI. In some embodiments, the patient is an Apoε4 carrier. In some embodiments, the patient is an Apoε4 carrier with TBI.

[0322] In some embodiments, the neuronal disorder is Fragile X syndrome (FXS). As is known in the art, FXS is a genetic syndrome associated with a variety of conditions, such as autism and inherited intellectual disability. The disability can present as a range of values ​​from mild to severe. It has been observed that men with FXS begin to experience progressively more severe problems in performing tasks requiring working memory, typically starting after age 40. This has been observed to be particularly true for verbal working memory. In some embodiments, the neuronal disorder is autism. As is known in the art, autism is a neurodevelopmental disorder. Without wishing to be bound by any theory, it is believed that autism affects information processing in the brain by altering how neurons and synapses connect and organize.

[0323] In other embodiments, compositions and methods are provided for alleviating, reducing, or reversing symptoms of neuronal diseases or conditions. Symptoms can be any of the symptoms described herein.

[0324] The term "memory," etc., in its usual and conventional sense refers to the process by which a subject encodes, stores, and retrieves information. In the context of memory, the terms "encoding," "registration," etc., in their usual and conventional sense refer to receiving, processing, and combining information that influences sensations induced by chemical or physical stimuli. In this context, the term "storage," etc., in its usual and conventional sense refers to the creation of a record of encoded information. In this context, the terms "retrieval," "recall," etc., in their usual and conventional sense refer to recalling stored information. As is known in the art, retrieval can be a response to a prompt. In some embodiments, memory loss refers to a reduced ability to encode, store, or retrieve information. In some embodiments, memory can be a recognition memory or a recall memory. In this context, "recognition memory" refers to the recall of a previously encountered stimulus. As is known in the art, a stimulus can be, for example, a word, scene, sound, smell, etc. A broader category of memory is "recall memory," which requires the retrieval of previously learned information, such as a series of actions, a list of words or numbers, etc., previously encountered by the subject. Methods for assessing the level of memory encoding, storage, and retrieval demonstrated by a subject are well known in the art and include the methods disclosed herein. For example, in some embodiments, methods improve the memory of a subject with a neuronal disease. In some embodiments, the method improves the subject's memory. In some embodiments, the method treats neuronal or cognitive impairment in the subject. In some embodiments, the method treats neuronal damage in the subject. In some embodiments, the method treats cognitive impairment in the subject.

[0325] Furthermore, for any aspect disclosed herein, in some embodiments, the subject suffers from brain injury. Types of brain injury include brain damage (i.e., destruction or degeneration of brain cells), traumatic brain injury (i.e., damage due to external force on the brain), stroke (i.e., a vascular event that temporarily or permanently damages the brain through hypoxia), and acquired brain injury (i.e., brain injury not present at birth). In some embodiments, the method improves the subject's memory. In some embodiments, the method improves the subject's learning. In some embodiments, the method treats neuronal or cognitive impairment in the subject. In some embodiments, the method treats neuronal damage in the subject. In some embodiments, the method treats cognitive impairment in the subject.

[0326] In some embodiments, a method for promoting dendritic spine formation in a patient in need is provided, the method comprising administering to the patient a compound that inhibits myotrigin. In some embodiments, a method for treating or preventing neuronal diseases or conditions is provided, the method comprising administering to a patient in need a therapeutically effective amount of an agent that binds to myotrigin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound for treating neuronal diseases or conditions is provided, wherein the compound is a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is provided for manufacturing a medicament for treating a neuronal disease or condition, wherein the compound is a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the neuronal disease or condition is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, Fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or condition is Alzheimer's disease. In some embodiments, an agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof, inhibits the cross-linking of f-actin. In some embodiments, an agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10 or 11, or a pharmaceutically acceptable salt thereof, is anti-transfer.

[0327] Combination therapy

[0328] In one embodiment, the compounds disclosed herein may be used in combination with one or more other therapeutic agents for treating neuronal diseases or conditions and / or developed to treat neuronal diseases or conditions.

[0329] When used to treat or prevent the aforementioned diseases and conditions, an agent that binds to myofascitis at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI as provided herein, or a pharmaceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharmaceutically acceptable salt thereof, may be administered in combination with one or more other therapeutic agents, such as other therapeutic agents approved for the treatment or prevention of a particular disease or condition, and more specifically, agents considered to form the current standard of care. In cases where combination therapy is envisioned, the active agent may be administered simultaneously, alone, or sequentially in one or more pharmaceutical compositions.

[0330] Therefore, recent strategies for treating AD involve controlling the production or aggregation of specific isoforms of Aβ peptides. Other strategies include preventing, reducing, or removing the toxic forms of phosphorylated tau. Still other strategies involve targeting small molecule enzymes that play a role in attempting to reduce the abundance of Aβ peptides in the brain by processing amyloid precursor proteins to produce Aβ peptides. Furthermore, increasing information regarding the role of non-amyloid neuropathy (such as tau proteinopathy or sporadic inheritance of specific mutations in the apolipoprotein E gene) is stimulating further strategies to combat neurodegeneration.

[0331] One or more of the following treatment agents may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, lisuride, rasagiline, tolcapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, or rivastigmine. gmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omegapil, CEP-1347, isradipine, DOPA, lithium, riluzole, levetiracetam, ezogabine, pregabalin, rufmamide, felbamate, carbamazepine, sodium valproateValproate, Lamotrigine, Phenytoin, Oxcarbazepine, Ethosuximide, Gabapentin, Tiagabine, Topiramate, Vigabatrin, Phenobarbital, Primidone, Clonazepam, Interferon β-LA, Interferon β-LB, Mitoxantrone, Natalizumab, Fmgolimod, Teriflunomide, Dimethyl fumarate fumarate, glatiramer, ATOH1 gene therapy, ozanezumab, arimoclomol, tirasemtiv, dexramipexole, pridopidine, or galantamine; or phosphoglycerate kinase (PGK) as described in US 2018 / 0147263. In some embodiments, one or more additional therapeutic agents may be acetylcholinesterase inhibitors (AChEIs), such as acotiamide, alpha-pinene, ambenonium, demecarium, DFP (diisopropylfluorophosphate), donepezil, edrophonium, galantamine, huperzine A, lactucopicrin, ladostigil, neostigmine, physostigmine, pyridostigmine, dyflos, echotiophate, rivastigmine, and rosmarinic acid.The following are listed as potential therapeutic agents: tacrine, ungeremine, zanapezil, ganstigmine, phenserine, phenethylnorcymserine (PENC), cymserine, thiacymserine, SPH1371 (galantamine+), ER 127528, RS 1259, or F3796. In some embodiments, one or more additional therapeutic agents may be amyloid clearance antibodies, such as bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, BAN2401, or aducanumab.

[0332] One or more additional therapeutic agents may be sedative-hypnotic agents, such as chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, or zolpidem tartrate; anticonvulsants, such as acetazolamide sodium, carbamazepine, clonazepam, or clorazepate. dipotassium, diazepam, divalproexsodium, ethosuximide, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobarbital sodium, phenytoin, phenytoin sodium, primidone, tiagabine hydrochloride, topiramate, valproate sodium, or valproic acid;Antidepressants, such as amitriptyline hydrochloride, amitriptyline pamoate, amoxapine, bupropion hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine hydrochloride, imipramine hydrochloride, imipramine pamoate, mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phenelzine sulfate, and sertraline hydrochloride. Hydrochloride, tranylcypromine sulfate, trimipramine maleate, or venlafaxine hydrochloride; anti-anxiety drugs, such as alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzinepamoate, lorazepam, mephrobamate, midazolam hydrochloride, or oxazepam;Antipsychotic drugs, such as chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, and quetiapine fumarate. fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, or trifluoperazine hydrochloride; central nervous system stimulants, such as amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, modafinil, pemoline, or phentermine hydrochloride;Anti-Parkinson's disease drugs, such as amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexoledihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, or trihexyphenidyl hydrochloride; or central nervous system drugs, such as bupropion hydrochloride and donepezil hydrochloride. Hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrix, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan;Cholinergics (e.g., parasympathomimetic agonists), such as bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, or pyridostigmine bromide; anticholinergics, such as atropine sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate, propantheline bromide, scopolamine, scopolamine butylbromide, or scopolamine hydrobromide. Hydrobromide; Adrenergic agents (sympathomimetic agents), such as dobutamine hydrochloride, dopamine hydrochloride, metataraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, or pseudoephedrine sulfate; Adrenergic blockers (antisympathetic agents), such as dihydroergotamine mesylate, ergotamine tartrate, mesysergide maleate, or propranolol hydrochloride;Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, or tizanidine hydrochloride; neuromuscular blocking agents, such as atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, and tubocurarine chloride. chloride) or vecuronium bromide;Or corticosteroids, such as betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate. Prednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, or triamcinolone diacetate.

[0333] One or more additional therapeutic agents may be selected from the following antidepressants: levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, bicifadine, tesofensine, brasofensine, isocarboxazid, moclobemide ( moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine ramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, trimipramine, fluoxetine, norfluoxetine, citalopram am), dapoxetine, escitalopram, fluvoxamine, paroxetine, sertraline, ketamine, esketamine, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, and St. John's Wort.

[0334] Reagent test kit

[0335] This document also provides a kit comprising a compound described herein or a pharmaceutically acceptable salt thereof, optionally a second active ingredient, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the pharmaceutical composition in a therapeutic indication comprising the diseases or symptoms described herein.

[0336] This article also provides articles containing the compounds described herein or their pharmaceutically acceptable salts in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, nebulizers, aerosol dispensers, droppers, or intravenous bags.

[0337] Pharmaceutical Compositions and Administration Methods

[0338] The compounds described herein are typically administered in the form of pharmaceutical compositions. Therefore, this document also provides pharmaceutical compositions comprising one or more of the compounds described herein, said pharmaceutical compositions typically comprising the compounds described herein or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable mediators selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable mediators may comprise, for example, inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, *Remington's Pharmaceutical Sciences*, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and *Modern Pharmaceutics*, Marcel Dekker, 3rd edition (edited by G.S. Banker and C.T. Hodes).

[0339] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal (“ip”), parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0340] One method of administration is parenteral, such as by injection. The pharmaceutical compositions described herein may be incorporated into forms intended for administration by injection, for example, aqueous or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, glucose, or sterile aqueous solutions and similar pharmaceutical mediators.

[0341] Oral administration may be another route of administration for the compositions described herein. Administration may be via, for example, capsules or enteric-coated tablets. In the preparation of pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, the active ingredient is typically diluted and / or encapsulated within a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a medium, carrier, or mediator of the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid form), ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile encapsulated powders.

[0342] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may also contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0343] The pharmaceutical composition and any containers in which it is distributed may be sterile. The pharmaceutical composition may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for altering osmotic pressure, viscosity reminding agents, or buffers.

[0344] Compositions comprising at least one compound described herein, such as those described herein, or pharmaceutically acceptable salts thereof, can be formulated to provide a rapid, sustained, or delayed release of an active ingredient after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration comprise osmotic pump systems and dissolution systems comprising polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use with the methods disclosed herein employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or intermittent infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be configured for continuous, pulsed, or on-demand drug delivery.

[0345] To prepare solid compositions, such as tablets, a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds described herein or their pharmaceutically acceptable salts. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0346] The compounds described herein can be coated or otherwise compounded into tablets or pills to provide a dosage with the advantage of prolonged action or to protect the stomach from acidic conditions. For example, tablets or pills may contain an internal dose component and an external dose component, the latter in the form of a coating over the former. The two components can be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to be delivered intact into the duodenum or to be released with a delay. A variety of materials can be used for such enteric coatings or coatings, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, hexadecyl alcohol, and cellulose acetate.

[0347] Pharmaceutical compositions can be formulated for nasal administration. Such pharmaceutical compositions may contain one or more active ingredients in different physical states, such as the compounds described herein or pharmaceutically acceptable salts thereof. For example, the active ingredient may be dissolved or suspended in a liquid carrier. The active ingredient may be in a dry form. The dry form may be a powder. The active ingredient in the powder may be amorphous or crystalline. For example, the compounds described herein or pharmaceutically acceptable salts thereof may be amorphous or crystalline. Crystalline active materials may be hydrates or solvates.

[0348] Solid compounds or their salts or crystals may be present in the formulation at a selected average particle size. The average particle size (in terms of the longest dimension) may be 10 nm, 100 nm, 300 nm, 500 nm, 1 μm, 10 μm, 50 μm, 100 μm, 300 μm, or 500 μm, or a range between any two values.

[0349] Administration can be by inhalation or inhalation. Compositions for inhalation or inhalation may comprise solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation. The effect may be local or systemic. In certain embodiments, the action is localized to skull tissue. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be connected to a mask tent or intermittent positive pressure ventilation machine. The solution, suspension, or powder composition can preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner. Pharmaceutical compositions for inhalation or inhalation may be aerosols.

[0350] The pharmaceutical composition may include a liquid suspension or solution comprising about 0.05%, about 0.1%, about 0.3%, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, or about 5% w / w of the active ingredient. The liquid may include water and / or alcohol. The liquid may contain a pH adjuster such that the pH is a value of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range thereof.

[0351] Pharmaceutical compositions may include pharmaceutically acceptable preservatives. Preservatives suitable for use herein include, but are not limited to, those that protect solutions from contamination by pathogenic particles, including phenethyl alcohol, benzalkonium chloride, benzoic acid, or benzoate such as sodium benzoate. In some embodiments, the pharmaceutical composition includes about 0.01 w / w% to about 1.0 w / w% of benzalkonium chloride or about 0.01 v / w% to about 1 v / w% of phenethyl alcohol. The preservative may also be present in an amount of about 0.01% to about 1%, preferably about 0.002% to about 0.02%, based on the total weight or volume of the composition.

[0352] The pharmaceutical composition may also include one or more of the following: from about 0.01 w / w% to about 90 w / w%, or from about 0.01 w / w% to about 50 w / w%, or from about 0.01 w / w% to about 25 w / w%, or from about 0.01 w / w% to about 10 w / w%, or from about 0.01 w / w% to about 1 w / w%. Such pharmaceutical agents used herein include, but are not limited to, polyoxyethylene sorbitan esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monopalmitate, etc. Sorbitan monostearate; lecithin; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; 1,2-propanediol alginate; agar; carrageenan; locust bean gum; guar gum; astragalus gum; gum arabic; xanthan gum; carrageenan gum; pectin; amidated pectin; phosphatidyl esters; microcrystalline cellulose; methylcellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose; ethyl methylcellulose; carboxymethyl cellulose; sodium, potassium, and calcium salts of fatty acids; Monoglycerides and diglycerides of fatty acids; acetates of monoglycerides and diglycerides of fatty acids; lactates of monoglycerides and diglycerides of fatty acids; citrates of monoglycerides and diglycerides of fatty acids; tartrates of monoglycerides and diglycerides of fatty acids; monoacetyl tartrates and diacetyl tartrates of monoglycerides and diglycerides of fatty acids; mixed acetates and tartrates of monoglycerides and diglycerides of fatty acids; sucrose esters of fatty acids; sucrose glycerides; polyglycerides of fatty acids; polyglycerides of castor oil containing polycondensed fatty acids; 1,2-propanediol esters of fatty acids; sodium stearoyl-2-lactate; calcium stearoyl-2-lactate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; extracts of soapberry bark; polyglycerides of soybean oil containing dimer fatty acids; oxidatively polymerized soybean oil; and pectin extracts.

[0353] In another embodiment, the pharmaceutical composition for nasal administration may be provided in powder form. For example, the powdered nasal composition may be used directly as a unit dosage form of powder. If desired, the powder may be filled into capsules, such as hard gelatin capsules. The contents of the capsule or single-dose device may be administered using, for example, a blower.

[0354] Therefore, a method for treating neuronal disorders may include the following steps: administering a pharmaceutical composition comprising the compounds described herein or salts thereof to a subject in need via nasal administration.

[0355] Dosage

[0356] The specific dosage level of the active ingredient of this application, such as the salt of the compound described herein, for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration and rate of secretion, drug combination, and the severity of the specific disease of the subject undergoing treatment. For example, the dosage may be expressed as milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). Doses between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's body weight may be particularly useful when adjusting the dosage between subjects of widely different sizes, such as when the drug is used in both children and adult humans, or when converting an effective dose for a non-human subject (such as a dog) to a dose suitable for a human subject.

[0357] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound described herein or its salts may be between about 1 mg and 4,000 mg, between about 2,000 mg / day and 4,000 mg / day, between about 1 mg / day and 2,000 mg / day, between about 1 mg / day and 1,000 mg / day, between about 10 mg / day and 500 mg / day, between about 20 mg / day and 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 15 mg / day and 150 mg / day.

[0358] When administered nasally, the total daily dose for human subjects may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day. In various embodiments, the daily dose is about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range thereof.

[0359] The active ingredient or pharmaceutical composition thereof of this application may be administered once, twice, three times, or four times daily in any of the suitable modes described above. Similarly, administration or treatment may continue for several days; for example, for a single cycle of treatment, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles are well-known and often alternate between periods of about 1 to 28 days, typically about 7 or about 14 days. In other embodiments, treatment cycles may also be continuous. Administration or treatment may continue indefinitely.

[0360] In certain embodiments, the method includes administering to a subject an initial daily dose of about 1 mg to 800 mg of the compound described herein, and incrementally increasing the dose until clinical efficacy is achieved. The dose may be increased in increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0361] Example

[0362] Example 1

[0363] Analysis and preparation of myofascitis protein crystal structures

[0364] All available myofascitis protein crystal structures were downloaded from the PDB and prepared for structural analysis. Structures were analyzed visually and via standard automated protocols embedded in MolSoft's ICM-Pro software. Hydrogen atoms were added to the structures, and the following were considered: correct orientation of the Asn and Gln side chains, ligand and protein charge, histidine orientation and protonation state, and any crystal quality markers such as high b-factor or low occupancy.

[0365] MolSoft's ICMPocketFinder algorithm was used to identify potential ligand-binding pockets and cavities in all available myofascitis protein crystal structures. Pockets were searched in the active chain A of crystal structure 3LLP, which had the highest resolution. Figures 2A-2D The document provides “front,” “bottom,” “top,” and “back” views of myofascitis, with each view indicating the pocket AD.

[0366] Four “drug-like” pockets (pocket AD) are identified, and these pockets are believed to have properties suitable for binding small molecules.

[0367] Ligand docking and scoring

[0368] Using MolSoft's ICM-Docking software (version 3.8-6a), the head groups and head + tail groups of comparative compounds 2, 3, and 4 were aligned. Figure 1Each of the four pockets shown is illustrated in Table 1. The docking score for each pocket is shown in Table 1 – a lower docking score indicates better ligand interaction.

[0369] Comparative compound 2 has the following structure:

[0370]

[0371] Comparative compound 3 has the following structure:

[0372] and

[0373] Comparative compound 4 has the following structure:

[0374]

[0375] Table 1. Figure 1 The docking scores of the colored ligands to the four pockets A, B, C, and D are shown.

[0376] In all cases, with one exception, the ligand binding to pocket B has a higher score.

[0377]

[0378] like Figure 1 The pocket B located at actin binding site 1, as observed in the study, resulted in the lowest docking score. This site was further investigated in other myotrigin crystal structures, and this pocket is located near the pentaethylene glycol binding site in PDB3P53. Head-base docking with pocket B in PDB3P53 resulted in a significantly higher docking score.

[0379] Table 2. Results of orienting the head groups of comparative compounds 2, 3 and 4 into pocket B of PDB 3P53 containing pentaethylene glycol.

[0380]

[0381] Then, the head base is used as an anchor point for docking the tail. The final energy-favorable ligand posture is shown in ( Figures 3A-3C )middle.

[0382] Figures 3A-3C The docking complexes of human myofascitis 1 with comparative compounds 2, 3, and 4 were depicted. All three ligands formed hydrogen bonds from the nitrogen atom in the benzothiazole ring to ARG389, and the first ethylene glycol formed a hydrogen bond with LYS460.

[0383] Figure 4A 2D interaction diagram of the complex of contrasting compound 2 and human myofascitis 1 is depicted. Dashed arrows represent hydrogen bonds. Thick lines around the ligand shape represent accessible surfaces. The size of the residual ellipse represents the contact strength. The 2D distance between the residue marker and the ligand represents the proximity.

[0384] Example 2

[0385] Crystal structures of myofascitis proteins bound to compound 1 were prepared (Protein Database (PDB) 6B0T) for structural analysis, such as... Figure 5 The structure was described in the diagram. It was analyzed visually and via standard automated protocols embedded in MolSoft's ICM-Pro software. Hydrogen atoms were added to the structure, and the following were considered: the correct orientation of the Asn and Gln side chains, ligand and protein charges, histidine orientation and protonation state, and any crystal quality markers such as high b-factor or low occupancy. MolSoft's ICMPocketFinder was used to define the end pocket for docking. The end pocket is defined by the residue closest to the ligand (…). The residues within a certain distance describe the binding site of myofascitis proteins. (Reference) Figure 5 Myofascitis binding sites 1 are defined as follows: V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and Y493. Binding sites 2 are defined as follows: F14, L16, L48, Q50, L62, W101, L103, E215, and S218.

[0386] Ligand docking and scoring

[0387] Comparative compounds 2, 3, and 4 were hooked to each binding site to determine the most favorable binding site for each compound. The expected energy-favorable binding configurations for comparative compounds 2, 3, and 4 are reported above.

[0388] The head groups and head + tail groups of comparative compounds 2, 3, and 4 were docked to binding site 2 (see rows in Table 3). Table 3 shows the docking score for each pocket in the pocket. The lower the docking score, the better the ligand interaction. When comparative compounds 2, 3, and 4 were docked to binding site 2, the scores were significantly higher, indicating less favorable binding.

[0389] Table 3 shows the docking scores of comparative compounds 2, 3, and 4 that docked to the predicted binding sites 1 and 2.

[0390]

[0391]

[0392] Two compounds, compound 5 and compound 6, are attached to binding site 1 and binding site 2, respectively, and the compounds have the following structures:

[0393]

[0394] The docking scores are shown in Table 4. Based on the results, it appears that neither compound 5 nor compound 6 could bind to binding site 1 or binding site 2.

[0395] Table 4. Docking scores of compounds 5 and 6 to binding sites 1 and 2.

[0396] pocket Compound 5 Compound 6 Binding site 1 -13 -5 binding site 2 -17 -16

[0397] Example 3

[0398] The effect of the indicated compound on the synaptic density of primary mouse cortical neurons was determined after 24 hours of treatment. Figure 6 On day 15, primary mouse cortical neurons were treated in vitro with 1 μM myofascitis inhibitor or with a mediator (DMSO). Twenty-four hours after treatment, neurons were fixed and immunolabeled for synaptic protein components, presynaptic vesicle proteins, and synaptophysin (P38), followed by staining with the nuclear dye DAPI. Immunolabeled neurons were imaged using a Leica confocal microscope. The number of P38 immunopositive synapses was analyzed using FIJI with the Squash plugin. Data were analyzed and plotted in Graphpad Prism (**p < 0.0001, *p = 0.0012, 2-tailed T test). Figure 6 The results of synaptic growth of Comparative Compound 2, Comparative Compound 7, and Compound 1 compared to the caustic agent control are shown in one embodiment. Comparative Compound 7 has the following structure:

[0399]

[0400] Example 4

[0401] Efficacy testing procedure

[0402] Female APOe4-TR mice were selected because some studies have shown that females with APOe4 may have poorer memory performance, greater brain atrophy, and lower brain metabolism than males. Females with APOe4 are also more likely to have mild cognitive impairment or Alzheimer's disease compared to males with the allele. Mice expressing the APOe3 allele (APOe3-TR) served as controls. Controlled cortical impaction (CCI) was administered to both APOe4-TR and APOe3 mice to induce reliable, calibrated TBI events. Mice anesthetized with CCI received an impact at a velocity of 5.0 m / s, a depth of 1.0 mm, and a residence time of 50 ms. Dummy animals underwent the same procedure for approximately 20–25 minutes without impact.

[0403] The determination of CCI exacerbated cognitive decline in APOe4-TR mice. It was hypothesized that the synergistic effect of TBI and APOe4 genotypes on dendritic spinous synapses would impair cognitive and motor abilities in APOe4 mice. To test this, 8-month-old APOe4-TR and APOe3-TR mice (n=12 per group) were administered CCI (or a no-impact sham program), followed by behavioral tests at 10 and 12 months of age. Behavioral tests were arranged from least-stress to most-stress tasks (i.e., least-handling tasks versus aversive tasks involving constraint), as follows (behavioral phenotypes were performed using Ethovision Xt (Noldus)). Field testing (Day 1): Anxiety was assessed using video tracking, with the time and frequency of time spent in the center and periphery of the enclosure used to evaluate anxiety, where increased time spent in the periphery indicated increased anxiety, and the distance and speed of movement indicated motor / spontaneous activity. Novel Location and Object Recognition (Days 6–7): After 4 days of adaptation (Day 6), mice studied two identical objects in the enclosure. Then, on the second day (Day 7), they were returned to the enclosure, and one of the objects was replaced with a novel object. Increased time spent studying familiar or novel objects in novel locations indicated improved memory. Y-Maze (Day 8): Spontaneous alternation of the Y-maze was performed to measure the rodents' willingness to explore new environments. Mice preferred to explore new arms rather than return to previously visited arms. Each mouse was placed at the end of one arm and allowed free movement within the maze for an 8-minute period. Alternation was defined as consecutive entry into three arms on an overlapping set of triplets. Barnes Maze (Days 9–13): This test evaluated hippocampal-dependent spatial learning and memory. In the acquisition area, mice were trained to locate a hidden escape hole in a round table using additional maze visual cues. Mice were tested twice a day, with approximately 30 minutes between tests. If a mouse failed to enter the escape cage within 5 minutes, it was guided to the correct escape location. Tail Suspension (Day 14): The tail suspension test involved suspending the mouse from the ground by its tail. The time at rest (in seconds) was used as a measure of stress. Situational Fear Symptoms (Days 15-16): Mice were placed in a novel chamber where electric shocks were delivered. Twenty-four hours later, the mice were returned to the chamber, and the amount of freezing behavior was recorded; increased freezing indicated increased memory of the situation.

[0404] Expected Outcomes and Alternative Consequences: The effects of TBI and APOe4 genotypes on synaptic loss and cognition were characterized. Therefore, the combination of these Alzheimer's risk factors is expected to lead to further impairment in the measured tasks, particularly spatial memory (in addition to APOe4 alone), as it depends on structures severely impacted by synaptic loss during Alzheimer's disease and TBI. While unlikely, it is possible that no performance decline in any task will be observed with the addition of TBI. In this case, optimizing the CCI paradigm to induce more robust synaptic loss will be considered. It is possible that some impairments will not amplify with detectable synaptic loss. The addition of TBI may make any impairment, regardless of its location, more difficult to salvage and thus provides an effective test of the ability of SPGs to treat common gene-environment interactions in Alzheimer's disease.

[0405] The compound was identified to improve cognitive decline caused by TBI in APOe4-TR mice. The compound's acanthogenic effect counteracts synaptic loss induced by the addition of the APOe4 genotype and TBI, leading to improved functional recovery. APOe4-TR and APOe3-TR mice subjected to CCI at 8 months of age, as described in Target 1, were treated at 10 and 12 months of age with the compound (30 mg / kg / day, ip) or a mediator, immediately following the CCI procedure and continuing until the behavioral tests (as described in Target 1) were performed. The ip administration route was used for daily dosing to rodents over an extended period.

[0406] Expected Outcomes and Alternative Consequences: Cognitive and motor function were improved in APOe4-TR mice exposed to CCI. In some cases, neuronal viability in specific brain regions was salvaged in only one symptom domain (e.g., spatial memory, but not motor performance) due to the synergistic effect between APOe4 status and TBI – beyond a certain level of neuronal death, salvaging synaptic density was not possible. Histological data were reviewed to calibrate for neuronal loss in accordance with the CCI protocol.

[0407] Objective 3: To evaluate the effects of compounds on dendritic spine density and Alzheimer's disease-related molecular biomarkers in APOe4-TR mice. It was hypothesized that mice treated with the compounds in Objective 2 (APOe4-TR+ / -CCI) would show improved spine density and reduced Ab-initiated dephosphorylation of filamentin. Additionally, since inhibition of myofascitis may reduce microglial migration and activation, it was hypothesized that the active compounds would reduce synaptic pruning in microglia. The properties measured included (i) synaptic density, (ii) phosphorylated filamentin, and (iii) synaptic-associated activation of microglia. Furthermore, the levels of phosphorylated tau and Ab were assessed.

[0408] Mice were anesthetized, perfused cardiacally with paraformaldehyde, and their brains were collected for histological and dendritic spine analysis. Neuronal loss in the hippocampus, entorhinal cortex, and several neocortical regions (e.g., insula, prefrontal cortex) was evaluated using unbiased stereochemical methods (MBF Biosciences' Stereo Investigator System) on sections stained with cresol purple and NeuN. Brain volume, particularly that in hippocampal formation, was measured using the Cavalieri method. Synaptic synapses were labeled with antibodies against synaptophysin (presynaptic terminal) and PSD95 (postsynaptic density) and counted using Bitplane Imaris. Similarly, myofascitis levels and their distribution relative to synapses were determined. Glial cell density and activation status were also assessed. IBA1 microglia were detected by immunohistochemistry, and automated microglial cell body counting was performed using Bitplane Imaris. Additional assays included stratifying microglia into synaptic-associated and extrasynaptic IBA+ cells based on proximity to PSD95 staining. Microglia were also stratified into plaque-associated and non-plaque-associated IBA1+ cells. Microglial activation status was assessed using antibodies against a range of known microglial surface markers including CD45 and CD68. Astrocyte number and activation status, as well as their distribution relative to synapses, were similarly assessed using antibodies against GFAP, BLPB, and S100b. Furthermore, Aβ and tau pathology were measured using 3D volumetric Aβ / tau load analysis with Imaris software and commercially available antibodies.

[0409] Stereo-Investigator software from Microbrightfield Biosciences (MBF Bioscience, Williston, VT, USA) was used to perform stereo-quantitation to determine the number of spines in the radiative (SR) and lacunar molecular layers of the CA3 region of the hippocampus. In short, every second slice was used in the entire anterostereological quantitation performed using Stereo-Investigator software from Microbrightfield Biosciences (MBF Bioscience, Williston, VT, USA) to determine the number of spines in the radiative (SR) and lacunar molecular layers of the CA3 region of the hippocampus. In short, every second slice was used in the entire pre-visual quantification to determine the number of spines in the radiative layer (SR) and lacunar molecular layer of the CA3 region of the hippocampus, performed using Stereo-Investigator software from Microbrightfield Biosciences (MBF Biosciences, Williston, Vermont, USA). In short, every second slice was used in the entire anterior dendritic spine density and dendritic morphology to determine the number of spines in the radiative layer (SR) and dentate gyrus (DG) of the hippocampus, measured using Neurolucida software (MBF Biosciences, Williston, Vermont, USA). Mouse brains were processed using the SuperGolgi kit (Bioenno Tech LLC, Santa Ana, CA) as previously described. Layer 2 of the CA1 radiative layer and dentate gyrus of the hippocampus, as well as layers 2 / 3 of the entorhinal cortex and the insula and medial prefrontal cortex, was defined using 5x objectives, and spines were counted using 100x / 1.4 objectives. Dendritic spine length and volume will be tracked using a 100x / 1.4 objective lens, and the data will be analyzed using Neurolucida Explorer software. Spike density will be correlated with behavioral rescue measures for Target 2. For dendritic morphology analysis, five neurons per animal (n=6) in the CA1 hippocampal region will be tracked using Neurolucida software, and evaluated using Sholl analysis.

[0410] Expected Outcomes and Alternative Consequences: Treatment increases the density of dendritic spines in the hippocampus by approximately 20% or more, which roughly offsets the loss induced by the APOe4 genotype and APOe4 X CCI and increases the level of phosphorylated filaggrins. In some cases, treatment reduces microglial clearance at synapses.

[0411] Example 5

[0412] Dendritic spine generation test

[0413] To determine whether small-molecule inhibitors of myofascitis 1 (MT1) induce the formation of new dendritic spine synapses in the prefrontal cortex, mice were treated with MT1 inhibitor compounds 1 and 11, followed by Golgi staining analysis of dendritic spine density and morphology. Specifically, 15 26-week-old C57BL / 6J mice were acclimatized to containment and treatment conditions for 3 days and then randomly assigned to three treatment groups (n=5 per group): (1) mediator (7% DMSO, 14% Tween 80, H2O) control; (2) 10 mg / kg compound 1; (3) 10 mg / kg compound 11. Mice were then injected intraperitoneally (IP) with either the mediator, compound 1, or compound 11 daily for 26 days. Two hours after the last injection, the mice were sacrificed and the brains were rapidly removed for fixation and subsequent Golgi staining. After Golgi staining, sections of the prefrontal cortex were cut in the coronal plane and mounted for microscopic imaging. The dendritic spine density of neurons in the prefrontal cortex of layer II / III was analyzed using the method described in Example 4 of this paper (n = X image / slice, Y slice / mouse).

[0414] 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 to which this disclosure pertains.

[0415] The embodiments described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” “containing,” etc., should be interpreted broadly and without limitation. Furthermore, the terminology and expressions used herein have been used as descriptive rather than restrictive terms, and such terminology and expressions are not intended to exclude any equivalents or portions thereof of the shown and described features, but it should be recognized that various modifications may be made.

[0416] Therefore, it should be understood that although this disclosure has been specifically disclosed through preferred embodiments and optional features, changes, modifications, and variations embodied herein can be made by those skilled in the art, and such modifications, modifications, and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided herein represent preferred embodiments, are exemplary, and are not intended to limit the scope of this disclosure.

[0417] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated in their entirety by reference, as if each were individually incorporated by reference. In the event of any conflict, this specification (including definitions) shall prevail.

Claims

1. Use of N-(l-(4-(trifluoromethyl)benzyl)-lH-indazol-3-yl)furan-2-carboxamide (Compound 1) having the structure: ###0001### or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting dendritic spine generation in a patient in need of such promotion.

2. Use of N-(l-(4-(trifluoromethyl)benzyl)-lH-indazol-3-yl)furan-2-carboxamide (Compound 1) having the structure: ###0002### or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in a patient in need of such treatment.

3. Use of N-(l-(4-(trifluoromethyl)ben

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