Benzothiazoles and related compounds

Abstract

To provide a method for treating a disease.SOLUTION: Disclosed is a compound that accelerates spine formation, can reduce neurotoxicity of β-amyloid peptide, and / or lightens symptoms of traumatic brain injury of a patient. In one embodiment, the present invention provides a method for reducing neurotoxicity of β-amyloid peptide to a neuron. The method includes a step of bringing β-amyloid peptide into contact with a therapeutically effective amount of a compound described in this specification, or a pharmaceutically acceptable salt thereof or solvate, or a composition under conditions sufficient for reducing neurotoxicity of β-amyloid peptide.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S. Provisional Patent Application No. 62 / 540,311, filed on 2 August 2017, the entirety of which is incorporated herein by reference for all purposes. [Background technology]

[0002] The complexity of dendrites, synapse formation, and the overall proper development and function of neurons are crucial for proper brain function. Traumatic brain injury (TBI) results in memory loss and the production of β-amyloid peptides, which are associated with Alzheimer's disease. One long-term consequence of TBI is a decrease in dendritic spine density in important areas of the brain. This invention provides compounds that can promote spine formation and / or reduce the neurotoxicity of β-amyloid peptides. [Overview of the Initiative]

[0003] In one embodiment, the present invention relates to compounds according to formula I and / or formula IA: [ka] (In the formula, The subscripts n and p are independently selected from 0, 1, or 2; Each R 1 This is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro; A is arylene, or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O)2-, and -NR 12 - Selected from the group consisting of R 12is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; X is -O-, -S-, -SO-, -S(O)2- and -NR 12 -, selected from the group consisting of, R 12 is as defined above, provided that when A is arylene and Y is -S- or -NR 12 -, X is not -S-; Y is -O-, -S-, -SO-, S(O)2- and -NR 12 -, selected from the group consisting of, R 12 is as defined above; Z is -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R 13 )O) q -, selected from the group consisting of -T, the subscript q is an integer selected from 1 to 100, R 13 is selected from the group consisting of hydrogen and methyl, T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide and -L-oligosaccharide, and L is selected from the group consisting of a bond, phosphate and sulfate) or a pharmaceutically acceptable salt, solvate and / or N-oxide thereof is provided.

[0004] In one embodiment, the present invention provides a compound according to formula II, formula III, formula IV, formula V and / or formula VI:

Chemical formula

[0005] In one embodiment, Y is -O-, -S- and -NR 12- Selected from the group consisting of R 12 This is as defined above.

[0006] In one embodiment, T is hydrogen.

[0007] In one embodiment, the present invention provides a compound described herein, or a pharmaceutically acceptable salt, solvate, and / or N-oxide thereof, selected from the following: [ka] [ka]

[0008] In one embodiment, the present invention relates to a compound according to formula VII: [ka] (In the formula, The subscripts n and p are independently selected from 0, 1, or 2; The subscript q is an integer selected from 2 to 8; Each R 1 and R 2 These include halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, and aminosulfo. (Independently selected from the group consisting of nyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro) The present invention provides a pharmaceutically acceptable salt or solvate thereof.

[0009] In one embodiment, the subscript q is an integer selected from 3 to 6; R 1R is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3 and -SO2NH2; 2 The group is selected from halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3, and -SO2N(CH3)2.

[0010] In one embodiment, the subscripts n and p are independently selected from 0 or 1, provided that both subscripts n and p are not 1.

[0011] In one embodiment, the present invention provides a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, selected from the following: [ka] [ka] [ka]

[0012] In one embodiment, R 1 R is selected from the group consisting of halo, -CH3, -OCH3, phenyl, and -CN; 2 The group is selected from halo, -CH3, -CF3, -OCH3, -OCF3, -CHCH2, -CH2CHCH2, phenyl, and -NO2.

[0013] In one embodiment, the present invention relates to a compound according to formula VIIa: [ka] (In the formula, The subscript q is an integer selected from 4 or 6; R 3 , R 4 , R 5 and R 6 It is independently selected from the group consisting of hydrogen, halo, -CH3, and -OCH3; R 7 , R 8 , R 9 and R 10 It is independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; (At least six of the R groups are hydrogen atoms.) The present invention provides a pharmaceutically acceptable salt or solvate thereof.

[0014] In one embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the following: [ka]

[0015] In one embodiment, the present invention provides the following compounds, or pharmaceutically acceptable salts or solvates thereof: [ka]

[0016] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0017] In one embodiment, the present invention provides a method for increasing the dendritic spine density of a neuron. This method comprises the step of contacting a neuron with a therapeutically effective amount of one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof, under conditions sufficient to increase the dendritic spine density of the neuron.

[0018] In one embodiment, a method for increasing the density of dendritic spines in neurons is performed after traumatic brain injury.

[0019] In one embodiment, the present invention provides a method for reducing the neurotoxicity of β-amyloid peptide to neurons. This method comprises the step of contacting β-amyloid peptide with a therapeutically effective amount of one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition, under conditions sufficient to reduce the neurotoxicity of β-amyloid peptide.

[0020] In one embodiment, the present invention provides a method for alleviating the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury. The method for alleviating the symptoms of traumatic brain injury in a patient comprises the step of administering a therapeutically effective amount of one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition, wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof, is sufficient to alleviate the symptoms of traumatic brain injury.

[0021] In one embodiment, a method for alleviating the symptoms of traumatic brain injury in a patient is performed within approximately 0 to 72 hours of the traumatic brain injury.

[0022] In one embodiment of a method for alleviating symptoms of traumatic brain injury in a patient, the alleviation of traumatic symptoms is measured by an improvement of at least 20%–30% in the performance of one or more functional domains within approximately 7 days of treatment, compared to the performance of one or more functional domains measured before treatment but after injury. [Brief explanation of the drawing]

[0023] [Figure 1] The chemical structures of benzothiazole-I (i.e., ((4-(6-methylbenzo[d]thiazole-2-yl)phenyl)amino)-(CH2CH2O)4H), benzothiazole-II (i.e., ((4-(benzo[d]thiazole-2-yl)phenyl)thio)-(CH2CH2O)6H), benzothiazole-IIIA (i.e., ((4-(benzo[d]thiazole-2-yl)phenoxy)-(CH2CH2O)6H), and benzothiazole-IIIB (i.e., ((4-(benzo[d]thiazole-2-yl)phenoxy)-(CH2CH2O)4H) are shown.

[0024] [Figure 2] Effect of benzothiazole compound (5 μM) on the number of spots from primary mouse cortical neurons (DIV 16) 24 hours after treatment initiated at DIV 15. *p<0.05, **p<0.01.

[0025] [Figure 3] Effect of benzothiazole compound (1 μM) on synaptic density from primary mouse cortical neurons (DIV 16) 24 hours after treatment initiated at DIV 15. *p<0.05, **p<0.01.

[0026] [Figure 4] Front views of the four potential ligand-binding pockets of human fasin 1 (ribbon structure) are shown as labeled grayscale surfaces A, B, C, and D.

[0027] [Figure 5] The bottom views of the four potential ligand-binding pockets of human fasin 1 (ribbon structure) are shown as grayscale surfaces labeled A, B, C, and D.

[0028] [Figure 6]The top views of the four potential ligand-binding pockets of human fasin 1 (ribbon structure) are shown as grayscale surfaces labeled A, B, C, and D.

[0029] [Figure 7] The back views of the four potential ligand-binding pockets of human fasin 1 (ribbon structure) are shown as grayscale surfaces labeled A, B, C, and D.

[0030] [Figure 8] A complex formed by docking human facin 1 (ribbon structure) with benzothiazole-I, benzothiazole-II, and benzothiazole-IIIA. The pocket surface incorporates aromatic lipophilic surfaces, other (mostly aliphatic) non-aromatic lipophilic surfaces, hydrogen bond acceptor potentials, and hydrogen bond donor potentials.

[0031] [Figure 9] 2D interaction diagram of the benzothiazole-I and human facin-1 complex. Areas with black circles represent hydrophobic regions. Shaded black squares represent hydrogen bond acceptors. Dashed lines represent hydrogen bonds. Solid gray parabolas represent large accessible surfaces. Thick dashed lines around compound shapes indicate accessible surfaces. The size of the residue ellipse represents the strength of contact. The 2D distance between the residue label and the ligand represents proximity. [Modes for carrying out the invention]

[0032] The present invention provides compounds and compositions for promoting spine formation. The compounds and compositions of the present invention are useful for increasing the density of dendritic spines in neurons and are also useful for reducing the neurotoxicity of β-amyloid peptides to neurons. I. Definition

[0033] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0034] When used herein and in the appended claims, singular articles and similar referents such as "a," "an," and "the" in the context describing the elements (particularly in the context of the following claims) should be interpreted as encompassing both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts this. The enumeration of value ranges herein is intended merely as a concise way of referring individually to each individual value that falls within that range unless otherwise indicated herein, and each individual value is incorporated into the specification as if it were individually listed herein. All methods described herein, unless otherwise indicated herein or unless the context clearly contradicts this, should be interpreted as encompassing both singular and plural forms. The invention may be implemented in any appropriate order, as long as it does not more clearly contradict the invention. The use of any and all examples or exemplary language provided herein (e.g., "etc.") is intended solely to better illustrate the embodiments and not to limit the scope of the claims, unless otherwise specified. The language of the specification should not be construed as indicating that any non-claimed element is essential.

[0035] Where used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of this term that is not obvious to those skilled in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0036] Generally, references to specific elements such as hydrogen or H are intended to include all isotopes of that element. For example, if the R group is defined as containing hydrogen or H, this also includes deuterium and tritium. Thus, tritium, C 14 , P 32 and S 35 Compounds containing radioactive isotopes such as those mentioned above are within the scope of the present invention. Procedures for inserting such labels into compounds of the present invention will be readily apparent to those skilled in the art based on the disclosure herein.

[0037] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. This term includes, by example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0038] "Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyls are C2, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 It may contain any number of carbon atoms, such as C6. The alkenyl group may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexadienyl. The alkenyl group may be substituted or unsubstituted.

[0039] "Substituting alkyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclicoxy Composed of nitro, -SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol. This refers to an alkyl group having 1 to 5 substituents, preferably 1 to 3, more preferably 1 or 2 substituents, selected from the group.

[0040] "Substituted alkenyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl This refers to an alkenyl group having 1 to 3 substituents, preferably 1 or 2 substituents, selected from the group consisting of substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol, provided that none of the hydroxyl substitutions or thiol substitutions are bonded to a vinyl (unsaturated) carbon atom.

[0041] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6, more preferably 1 to 3, in a straight or branched chain. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene (-CH2CH2CH2CH2-), isobutylene (-CH2CH(CH3)CH2-), and sec-butylene (-CH(CH3)CH2CH2- or -CH2CH2(CH3)CH-). Similarly, "alkenylene" refers to an alkylene moiety containing one or two carbon-carbon double bonds, respectively.

[0042] "Substituting alkylene" refers to an alkylene group in which 1 to 3 hydrogen atoms are replaced by substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo, and such substituents are defined herein.

[0043] "Alkoxy" refers to the -O-alkyl group as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. "Substituting alkoxy" refers to the -O-(substituted alkyl) group as defined herein.

[0044] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Acyls contain the "acetyl" group CH3C(O)-.

[0045] "Acylamino" is based on the -NR group. 47 C(O)alkyl, -NR 47 C(O) substituted alkyl, -NR 47 C(O) cycloalkyl, -NR 47 C(O) substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O) alkenyl, -NR 47 C(O) substituted alkenyl, -NR47 C(O) Ally Ru, -NR 47 C(O) substituted aryl, -NR 47 C(O) heteroaryl, -NR 47 C(O) substituted heteroaryl, -NR 47 C(O) heteroalgebra and -NR 47 C(O) substitution heteroalgebra (wherein R 47 (referring to hydrogen or alkyl).

[0046] "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-.

[0047] "Amino" refers to the group -NH2. "Substituting amino" refers to the group -NR 48 R 49 (In the formula, R 48 and R 49 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocycle and -SO2-substituted heterocycle, 48 and R 49 These, together with the nitrogen atoms bonded to them, and bond as needed, form a heterocyclic group or a substituted heterocyclic group, however, R 48 and R 49(Neither of these will become hydrogen.)

[0048] "Aminocarbonyl" is the group -C(O)NR 50 R 51 (In the formula, R 50 and R 51 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, 50 and R 51 This refers to the nitrogen atoms bonded to these atoms, and, if necessary, bond to form a heterocyclic group or a substituted heterocyclic group.

[0049] "Aminocarbonylamino" is based on the group -NR 47 C(O)NR 50 R 51 (In the formula, R 47 R is hydrogen or alkyl; 50 and R 51 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, 50 and R 51 This refers to the nitrogen atoms bonded to these atoms, and, if necessary, bond to form a heterocyclic group or a substituted heterocyclic group.

[0050] "Aminocarbonyloxy" is the base -OC(O)NR 50 R 51 (In the formula, R 50 and R 51 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, 50 and R51 refers to (which combines with the nitrogen bonded thereto and optionally bonds to form a heterocyclic group or a substituted heterocyclic group).

[0051] "Aminosulfonyl" refers to the group -SO2NR 50 R 51 (wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 50 and R 51 refers to (which combines with the nitrogen bonded thereto and optionally bonds to form a heterocyclic group or a substituted heterocyclic group). refers to (which combines with the nitrogen bonded thereto and optionally bonds to form a heterocyclic group or a substituted heterocyclic group). [[ID=2l]]

[0052] "Aminosulfonyloxy" refers to the group -O-SO2NR 50 R 51 (wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 50 and R 51 refers to (which combines with the nitrogen bonded thereto and optionally bonds to form a heterocyclic group or a substituted heterocyclic group).

[0053] "Aminosulfonylamino" refers to the group -NR 47 SO2NR 50 >R 51 (wherein R 47 is hydrogen or alkyl; R 50 and R 51R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, 50 and R 51 This refers to the nitrogen atoms bonded to these atoms, and, if necessary, bond to form a heterocyclic group or a substituted heterocyclic group.

[0054] "Amidino" is a base-C(=NR 52 )NR 50 R 51 (In the formula, R 50 , R 51 and R 52 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, 50 and R 51 This refers to the nitrogen atoms bonded to these atoms, and, if necessary, bond to form a heterocyclic group or a substituted heterocyclic group.

[0055] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). The fused rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl), provided that the bond site is located on an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0056] "Substituted aryl" includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo This refers to an aryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 or 2 substituents, selected from the group consisting of r-alkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0057] "Arylene" refers to a divalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple fused rings. "Substitutive arylene" refers to an arylene having 1 to 5 substituents, preferably 1 to 3, more preferably 1 or 2 substituents, as defined for the aryl group.

[0058] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy. "Substituting aryloxy" refers to the group -O-(substituted aryl).

[0059] "Carbonyl" refers to the divalent group -C(O)- (i.e., -C(=O)-).

[0060] "Carboxyl" or "carboxy" refers to the -COOH group, or its salt.

[0061] "Carboxyl ester" or "carboxyester" refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic.

[0062] "(Carboxyl ester)amino" is the group -NR 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl, -NR 47 C(O)O-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-aryl, -NR 47 C(O)(O)-substituted aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -NR 47 C(O)(O)-heterogeneic rings and -NR 47 This refers to the C(O)(O)-substitution complex algebra.

[0063] "(carboxyl ester)oxy" refers to the group -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic.

[0064] "Cyano" refers to the group -CN.

[0065] "Cycloalkyl" refers to saturated or partially unsaturated monocyclic, fused bicyclic, or bridging polycyclic ring assemblies containing 3 to 12 ring atoms or the indicated number of atoms. Cycloalkyl is C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 and C 3~12 It can contain any number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. "Cycloalkenyl" refers to a partially unsaturated cycloalkyl group having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. 3~8In the case of cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. It contains cycloheptyl and cyclooctyl. The cycloalkyl is saturated monocyclic C 3~6 In the case of cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl and cycloalkenyl groups may be substituted or unsubstituted.

[0066] "Substituted cycloalkyl" and "substituted cycloalkenyl" are oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloal This refers to a cycloalkyl or cycloalkenyl group having 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0067] "Cycloalkyloxy" refers to -O-cycloalkyl. "Substituting cycloalkyloxy" refers to -O-(substituted cycloalkyl).

[0068] "Cycloalkenyloxy" refers to -O-cycloalkenyl. "Substituting cycloalkenyloxy" refers to -O-(substituted cycloalkenyl).

[0069] "Guanidino" refers to the group -NHC (=NH)NH2.

[0070] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0071] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0072] A "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. However, additional heteroatoms, including B, Al, Si, and P, may also be useful. Furthermore, the heteroatoms may be oxidized, such as -S(O)- and -S(O)2-. A heteroaryl group can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. A heteroaryl group can contain any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. A heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups may include pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can condense with or without heteroatoms, such as benzopyrroles (indole and isoindole), benzopyridines (quinoline and isoquinoline), and benzopyrroles (quinoline and isoquinoline). Members including benzopyridazines such as din (quinoxaline), benzopyrimidine (quinazoline), phthalazine, and cinnoline, benzothiophene, benzofuran, indidine, or benzotiene can also be formed. Heteroaryl groups can also be condensed into non-aromatic ring systems, which may or may not contain heteroatoms, provided that the bonding site is mediated by an atom of the aromatic heteroaryl group. For example, the nitrogen and / or sulfur ring atoms of the heteroaryl group can be oxidized as needed to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by bonding, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0073] "Substitutive heteroaryl" refers to a heteroaryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2, selected from the same group of substituents defined for substituted aryls.

[0074] "Heteroaryloxy" refers to -O-heteroaryl. "Substituting heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[0075] A "heterocyclic" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. However, additional heteroatoms, including B, Al, Si, and P, may also be useful. Furthermore, the heteroatoms may be oxidized, such as -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4, can be included in a heterocycloalkyl group. Heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiran, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be condensed into aromatic or non-aromatic ring systems to form members containing indoline, but not limited to these. In condensed ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the bonding site is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are oxidized as needed to provide an N-oxide, sulfinyl, or sulfonyl moiety. The heterocycloalkyl group may be unsubstituted or substituted. For example, the heterocycloalkyl group may be, in particular, C 1~6 It may be substituted with alkyl, oxo (=O), nitro (-NO2), or sulfonyl (-S(O)2-).

[0076] "Substituting heterocycle," "substituted heterocycloalkyl," or "substituted heterocyclyl" refers to a heterocyclyl group substituted with the same substituents as defined for 1 to 5, preferably 1 to 3, substituted cycloalkyl groups.

[0077] "Heterocyclyloxy" refers to the group -O-heterocyclyl. "Substituting heterocyclyloxy" refers to the group -O-(substituting heterocyclyl).

[0078] Examples of heterocyclyls and heteroaryls, though not limited to these, include azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthoridine, acridine, phenanthroline, and isothiazone. Examples include phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, and tetrahydrofuranil.

[0079] "Spirocycloalkyl" and "spiro ring system" refer to a divalent cyclic group of 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro bond (a bond formed by a single atom that is the only common member of the ring), as exemplified by the following structures: [ka]

[0080] "Substituting sulfonyls" refer to groups such as -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic. Substituting sulfonyls include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0081] "Substituting sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic.

[0082] As used herein, the term “sugars” refers to sugars 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 refer to 2 to 10 sugars linked together, preferably through α-bonds. Examples of oligosaccharides include maltose, lactose, and sucrose. Polysaccharides include, but are not limited to, cellulose, hemicellulose, and lignocellulose or starch. Sugars or saccharides useful in the present invention include, but are not limited to, any and all naturally occurring sugars such as glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, and sialic acid, including their aldol and pyranose forms, as well as their D and L isomers.

[0083] The substituted ring may be replaced by one or more condensations and / or spiro rings. Such condensed rings include condensed cycloalkyl, condensed heterocyclyl, condensed aryl, and condensed heteroaryl rings, each of which may be unsubstituted or substituted. Such spiro rings include condensed cycloalkyl and condensed heterocyclyl rings, each of which may be unsubstituted or substituted.

[0084] The groups defined above may be substituted as needed by any appropriate number and type of substituents. Typical substituents, though not limited to these, include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, haloalkyl, haloalkoxy, -OR', =O, -OC(O)R', -(O)R', -O2R', -ONR'R'', -OC(O)NR'R'', =NR', =N-OR', -NR'R'', -NR”C(O)R', -NR'-(O)NR” R''', -NR”C(O)OR', -NH-(NH2)=NH, -NR'C(NH2)=NH, -NH-(NH2)=NR', -SR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, and -NO2. R', R'', and R''' are, independently, hydrogen and unsubstituted C. 1~6 This refers to unsubstituted alkyl groups, such as alkyl groups. Alternatively, if R' and R'', or R'' and R''', are bonded to the same nitrogen, they together with the nitrogen to which they are bonded form the heterocycloalkyl or heteroaryl ring defined above.

[0085] Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is reached by naming the terminal portion of the functional group, followed by the adjacent functional group toward the bond point. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0086] It is understood that polymers achieved by defining substituents on the above-defined substituted groups (e.g., substituted aryls having a substituted aryl group as a substituent that itself is substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is constrained, for example, by the limitation that the substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0087] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with five fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0088] A "tautomer" refers to a constituent isomer of an organic compound that is readily converted by tautomerization or tautomerism. This reaction typically results in the formal transfer of hydrogen atoms or protons, usually involving the switching of single bonds and adjacent double bonds. Tautomerism is a special case of structural isomerism, and due to its rapid interconversion, tautomers are generally considered to be the same compound. In a solution in which tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including, but not limited to, temperature, solvent, and pH. Exemplary common tautomer pairs include, but not limited to, ketones and enols, enamines and imines, ketenes and inols, nitroso and oximes, amides and imido acids, lactams and lactimes (amide and imido acid tautomerism in heterocycles), enamines and anomers of enamines and reducing sugars.

[0089] "Stereoisomers" refer to isomer molecules that have the same molecular formula and arrangement of bonded atoms (i.e., composition), but differ in the three-dimensional orientation of their atoms in space. This is in contrast to structural isomers, which share the same molecular formula but differ in bond connections or their order. By definition, molecules that are stereoisomers of each other represent the same structural isomer. Enantiomers are formed by reflection. Two related stereoisomers are mirror images that cannot be superimposed. All chiral centers of one are opposite to the stereoconfiguration of the other. Two compounds that are enantiomers of each other have the same physical properties except for the direction in which they rotate polarized light and the way they interact with various optical isomers of other compounds. Diastereomers and stereoisomers that are not related through reflection are not mirror images of each other. These include meso compounds, cis and trans (E and Z) isomers, and non-enantiomer optical isomers. Diastereomers rarely have the same physical properties. For the purposes of this disclosure, stereoisomers may refer to enantiomers, diastereomers, or both. Stereoiomers are often obtained in partially purified forms. For compounds of the present invention having stereoisomers, such partially purified forms include those having 60%, 70%, 80%, 90%, or 95% of one dominant stereoisomer.

[0090] The compounds of the present invention may also be in salt form, such as acid salts or base salts of the compounds of the present invention. “Pharmacologically acceptable salt” refers to a salt of the active compound prepared with an acid or base, depending on the specific substituents found in the compounds described herein. Exemplary examples of pharmaceutically acceptable salts that act as counterions to negatively charged groups include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or other well-known salts. Examples of pharmaceutically acceptable salts that act as counterions to positively charged groups include carboxylic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, citric acid, tartaric acid, and oxalic acid. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding appropriate pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, incorporated herein by reference.

[0091] The compounds of the present invention can exist in solvated forms, including non-solvated or anhydrous forms, as well as hydrated forms. Hydrates, as the name suggests, refer to the formation of complexes between water molecules and each molecule of the present invention. Solvates refer to the formation of complexes with organic solvents such as methanol, ethanol, and isopropanol. In general, solvated forms are equivalent to non-solvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms (e.g., anhydrous, solvate, and hydrate) are equivalent for the uses intended by the present invention and are intended to be within the scope of the present invention.

[0092] "Positional isomers" or "constitutive isomers" refer to different compounds that have the same number and type of atoms, and therefore the same molecular weight, but whose atoms are bonded in different ways.

[0093] As used herein, the term “β-amyloid” refers to a peptide of 36-43 amino acids involved in the formation of fibrils, plaques, and / or amyloid deposits by enzymatic cleavage from amyloid precursor proteins. The term also encompasses peptides that have substantial similarity to amyloid-like proteins, such as structural variants. In some cases, peptides may occur spontaneously or be constructed synthetically. The term β-amyloid also includes amyloid-forming proteins and proteins that produce amyloid-like morphologies.

[0094] As used herein, “substantial similarity” means that, when the two peptide sequences are optimally aligned, they share at least 50% sequence identity, or at least 60% sequence identity, or at least 70% sequence identity, or at least 80% sequence identity, or at least 90% sequence identity, or at least 95% sequence identity, or more (e.g., 99% sequence identity). Preferably, The non-identical residue positions are determined by conserved amino acid substitutions. Conserved amino acid substitutions refer to the interchangeability of residues with similar side chains. For example, amino acids with aliphatic side chains are glycine, alanine, valine, leucine, and isoleucine; amino acids with aliphatic hydroxyl side chains are serine and threonine; amino acids with amide-containing side chains are asparagine and glutamine; amino acids with aromatic side chains are phenylalanine, tyrosine, and tryptophan; amino acids with basic side chains are lysine, arginine, and histidine; and amino acids with sulfur-containing side chains include methionine and cysteine. Preferred conserved amino acid substitution groups are valine-leucine-isoleucine; phenylalanine-tyrosine; lysine-arginine; alanine-valine; and asparagine-glutamine. In some cases, non-identical residue positions also result in peptide analogues containing non-natural amino acids or their derivatives. Analogues typically differ from naturally occurring peptides in one, two, or several positions due to conservation substitutions. Some analogues also involve modifications at one, two, or several positions of unnatural amino acids or N- or C-terminal amino acids. Examples of unnatural amino acids include D-amino acids, α,α-disubstituted amino acids, N-alkyl amino acids, lactic acid, 4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-N-methylarginine, and isoaspartic acid.

[0095] As used herein, the term “stereochemically pure” in relation to a compound means that the compound or a composition thereof contains primarily one stereoisomer of the compound and substantially none of the other stereoisomers of the compound. For example, a stereochemically pure composition of a compound having one chiral center would substantially contain none of the opposite enantiomer of the compound. A stereochemically pure composition of a compound having two or more chiral centers would substantially contain none of the other diastereomers of the compound. A typical stereochemically pure compound contains about 80% or more by weight of one stereoisomer of the compound and about 20% or less by weight of none of the other stereoisomers of the compound. For example, in various embodiments, a stereochemically pure compound may include 90% or more by weight of one stereoisomer of the compound and about 10% or less by weight of other stereoisomers (one or more); about 95% or more by weight of one stereoisomer of the compound and about 5% or less by weight of other stereoisomers (one or more); about 97% or more by weight of one stereoisomer of the compound and about 3% or less by weight of other stereoisomers (one or more); about 98% or more by weight of one stereoisomer of the compound and about 2% or less by weight of other stereoisomers (one or more); and about 99% or more by weight of one stereoisomer of the compound and about 1% or less by weight of other stereoisomers (one or more).

[0096] The terms "administering" or "dosing" refer to any form of administration to a patient or subject, including oral administration, suppository administration, topical contact, parenteral administration, intravenous, intraperitoneal, intramuscular, intrafocal, intranasal or subcutaneous administration, intrathecal administration, or any sustained-release device, such as the implantation of a mini osmotic pump. Appropriate routes of administration are well known to those skilled in the art.

[0097] "Therapeutably effective amount," "therapeutably effective dose," "therapeutably sufficient amount," "therapeutably sufficient dose," or "effective or sufficient amount or dose" refers to the amount or dose of the compound or composition of the present invention that produces the therapeutic effect when administered for that purpose. For example, a therapeutically effective amount or dose may be an amount sufficient to increase dendritic spine formation, and / or an amount that reduces the neurotoxicity of abnormal protein structures, protein aggregates, or protein misfoldings, such as amyloid plaques and / or amyloid depositions. Such depositions include β-amyloid tannins, such as those in neurological diseases or conditions. This correlates with the risk or presence of a patient with a protein-related disease or condition. In some cases, such diseases or conditions are referred to as amyloid-based diseases or conditions. These diseases and conditions include, for example, neurological disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and diseases and / or conditions characterized by loss of cognitive and memory abilities, such as mild cognitive impairment, Lewy body dementia, Down syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), and the Guam Parkinson's-dementia complex. Other diseases and / or conditions based on or related to β-amyloid include progressive supranuclear palsy, multiple sclerosis, Creutzfeldt-Jakob disease, HIV-associated dementia, ALS (amyotrophic lateral sclerosis), inclusion body myositis (IBM), adult-onset diabetes mellitus, senile cardiac amyloidosis, endocrine neoplasia, and other diseases including amyloid-related eye diseases that target various tissues of the eye, such as the visual cortex including cortical visual impairment; the anterior chamber and optic nerve including glaucoma; the lens including cataracts due to amyloid-like deposits; the vitreous humor including ocular amyloidosis; the retina including primary retinal degeneration and macular degeneration, particularly age-related macular degeneration; the optic nerve including optic drusen, optic neuropathy and optic neuritis; and the cornea including lattice dystrophy, as well as cognitive loss due to brain injury alone or as a whole (e.g., cumulative brain injury due to repeated concussion).

[0098] The precise dosage and frequency of administration of the compound or composition of the present invention depend on the severity of the condition being treated, the patient's age, weight, and sex, as well as other factors well known in the art, and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose may often be lower than the conventional therapeutically effective dose for unsensitized cells.

[0099] The compounds and / or compositions of the present invention can be used alone or in combination with one or more further therapeutic agents. When used in combination, the compounds and / or compositions of the present invention can be administered simultaneously with (i.e., at the same time) or sequentially with one or more further therapeutic agents. Sequential administration is intended to encompass various administration sequences of the therapeutic agent(s) and the compounds(s) / compositions of the present invention to the target.

[0100] The term "spine formation" refers to the growth of new dendritic spines on neurons.

[0101] As used herein, the term “dendrite” refers to the branched extension of a neuron cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axon of an adjacent neuron. The terms “dendritic spine” or “dendrite spine” refer to a protoplasmic elevation on a neuron cell (e.g., a dendrite). In some embodiments, a dendritic spine may be described as having a membranous neck that can terminate at a head (e.g., a head), and is classified according to its shape: headless, slender, stout, mushroom-like, or branched. Thus, dendritic spine density refers to the total number of dendritic spines per unit length of a neuron cell.

[0102] Terms such as "dendritic spine formation" refer to the process that results in an increase in the number of dendritic spines or an increase in the development of dendritic spines. Terms such as "dendritic spine morphology" refer to the process that results in an increase in the number of dendritic spines or an increase in the development of dendritic spines. This refers to the physical properties (e.g., shape and structure) of dendritic spines.

[0103] "Patient" or "subject requiring it" refers to a living organism suffering from or susceptible to a condition that can be treated by administration of the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, and other non-mammalian animals.

[0104] "To treat," "to treat," and "treatment" refer to any indication of success or improvement in the treatment of an injury, condition, or state, including any objective or subjective parameters such as relief; remission; or reduction of symptoms; making the injury, condition, or state more tolerable to the patient; slowing the rate of degeneration or decline; making the final stage of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0105] "Disorder" or "condition" refers to a state of existence or health condition of a patient or subject that can be treated with the compounds of the present invention. Examples of disorders or conditions, but not limited to, include, low dendritic spine density of neurons, neurotoxicity of β-amyloid peptides to neurons, and traumatic brain injury.

[0106] "Traumatic brain injury" or "TBI" refers to acquired brain injury or head injury where trauma causes damage to the brain. Trauma includes, for example, post-traumatic head injury, impact trauma, and other head injuries such as accident-induced and / or sports injuries, concussion injuries, penetrating head injuries, brain tumors, strokes, heart attacks, meningitis, viral encephalitis, and other conditions that deprive the brain of oxygen. In certain embodiments, the trauma is an external physical force. In another embodiment, the trauma is "blast-induced traumatic brain injury," referring to TBI caused by direct or indirect exposure to an explosion.

[0107] "Blunt impact" refers to brain damage that occurs when the head is suddenly and forcefully struck by an object, but the object does not penetrate the skull.

[0108] A concussion refers to a mild form of traumatic brain injury that results in temporary impairment of neurological function that recovers rapidly on its own, and generally does not result in significant structural changes to the brain. Concussions are generally thought to occur as a result of a blow to the head or other forceful event, and typically result in loss of consciousness for less than 30 minutes.

[0109] "Assessment" and "testing" refer to assessments used to determine the severity of traumatic brain injury, details of which are described herein.

[0110] "An amount sufficient to alleviate the symptoms of traumatic brain injury" refers to the amount of compound administered to a patient with traumatic brain injury that is necessary to observe a reduction in the patient's symptoms of traumatic brain injury. "Symptoms" of traumatic brain injury may include elevated levels of biomarkers in the patient's blood. Examples of biomarkers elevated in the blood of patients with traumatic brain injury are GFAP and UCH-L1. Other symptoms of traumatic brain injury are deficits in the following functional domains: physical, visual, auditory, neurobehavioral, cognitive communication, and sleep. Details of biomarkers and each functional domain are described herein. An adequate amount of the compound administered to a patient with traumatic brain injury symptoms would result in at least a 20-30% reduction in symptoms compared to a statistically significant cohort of patients with traumatic brain injury who did not receive an adequate amount of the compound.

[0111] The embodiments described herein as exemplary may be adequately implemented in the absence of any one or more elements, one or more limitations, not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly, not restrictively. Furthermore, the terms and expressions used herein are descriptive and not restrictive, and the use of such terms and expressions is not intended to exclude any equivalent or part of the indicated and described functions, and various modifications are permitted within the scope of the claimed technology. Additionally, the phrase “essentially consisting of” is understood to include the specifically enumerated elements, as well as additional elements that do not substantially affect the fundamental and novel characteristics of the claimed technology. The phrase “consisting of” excludes any elements not specified.

[0112] Where any feature or aspect of this disclosure is described in relation to the Markush group, a person skilled in the art will recognize that this disclosure also describes any individual member or subgroup of a member of the Markush group. Each of the narrower species and sub-conceptual groups that fall into the general disclosure also forms part of the invention. This includes the general description of the invention with any proviso or negative limitation that removes any subject matter from a genus, whether or not the deleted material is specifically enumerated herein.

[0113] As will be understood by those skilled in the art, for any and all purposes, particularly with regard to the provision of written explanations, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any enumerated scope can be readily recognized as sufficiently describable and enable the decomposition of that scope into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can readily be decomposed into a lower third, a middle third, an upper third, etc. Also, as will be understood by those skilled in the art, all language such as “up to,” “at least,” “greater than,” and “less than” includes the enumerated number and refers to a scope that can then be decomposed into subscopes as discussed above. Finally, as will be understood by those skilled in the art, a scope includes each individual member. II. Compounds

[0114] In some embodiments, the present invention relates to compounds of formula I and / or formula IA: [ka] (In the formula, The subscripts n and p are independently selected from 0, 1, or 2; Each R 1This is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro; A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O)2-, and -NR 12 - Selected from the group consisting of R 12 This includes hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl. Selected from the following groups; X is -O-, -S-, -SO-, -S(O)2-, and -NR 12 - Selected from the group consisting of R 12 As defined above, where A is arylene and Y is -S- or -NR 12 -If X is -S-, then X is not -S-; Y is -O-, -S-, -SO-, S(O)2-, and -NR 12 - Selected from the group consisting of R 12 It is as defined above; Z is -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R 13 )O) q -Selected from the group consisting of T, where the subscript q is an integer selected from 1 to 100, R 13 (where T is selected from the group consisting of hydrogen and methyl, T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide and -L-oligosaccharide, and L is selected from the group consisting of bond, phosphate and sulfate) Alternatively, the present invention provides a pharmaceutically acceptable salt, solvate, and / or N-oxide thereof.

[0115] In some embodiments, the present invention relates to compounds according to formulas II, III, IV, V and / or VI: [ka] (In the formula, R 1 , R 12 A, Y, Z, n, and p are as defined above; (The subscript m is selected from 0, 1, or 2.) The present invention provides a pharmaceutically acceptable salt, solvate, and / or N-oxide thereof.

[0116] In some embodiments, A is a heteroaryl (heteroarylene) group selected from pyridinylene, 1,3-imidazoylene, furanylene, pyrrolylene, thiophenylene, indolylene, etc. In some embodiments, A is an aryl (arylene) group such as phenylene or naphthylene.

[0117] In some embodiments, the present invention is [ka] [ka] The present invention provides compounds of formula I and / or formula IA selected from, or pharmaceutically acceptable salts and / or solvates thereof.

[0118] In some embodiments, the present invention relates to compounds of formula VII: [ka] (In the formula, the subscripts n and p are independently selected from 0 to 4; the subscript q is an integer selected from 1 to 20; each R 1 and R 2 is halo, alkyl, substituted alkyl, aldehyde (Independently selected from the group consisting of kenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro) The present invention provides a pharmaceutically acceptable salt or solvate thereof.

[0119] In some embodiments of the present invention, each R of formula (VII) 1 and R 2However, -F;-Cl;-Br;-I; substituted or unsubstituted alkyls (e.g., C1-C8, C1-C6, C1-C4 or C1-C2); substituted or unsubstituted alkenyls (e.g., vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl or 1,4-pentadienyl); substituted or unsubstituted alkoxys (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy or n-pentoxy) Cyano; Acyl; Acylamino; Aminocarbonyl (e.g., amide or substituted amide); Aminosulfonyl (e.g., sulfonamide or substituted sulfonamide); Amino, substituted amino; Substituted or unsubstituted aryl (e.g., phenyl, naphthyl, anthryl, 2-benzoxazolinone or 2H-1,4-benzoxazine-3(4H)-on-7-yl); Carboxyl; Carboxyl ester; Cyano; Substituted or unsubstituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, norbornane, [2.2.2] Bicyclooctane, decahydronaphthalene, adamantine, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene or norbornadiene); substituted or unsubstituted heteroaryls (e.g., pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine, thiophene, furan, thiazole, isothiazole, oxazole or isoxazole); A variety of heterocyclyl compounds (e.g., aziridine, azetidine, pyrrolidine, piperidine, azepan, azocan, quinuclidine, pyrazolidine, imidazolidine, piperazine, oxirane, oxetane, tetrahydrofuran, oxane, oxepan, thiran, thiethane, thiolan, thian, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolan, morpholine, thiomorpholine, dioxane, or dithian) are independently selected from the group consisting of hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro compounds.

[0120] In some embodiments of the present invention, each R of formula (VII) 1 and R 2However, -F;-Cl;-Br;-I; substituted or unsubstituted alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl); substituted or unsubstituted alkenyl (e.g., vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl); substituted or unsubstituted alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, or n-pentoxy); acyl; acylamino; amino Independently selected from the group consisting of carbonyl (e.g., amide or substituted amide); aminosulfonyl (e.g., sulfonamide or substituted sulfonamide); amino, substituted amino; substituted or unsubstituted aryl (e.g., phenyl, naphthyl, anthryl or 2-benzoxazolinone); carboxyl; carboxyl ester; cyano; substituted or unsubstituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); hydroxyl; sulfonyl, substituted sulfonyl; thiol; thioalkyl; and nitro.

[0121] In some embodiments of the present invention, each R of formula (VII) 1 and R 2 The following are independently selected from the group consisting of -F;-Cl;-Br;-I;methyl;ethyl;n-propyl, isopropyl;substituted lower alkyl;vinyl;propenyl;methoxy;ethoxy;n-propoxy;acyl;acylamino;aminocarbonyl;aminosulfonyl;amino;substituted amino;phenyl;carboxyl;carboxyl ester;cyano;cyclopropyl;cyclobutyl;cyclopentyl;cyclohexyl;hydroxyl;sulfonyl;substituted sulfonyl;thiol;thioalkyl; and nitro.

[0122] In some embodiments of the present invention, each R of formula (VII) 1 and R 2However, one can be independently selected from the group consisting of halo, -CH3-OH, -CH2SO2NH2, -SO2NH2, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3, and -SO2N(CH3)2.

[0123] In some embodiments of the present invention, each R of formula (VII) 1 However, each R in formula (VII) is independently selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3, and -SO2NH2; 2 However, one is independently selected from the group consisting of halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3, and -SO2N(CH3)2.

[0124] In some embodiments, the subscripts n and p of formula (VII) are independently selected from 0 to 4. In some embodiments, the subscripts n and p are independently 0, 1, 2, 3, or 4. In some embodiments, the subscripts n and p are independently 0, 1, 2, or 3. In some other embodiments, the subscripts n and p are independently 0, 1, or 2. In some embodiments, the subscripts n and p are independently 0 or 1. In some embodiments, the subscripts n and p are independently 0 or 1, but not both are 1. In some embodiments, the subscript n is 1 and the subscript p is 0. In other embodiments, the subscript n is 0 and the subscript p is 1. In some embodiments, both the subscripts n and p are 0.

[0125] In some embodiments, the subscript q in formula (VII) is an integer between 1 and 20. In some embodiments, the subscript q is an integer between 1 and 15, 2 and 14, 3 and 13, 4 and 12, 5 and 11, 6 and 10, or 7 and 9. In some embodiments, the subscript q may be an integer between 2 and 12, 2 and 10, 2 and 8, 2 and 6, 2 and 5, or 2 and 4. In other embodiments, the subscript q may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the subscript q may be an integer between 2 and 8. In other embodiments, the subscript q may be an integer between 3 and 6. In other embodiments, the subscript q may be an integer between 4 and 6. In other embodiments, the subscript q may be 4 or 6.

[0126] In some embodiments, the present invention relates to compounds of formula VII: [ka] (In the formula, the subscripts n and p are independently selected from 0, 1, or 2; the subscript q is an integer selected from 2 to 8; each R 1 and R 2(This is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.) The present invention provides a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments of the present invention, the subscript q of formula (VII) may be an integer selected from 3 to 6; the subscripts n and p may be independently selected from 0, 1, or 2; R 1 However, selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3, and -SO2NH2; R 2 The group is selected from halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3, and -SO2N(CH3)2.

[0128] In some embodiments of the present invention, the subscript q of formula (VII) may be an integer selected from 3 to 6; the subscripts n and p may be independently selected from 0 or 1, provided that both subscripts n and p are not 1; R 1 However, selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3, and -SO2NH2; R 2The group is selected from halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3, and -SO2N(CH3)2.

[0129] In some embodiments, the compound of formula (VII), or a pharmaceutically acceptable salt or solvate thereof, may be selected from the following: [ka] [ka] [ka] [ka]

[0130] In some embodiments of the present invention, each R of formula (VII) 1 However, each R of formula (VII) is independently selected from the group consisting of halo, -CH3, -OCH3, phenyl, and -CN; 2 However, it is independently selected from the group consisting of halo, -CH3, -CF3, -OCH3, -OCF3, -CHCH2, -CH2CHCH2, phenyl, and -NO2.

[0131] In some embodiments, the present invention relates to compounds according to formula VIIa, or pharmaceutically acceptable salts or solvates thereof: [ka] (In the formula, the subscript q is an integer selected from 4 or 6; R 3 , R 4 , R5 and R 6 R is independently selected from the group consisting of hydrogen, halo, -CH3, and -OCH3; 7 , R 8 , R 9 and R 10 (The R group is independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; at least six of the R groups are hydrogen.) To provide.

[0132] In some embodiments, a compound of formula (VII) or (VIIa), or a pharmaceutically acceptable salt or solvate thereof, is of formula: [ka] It holds.

[0133] In some embodiments, a compound of formula (VII) or (VIIa), or a pharmaceutically acceptable salt or solvate thereof, is of formula: [ka] It holds. III.Synthesis

[0134] The compounds of the present invention can be prepared from readily available starting materials by various methods known to those skilled in the art (see Comprehensive Organic Transformations, Richard C. Larock, 1989) or by a suitable combination of generally known synthetic methods. Techniques useful for the synthesis of the compounds of the present invention are readily apparent and available to those skilled in the relevant art. The following discussion is provided to illustrate some of the diverse methods available in assembling the compounds of the present invention. However, the discussion is not intended to define a range of reactions or reaction sequences useful for the preparation of the compounds of the present invention. Those skilled in the art will understand that other methods and alternative reaction conditions (e.g., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) for producing the compounds are useful in the present invention.

[0135] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Protecting groups suitable for various functional groups, as well as appropriate conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, 3rd edition, Wiley, New York, 1999, and the references cited therein.

[0136] If a compound of the present invention contains one or more chiral centers, such a compound can be prepared or isolated as a pure stereoisomer (i.e., as individual enantiomers or as a stereoisomer-enriched mixture). All such stereoisomers (and enriched mixtures) are included within the scope of the present invention unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0137] The starting materials and reagents used in the preparation of the compounds of the present invention are available from commercial suppliers such as Sigma-Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Cheme (St. Louis, Missouri, USA). Alternatively, the starting materials and reagents used in the preparation of the compounds of the present invention may be Fieser and Fieser's Reagents for Organic. The materials are prepared by methods known to those skilled in the art, following the procedures outlined in references such as Synthesis, Vol. 1–28 (Wiley, 2016); Advanced Organic Chemistry, 7th edition, March (Wiley, 2013); Chemistry of Carbon Compounds, Vol. 1–5 and Supplement, Rodd (Elsevier Science Publishers, 1989); and Comprehensive Organic Transformations, 2nd edition, Larock (Wiley, 1999). The starting materials and intermediates of the reaction can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, and chromatography, if desired. Such materials can be characterized using conventional means, including measurement of physical constants and acquisition of spectral data.

[0138] The compounds of the present invention are summarized in Scheme 1 and can be prepared by the following approach described below. As shown in Scheme 1, the hydroxyl group of compound (i) can be deprotonated with any suitable reagent to form the corresponding oxide (ii) (wherein R 1A, X, n, and p are as defined herein, and E is a countercation (e.g., sodium, lithium, and potassium). For example, contact of compound (i) with a strong base such as metallic sodium, sodium hydride, or lithium diisopropylamide (LDA) under appropriate conditions yields the corresponding oxide (ii). Alternatively, potassium carbonate in a suitable aprotic solvent can be used. The resulting oxide (ii) can then be contacted with compound (iii) (e.g., 2-haloethanol or an α-halo-ωhydroxyl polyoxyethylene compound of 2 to 10 repeating oxyethylene groups) to form compound (iv) (wherein q is as defined herein, and Q is a halo group or a leaving group (e.g., chloro, bromo, and iodine, or triflate, tosylate, and mesylate)). For example, commercially available compounds such as (2-chloroethoxy)ethanol (Sigma Aldrich) and 2-[(2-chloroethoxy)-2-(ethoxy)ethanol] (Sigma Aldrich) may be used as compound (iii). The resulting product (iv) can be recovered by conventional means and purified by crystallization, chromatography, precipitation, etc. In some cases, the oxyalkylene chain of compound (iv) can be modified by the addition of sugars or oligosaccharides using standard procedures for generating aglycones. Scheme 1 [ka]

[0139] The starting compound (i) can be obtained using known synthetic routes and commercially available starting reagents. For example, compound (ia) can be prepared from commercially available 2-bromobenzo[d]thiazole (ic) and commercially available 6-bromopyridine-3-ol (ib) under Suzuki coupling conditions, as shown below in Scheme 2. Compound (ib), whose hydroxyl group can be protected as needed, is converted to the corresponding boronic acid coupling partner and subjected to conventional Suzuki conditions with (ic) to obtain 6-(benzo[d]thiazole-2-yl)pyridine-3-ol (ia). Conditions for the Suzuki reaction are readily available in the literature. Scheme 2 [ka]

[0140] A person skilled in the art would know that compound (i) or compound (ia) contains one or more R atoms other than hydrogen atoms. 1 You will understand the methods and principles of synthesizing chemical bonds for substituting groups. Alternatively, one or more R other than hydrogen. 1 Compounds of formula (i) and (ia) with substitutions are commercially available. Other starting materials are well known and commercially available, for example, 2-bromobenzimidazole, 2-bromobenzoxazole and their substituted versions. Compounds of formula IA can be prepared in the same way as compounds of formula I, starting with reagents such as 2-bromoindole, 2-bromobenzofuran, 2-bromobenzothiophene and their substituted versions.

[0141] In some specific embodiments of the present invention, compounds of formula (VII) and formula (VIIa) can be prepared by the following approach, summarized in Scheme 3 and described below. As shown in Scheme 3, the direct condensation of o-aminothiophenol (i) and p-hydroxybenzaldehyde (ii), followed by oxidative cyclization of a Schiff base intermediate to form the corresponding 2-substituted benzothiazole (iii) can be catalyzed by any suitable acidic reagent (wherein R 1 , R2 (wherein n and p are as defined herein for formulas (VII) and (VIIa). For example, compound (i) and (ii) are combined under suitable conditions in the presence of a suitable Lewis acid catalyst (e.g., FeCl3, ZrOCl2, In(OTf)3, Yb(OTf)3, or Sc(OTf)3) to obtain the corresponding disubstituted benzothiazole (iii). The resulting benzothiazole (iii) can then be contacted with compound (iv) (e.g., a 2-substituted polyethylene glycol compound) to form compound (v) (wherein q is as defined herein, and Q is a halo group or a leaving group (e.g., chloro, bromo, and iodine, or triflate, tosylate, and mesylate)). For example, commercially available compounds such as (2-chloroethoxy)ethanol (Sigma Aldrich) and 2-[(2-chloroethoxy)-2-(ethoxy)ethanol] (Sigma Aldrich) may be used as compound (iv). The obtained product (v) can be recovered by conventional means and purified by crystallization, chromatography, precipitation, etc. Scheme 3 [ka] IV. Pharmaceutical Compositions

[0142] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention as described herein, or a pharmaceutically acceptable salt, solvate, and / or N-oxide thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions provided by the present invention include compositions in which the active ingredient is a compound of formula I, formula IA, formula II, formula III, formula IV, formula V, formula VI, formula VII, and / or formula VIIa as described herein. In some embodiments, the pharmaceutical composition contains a compound of formula (VII) or formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof.

[0143] The pharmaceutical composition of the present invention contains a therapeutically effective amount of an active ingredient. In some embodiments of the present invention, the therapeutically effective amount of the active ingredient is an amount effective in achieving its intended purpose. In some embodiments of the present invention, the therapeutically effective amount of the active ingredient may be an amount effective in increasing the density of dendritic spines in neurons. In some embodiments of the present invention, the therapeutically effective amount of the active ingredient may be an amount effective in reducing the neurotoxicity of β-amyloid peptide to neurons. In some embodiments of the present invention, the therapeutically effective amount of the active ingredient may be an amount effective in alleviating the symptoms of traumatic brain injury.

[0144] The actual amount effective for a particular use may depend, among other things, on the condition being treated (i.e., low dendritic spine density, β-amyloid peptide neurotoxicity, traumatic brain injury). When administered in a manner that treats a condition or disease (i.e., low dendritic spine density, β-amyloid peptide neurotoxicity, traumatic brain injury), such compositions contain an amount of the active ingredient effective in achieving the desired result. Determining the therapeutically effective amount of the compounds of the present invention is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure herein.

[0145] Such compositions can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for patient intake. The compounds of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, duodenumly, or intraperitoneally. Furthermore, the compounds described herein can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. The compounds of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes, including suppositories, gas infusions, powders, and aerosol formulations (see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995 for examples of steroid inhalants). Therefore, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and either the compound of the present invention or a pharmaceutically acceptable salt of the compound of the present invention.

[0146] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable excipients may be either solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid excipients may be one or more substances that also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Technical details for formulation and administration are described in detail in scientific literature and patent documents, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0147] In powder form, the excipient is a finely pulverized solid, and the mixture is with the finely pulverized compound of the present invention. In tablet form, the compound of the present invention is mixed in an appropriate proportion with an excipient having the required binding properties, and compressed into a desired shape and size. The powder and tablets preferably contain 5% or 10% to 70% of the compound of the present invention.

[0148] The composition typically comprises conventional pharmaceutical excipients and may further contain other agents, carriers, adjuvants, diluents, tissue permeability enhancers, solubilizers, and the like. Preferably, the composition contains about 0.01% to about 90%, preferably about 0.1% to about 75%, more preferably about 0.1% to about 50%, and even more preferably about 0.1% to 10% by weight of the compound or combination thereof of the present invention, with the remainder consisting of appropriate pharmaceutical excipients. Appropriate excipients can be adjusted to suit specific compositions and routes of administration by methods well known in the art, for example, by Remington's Pharmaceutical Sciences mentioned above.

[0149] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; calcium phosphate; calcium silicate; talc; pectin; dextran, dextrin and cyclodextrin inclusion complexes; low-melting-point waxes; cocoa butter; carbohydrates; but are not limited to, sugars including lactose, dextrose, sucrose, mannitol or sorbitol; but are not limited to, starches including starches derived from corn, wheat, rice, potato or other plants; methylcellulose, hydroxypropyl Celluloses such as methylcellulose or sodium carboxymethylcellulose; rubbers including arabic, tragacanth, and acacia; proteins including gelatin and collagen, but not limited to these; microcrystalline cellulose, water, saline, syrup, ethylcellulose, and polyacrylic acids such as Carbopol, e.g., Carbopol 941, Carbopol 980, Carbopol 981; lubricants; mineral oil; wetting agents; emulsifiers; suspending agents; preservatives such as methyl, ethyl, and propyl hydroxybenzoates (i.e., parabens); pH adjusters such as inorganic and organic acids and bases; sweeteners; and flavoring agents; biodegradable polymer beads. If desired, disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid, alginates or their salts, e.g., sodium alginate, may be added.

[0150] Pharmaceutically acceptable excipients may include, for example, physiologically acceptable compounds that act to stabilize the compounds of the present invention or to modulate their absorption, or other excipients if desired. Physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. Those skilled in the art will know that the selection of pharmaceutically acceptable excipients, including physiologically acceptable compounds, depends, for example, on the route of administration of the compounds of the present invention and the specific physicochemical properties of the compounds of the present invention.

[0151] In general, such excipients should be non-toxic to the recipient at the dosage and concentration used. Typically, the preparation of such compositions requires combining therapeutic agents with buffers, antioxidants such as ascorbic acid, low molecular weight (less than approximately 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, maltose, sucrose, or dextrin, chelating agents such as EDTA, glutathione, and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin are exemplary suitable diluents.

[0152] The sugar-coated tablet core is coated with a suitable coating, such as a concentrated sugar solution which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for product identification or to characterize the amount of compound (i.e., dosage). The pharmaceutical formulations of the present invention can also be used orally, for example, in the form of a press-fit capsule made of gelatin, and in the form of a soft-seal capsule made of gelatin and a coating such as glycerol or sorbitol. The press-fit capsule may contain the compound of the present invention mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and a stabilizer as needed. In the soft capsule, the compound of the present invention may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol, with or without a stabilizer.

[0153] To prepare the suppositories, a low-melting-point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the compound of the present invention is homogeneously dispersed therein by stirring or other means. The melted homogeneous mixture is then poured into a mold of a suitable size and cooled to solidify.

[0154] Liquid formulations include liquids, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid formulations can be formulated as a solution of polyethylene glycol aqueous solution.

[0155] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely ground compounds in water containing viscous materials such as natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth rubber, and acacia rubber, as well as dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose, aspartame, or saccharin. The formulation can be adjusted to suit the osmotic pressure.

[0156] The invention also includes solid formulations intended to be converted into liquid formulations for oral administration immediately before use. Such liquid forms include liquids, suspensions, and emulsions. These formulations may contain, in addition to the compounds of the present invention, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0157] The oily suspension can be formulated by suspending the compound of the present invention in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. The oily suspension can contain a thickener such as beeswax, solid paraffin or cetyl alcohol. A sweetening agent such as glycerol, sorbitol or sucrose can be added to provide an orally palatable formulation. These formulations can be preserved by adding an antioxidant such as ascorbic acid. For an example of an oil vehicle for injection, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulation of the present invention may be in the form of an oil-in-water emulsion. The oil phase can be the above vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum acacia and tragacanth gum, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monoleate, and condensation products of these partial esters and ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion can also contain a sweetening agent and a flavoring agent, such as in the formulations of syrup and elixir. Such formulations can also contain a lubricant, a preservative or a coloring agent.

[0158] The following are representative pharmaceutical compositions containing the compound of the present invention (i.e., the active ingredient). For example, the active ingredient can be a compound of formula (VII) or formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the active ingredient is of the formula:

Chemical formula

[0159] Mix the components in Table 1 completely and table them into single-score tablets.

Table 1

[0160] The ingredients listed in Table 2 are thoroughly mixed and filled into hard-shell gelatin capsules. [Table 2]

[0161] The components listed in Table 3 are mixed to form a suspension for oral administration. [Table 3]

[0162] The components listed in Table 4 are mixed to form an injectable preparation. [Table 4]

[0163] Mix the ingredients in Table 5 to form a suppository with a total weight of, for example, 2.5 g. Witepsol® H-15 is a mixture of saturated vegetable fatty acid triglycerides and is commercially available (e.g., Riches-Nelson, Inc., New York). [Table 5]

[0164] The therapeutically effective dose and frequency (single or multiple doses) of the compounds described herein administered to mammals may vary depending on various factors, such as whether the mammal has another condition or disease; the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and severity of the symptoms of the disease being treated, the type of concomitant treatment, complications from the disease being treated, or other health-related problems. Other therapeutic regimens or agents may be used in combination with the methods and compounds of the present invention. Adjustments and manipulations of established doses (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

[0165] For any of the compounds described herein, a therapeutically effective dose can be initially determined from a cell culture assay. The target concentration is the concentration of the active compound(s) capable of achieving the method described herein, measured using the method described herein or a method known in the art.

[0166] As is well known in the art, therapeutically effective doses for human use can also be determined from animal models. For example, human doses can be formulated to achieve concentrations known to be effective in animals. As described above, human doses can be adjusted by monitoring the efficacy of the compound and adjusting the dosage up or down. Adjusting the dose to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0167] The dosage may vary depending on the patient and the requirements of the compound used. In the context of the present invention, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response over time. In some embodiments, the dose of the compound administered to the patient may be effective or sufficient to increase the dendritic spine density of the patient's neurons. In some embodiments, the dose of the compound administered to the patient may be effective or sufficient to reduce the neurotoxicity of β-amyloid peptide to the patient's neurons. In some embodiments, the dose of the compound administered to the patient may be effective or sufficient to alleviate the symptoms of traumatic brain injury in the patient. The size of the dose can be determined by the presence, nature, and degree of any adverse side effects. Determining the appropriate dosage for a particular situation is a matter of the practitioner's skill. This is within the range of effectiveness. Generally, treatment is initiated with a dose lower than the optimal dose of the compound. The dose is then gradually increased until the optimal effect is achieved under the given circumstances.

[0168] Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that causes substantially no toxicity and is effective in treating clinical symptoms demonstrated by a particular patient. This plan may include the careful selection of an active compound by considering factors such as the potency of the compound, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent. V. Treatment Methods Increase in dendritic spine density and reduction of neurotoxicity of β-amyloid peptide

[0169] In some embodiments, the present invention provides a method of increasing the dendritic spine density of a neuron, the method comprising contacting the neuron with a therapeutically effective amount of a compound of the present invention (i.e., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII and / or Formula VIIa) under conditions sufficient to increase the dendritic spine density of the neuron. In some embodiments, the present invention provides a method of increasing the dendritic spine density of a neuron, the method comprising contacting the neuron with a therapeutically effective amount of a compound of Formula VII and / or Formula VIIa, or a pharmaceutical composition thereof.

[0170] In one embodiment, the method of increasing the dendritic spine density of a neuron is performed after a traumatic brain injury that exposes the patient to the risk of cognitive loss (short-term or long-term). Such brain injuries include traumatic brain injuries well known in the art, as well as other repetitive brain injuries (e.g., repeated concussions, transient ischemic events, etc.) that are similar to traumatic brain injuries in that their cumulative effects expose the patient to the risk of cognitive loss. Methods for diagnosing a patient having a traumatic brain injury, methods for treating a traumatic brain injury using the compounds and compositions of the present invention, and methods for measuring the effectiveness of such treatment are described in further detail below.

[0171] Dendritic spines are recognized as acting as learning sites for memory in the brain. Song et al., "A tetra(ethylene glycol) derivative of benzothiazole aniline amerliorates dendritic spine density and cognitive function in a mouse model of Alzheimer's disease," Exp. Neuro., 252:105-113 (2014), which is incorporated herein by reference in its entirety. Furthermore, the art has shown that the binding of small molecules to β-amyloid inhibits the formation of oligomers such as neurotoxic β-sheets. Moreover, it is recognized that spine density loss occurs in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, the method of the present invention provides a means to counteract these losses and thus alleviate the symptoms of such diseases.

[0172] In another embodiment, the present invention provides a method for reducing the neurotoxicity of β-amyloid peptide to neurons, comprising the step of contacting β-amyloid peptide with a therapeutically effective amount of the compound of the present invention (i.e., a compound of formula I, formula IA, formula II, formula III, formula IV, formula V, formula VI, formula VII and / or formula VIIa) under conditions sufficient to reduce the neurotoxicity of β-amyloid peptide. In some embodiments, the present invention provides a method for reducing the neurotoxicity of β-amyloid peptide to neurons, comprising the step of contacting β-amyloid peptide with a therapeutically effective amount of a compound of formula VII and / or formula VIIa, or a pharmaceutical composition thereof. In some embodiments, The neurons are human neurons. In some embodiments, the compounds of the present invention are suitable for treating β-amyloid-mediated diseases, which are provided in detail above.

[0173] The compounds described herein can be administered in any appropriate dose in methods for increasing dendritic spine density and / or reducing β-amyloid peptide neurotoxicity. Generally, the compounds are administered in doses ranging from about 0.01 milligrams to about 1000 milligrams per kilogram of body weight of the subject (i.e., about 0.01 to 1000 mg / kg). The dose of the compounds may be, for example, about 0.01 to 1000 mg / kg, or about 0.1 to 1000 mg / kg, or about 1 to 500 mg / kg, or about 25 to 250 mg / kg, or about 50 to 100 mg / kg. The dosage of the compound may be approximately 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg / kg. The dosage can be varied depending on the patient's requirements, the severity of the disorder being treated, and the specific formulation being administered. The dose administered to a patient should be sufficient to produce a beneficial therapeutic response. The size of the dose will also be determined by the presence, nature, and extent of any adverse side effects associated with the administration of the drug to a particular patient. Determining the appropriate dosage for a particular situation is within the scope of a typical practicing physician's skills. The total dose can be divided and administered in smaller doses over a period of time suitable for treating the disease or condition.

[0174] The compound may be administered over a period of time that varies depending on the nature of the specific disorder (i.e., low dendritic spine density, β-amyloid peptide neurotoxicity), its severity, and the overall condition of the subject to which the compound is administered. Administration may be twice daily, including every hour, every two hours, every three hours, every four hours, every six hours, every eight hours, or every twelve hours, or at any intervening interval. Administration may be once daily, or once every 36 or 48 hours, or once every month or every few months. After treatment, the subject may be monitored for changes in condition and relief of disorder symptoms. If the subject does not respond significantly to a particular dose level, the dose of the compound may be increased; or, if relief of disorder symptoms is observed, or the disorder is relieved, or if unacceptable side effects occur at a particular dose, the dose may be decreased.

[0175] A therapeutically effective amount of the compound of the present invention may be administered to a subject in a treatment regimen that includes intervals of at least 1 hour, 6 hours, 12 hours, 24 hours, 36 hours, or 48 hours between administrations. Administrations may be carried out at intervals of at least 72, 96, 120, 144, 168, 192, 216, or 240 hours (i.e., 3, 4, 5, 6, 7, 8, 9, or 10 days). In certain embodiments, one or more administrations of the compound of the present invention are carried out in a chronic manner over a period of several months to several years. Accordingly, some embodiments of the present invention provide a method for treating a disease or condition associated with low dendritic spine density or large amounts of neurotoxic β-amyloid peptide as described herein (i.e., a disorder associated with traumatic brain injury), wherein the compound is administered to the subject for at least one year. In some embodiments, the compound is administered to the subject for at least 10 years. In some embodiments, the compound is administered to the subject for at least 60 years.

[0176] Assays for determining the effect of candidate compounds on dendritic spine elongation are, together, incorporated herein by reference in their entirety by Lee et al., "Hexa(ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1-Ras dependent pathway." This has been shown in Biochimica et Biophysica Acta, 1862(2016):284-295 and Megill et al., "Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis", Journal of Neurosciences, 33(22)9306-9318(2013).

[0177] These protocols illustrate known methods for testing such candidate compounds and provide dendritic spine extension. Furthermore, the compounds described herein are also useful for enhancing cognitive function. Protocols for evaluating such activity are incorporated herein by reference in their entirety by Song et al., "A tetra(ethylene glycol) derivative of benzothiazole aniline ameliorates dendritic spine density and cognitive function in a mouse model of Provided by “Alzheimer’s disease” Exp. Neuro., 252:105-113 (2014).

[0178] Furthermore, in mammalian systems, facin, an actin bundling protein (approximately 55 kD), enhances cell motility in several human malignancies. (Hwang et al., Neoplasia, 2008(10)2:149-159). In fact, facin has been shown to downregulate the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). Moreover, facin upregulates NF-κB activity, which is essential for metastasis. Importantly, facin upregulates urokinase-type plasminogen activator (uPA) and other proteins known to be important for metastasis execution, such as matrix metalloproteinases (MMP)-2 and MMP-9. (Al-Awan et al., PLoS) One.2011;6(11):e27339.doi:10.1371 / journal.pone.0027339.Epub November 4, 2011.

[0179] The compounds of the present invention are designed to bind to fascin, thereby mitigating its activity and thus reducing tumor metastasis. Therefore, the compounds of the present invention are useful for mitigating tumor metastasis. In this method, the compounds are administered in the above effective amounts, preferably as a pharmaceutical composition. In normal adult tissue, fascin is expressed in neurons and dendritic cells. This suggests a neurological role for fascin. Since the compounds described herein bind to fascin, such binding may play an important role in understanding such neurological roles and how binding modulates these roles.

[0180] Accordingly, in one embodiment, a method is provided for modulating the activity of fascin by complexing fascin with a compound of the present invention. In a further embodiment, such modification includes mitigating the transfer properties of fascin. In yet another further embodiment, such modification includes upcontrolling or downcontrolling the neurological properties of fascin. Furthermore, in yet another embodiment, a complex of fascin with one or more molecules of formulas I, IA, II, III, IV, V, VI, VII and / or VIIa described herein is provided. Such complexes are thought to include any suitable binding interactions, such as ionic interactions, hydrophilic / hydrophobic interactions and, if possible, covalent bonds. Methods to alleviate TBI symptoms

[0181] In some embodiments, the present invention provides a method for alleviating the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury by administering a therapeutically effective amount of the compound of the present invention (i.e., a compound of formula I, formula IA, formula II, formula III, formula IV, formula V, formula VI, formula VII and / or formula VIIa) or a pharmaceutically acceptable salt or solvate thereof. The present invention provides a method for alleviating symptoms of traumatic brain injury in a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, that is sufficient to alleviate the symptoms of traumatic brain injury. In some embodiments, the present invention provides a method for alleviating symptoms of traumatic brain injury in a patient, comprising the step of administering a therapeutically effective amount of a compound of formula VII and / or formula VIIa, or a pharmaceutical composition thereof.

[0182] Traumatic brain injury (TBI) can occur as a result of head trauma. Head trauma may include any of the following: a nearby explosion or penetrating head injury, and / or impact to the head, blow to the head, head shake, sudden acceleration, sudden deceleration, sudden twisting of the head, or compression of the brain, as a result of any kind of force applied to the head that disrupts the normal function of the brain. In some embodiments of the present invention, TBI may be a result of head trauma, which may be caused, for example, by blunt force trauma to the head or a blow to the head.

[0183] In some embodiments of the present invention, the traumatic brain injury may be mild, moderate, or severe. In other embodiments, the TBI may be mild TBI (mTBI). In some embodiments, the mildest form of TBI (mTBI) may also be called a concussion and is characterized by a temporary loss of brain function. For example, a concussion patient may temporarily lose consciousness for several seconds to 30 minutes. When evaluating whether a patient should receive treatment for traumatic brain injury (i.e., treatment to alleviate the symptoms of traumatic brain injury), it is necessary to confirm whether the patient has acquired traumatic brain injury. Several methods and assessments that can be used to diagnostically determine the initial and subsequent levels of neurological damage in TBI patients are described herein.

[0184] In some embodiments of the present invention, a patient who has experienced a head injury may be diagnosed with mTBI by observing the patient and subsequently recognizing that the patient is experiencing symptoms of traumatic brain injury. For example, a patient with a head injury may be diagnosed with mTBI if the patient experiences one or more of the following conditions: (1) contusions, disorientation, or impaired consciousness, memory impairment, or loss of consciousness lasting less than 30 minutes, observed or self-reported at the time of the injury; and (2) symptoms immediately following the injury, such as headache, dizziness, fatigue, irritability, memory impairment, and difficulty concentrating.

[0185] In another embodiment of the present invention, a patient with a head injury may be diagnosed with TBI by assessing the severity of the head injury using a test or combination of tests. For example, a patient can be diagnosed with TBI by using the Glasgow Coma Scale (GCS). The GCS is an assessment that can measure and score eye-opening, speech, and motor responses in a patient who has experienced a head injury. The GCS score is the sum of the scores for each response measured. The GCS score may increase or decrease over time. The general definitions of the scores are severe (3-8), moderate (9-12), and mild (13-15). The GCS can be administered to assess the responses of a patient who has experienced a severe traumatic brain injury (i.e., an unconscious patient). The Glasgow Coma Scale is a commonly used method for diagnosing traumatic brain injury in a patient and is known to those skilled in the art (http: / / www.glasgowcomascale.org).

[0186] In some embodiments of the present invention, a patient with a head injury may be diagnosed with TBI using the Rivermead Post-Concussion Questionnaire (RPQ). The RPQ is useful for determining the severity of several symptoms and functional impairments in a patient who is recognized as having a concussion (mTBI). The patient may be asked to assess the severity of the symptoms they are experiencing. Symptoms assessed using the RPQ include: headache, dizziness, nausea and / or vomiting, hyperacusis, sleep disturbance, fatigue, blurred vision, diplopia, photosensitivity, restlessness, irritability, and cravings. Dissatisfaction, depression, memory loss, difficulty concentrating, and prolonged thinking are all possible symptoms. These symptoms can be assessed within 24 hours of the patient experiencing the head injury. The RPQ is a commonly used method for diagnosing traumatic brain injury in patients and is well known to those skilled in the art (King, N.; Crawford, S.; Wenden, F.; Moss, N.; and Wade, D. (1995) Journal of Neurology 242:587-592).

[0187] Other tests used to diagnose patients with TBI include the Military Acute Concussion Assessment (MACE) (Kennedy, CH; Moore, J., Literary Neuropsychology (2010)); the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) (https: / / www.impacttest.com); the Sports Concussion Assessment Tool (SCAT) (http: / / physicians.cattonline.com / scat / ); the Automated Neuropsychological Assessment Scale (ANAM) (Archives of Clinical Neuropsychology (2007), 22, Appendix 1, S1-S144); and Cogstate (https: / / cogstate.com). The assessments described herein are commonly used methods for diagnosing patients with TBI and are known to those skilled in the art.

[0188] A patient can be diagnosed with traumatic brain injury by monitoring the levels of specific biomarkers in their blood. Specifically, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are biomarkers that can be measured at multiple time points in patients with mild to moderate TBI (i.e., GCS 9-15). Blood tests measuring the levels of GFAP and UCH-L1 in a patient at multiple time points indicate whether TBI has occurred. For example, both GFAP and UCH-L1 levels rise immediately after TBI but then decrease to considerably lower levels within a week. Methods for diagnosing TBI using biomarkers are known to those skilled in the art (Papa, L. JAMA Neurol. (2016) 73(5), 551-560).

[0189] In some cases, neuroimaging techniques such as computed tomography (CAT or CT) and magnetic resonance imaging (MRI) can be used to diagnose traumatic brain injury in patients. CT and MRI scans can be used to determine the severity of brain injury. For example, while CT and MRI scans may be commonly used in hospitals to identify brain injury, they are often not useful in detecting mTBI where there is no apparent brain damage. In some embodiments, patients with mTBI accompanied by normal CT or MRI scans can be distinguished from patients with moderate TBI accompanied by intracerebral hemorrhage and abnormal CT or MRI scans. CT scans can be performed within the first 24 hours of brain injury and may be useful in detecting osteopathology and certain early cerebral hemorrhages. MRI scans are considered more useful when performed 48–72 hours after brain injury and may be useful for hemorrhagic cortical contusions, petechiae, axonal damage, and minor nerve damage. Generally, neuroimaging techniques may be most useful in patients who have experienced moderate to severe traumatic brain injury. Methods for diagnosing TBI using neuroimaging techniques are known to those skilled in the art (Lee, B. NeuroRX. (2005) 2(2), 372-383; International Application No. PCT / US2015 / 024739).

[0190] In some embodiments of the present invention, a patient may be diagnosed with traumatic brain injury by either the above method or any method known in the art, or any combination thereof. In other embodiments, a patient with head trauma may be diagnosed with TBI in addition to undergoing an assessment such as GCS or RPQ. TBI is diagnosed by observation and recognition of symptoms. In other embodiments, a patient with a head injury is diagnosed with TBI by observation and recognition of TBI symptoms, in addition to monitoring of biomarkers. In other embodiments, a patient with a head injury is diagnosed with TBI using multiple assessments such as GCS, RPQ, and MACE. In other embodiments, a patient with a head injury is diagnosed with TBI using neuroimaging techniques, in addition to monitoring of biomarkers and performing assessments such as GCS or RPQ. In other embodiments, a patient with a head injury is diagnosed with TBI using neuroimaging techniques, in addition to monitoring of biomarkers. In other embodiments, a patient with a head injury is diagnosed with TBI using neuroimaging techniques, in addition to performing assessments such as GCS or RPQ. In some other embodiments, a patient with a head injury is diagnosed with TBI using neuroimaging techniques such as MRI and CT scans. In some embodiments, a patient with a head injury is diagnosed with TBI by monitoring levels of biomarkers. In other embodiments, a patient with a head injury is diagnosed with TBI by observation and recognition of TBI symptoms. In other embodiments, a patient with a head injury is diagnosed with TBI using one assessment, such as the GCS or RPQ. In some embodiments, a patient with a head injury is diagnosed with TBI using the RPQ assessment.

[0191] In further embodiments of the present invention, a patient with a head injury is diagnosed with TBI immediately after the head injury, i.e., within 0 hours of the head injury, using any of the methods and evaluations described herein. In some embodiments, a patient with a head injury is diagnosed with TBI within approximately 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 4 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours of the head injury. In some embodiments, a patient with a head injury is diagnosed with TBI within approximately 0 to 48 hours of the head injury, or within approximately 5 minutes to 42 hours, or 10 minutes to 36 hours, or 15 minutes to 30 hours, or 20 minutes to 24 hours, or 30 minutes to 18 hours, or 45 minutes to 12 hours, or 1 to 4 hours of the head injury. In some embodiments, a patient with a head injury is diagnosed with TBI within approximately 0 to 1 hour of the head injury. In other embodiments, a patient with a head injury is diagnosed with TBI within approximately 30 minutes of the head injury.

[0192] In some cases, patients diagnosed with concussion / mTBI and more severe TBI may experience neurological effects caused by changes in neurochemical levels and subsequent neuronal damage. These neurological effects can last for days, weeks, months, or even years. These neurological effects can result in deficits in the following functional domains: physical, visual, auditory, neurobehavioral, cognitive communication, and sleep. Deficits in the physical domain may trigger any of the following symptoms: nausea, vomiting, dizziness, headache, seizures, altered consciousness, fatigue, muscle weakness, balance problems, and / or coordination problems. Deficits in the visual domain may trigger any of the following symptoms: photosensitivity, diplopia, decreased visual acuity, visual neglect, and / or altered pupillary near reflex. Deficits in the auditory domain may trigger any of the following symptoms: hyperacusis, tinnitus, hearing loss, and / or central auditory dysfunction. Deficiencies in the neurobehavioral domain may induce any of the following symptoms: agitation, anxiety, depression, mood swings, restlessness, disorientation, impulsivity, irritability, frustration, and / or stress disorder. Deficiencies in the cognitive communication domain may induce any of the following symptoms: attention deficit, executive function deficit, information processing disorder, memory impairment, learning disability, metacognitive impairment, spatial cognition impairment, aphasia, and / or motor language disorder. Deficiencies in the sleep domain may induce any of the following symptoms: insomnia, hypersomnia, and / or sleep disorders.

[0193] In some embodiments, patients diagnosed with TBI may have a deficiency in one or more functional domains. Patients diagnosed with TBI having a deficiency in one or more functional domains may receive a therapeutically effective amount of the compounds of the present invention (i.e., Formula I, Formula IA, Formula II, A patient may receive a therapeutically effective dose of a compound of formula III, formula IV, formula V, formula VI, formula VII and / or formula VIIa. In some embodiments, a patient diagnosed with TBI having a deficiency of one or more functional domains may receive a therapeutically effective dose of a compound of formula VII and / or formula VIIa, or a pharmaceutical composition thereof. For example, a patient diagnosed with TBI having a deficiency of one or more functional domains may receive a therapeutically effective dose of formula: [ka] Compounds thereof, or pharmaceutically acceptable salts or solvates thereof, or combinations thereof may be received.

[0194] Dosage and intervals can be individually adjusted to provide levels of the compound effective for the specific clinical indication being treated. This will provide a treatment regimen that is commensurate with the severity of traumatic brain injury and the patient's condition.

[0195] In some embodiments, suitable dose ranges of the activator (i.e., the compounds described herein) include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1,000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable doses of the activator include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1200 mg.

[0196] In some embodiments, the dosage of the orally administered pharmaceutical composition of the compound described herein may be about 0.1 mg / kg body weight per patient, or 0.5, 1, 5, 10, 25, 50, 100, 250, 500, 750, or 1000 mg / kg body weight per patient. In other embodiments, the dosage of the orally administered pharmaceutical composition of the compound described herein may be about 0.1 to 1000 mg / kg body weight per patient, or about 0.5 to 750, or about 1 to 500, or about 5 to 250, or about 10 to 100, or about 25 to 50 mg / kg body weight per patient. In yet another embodiment, the dosage may be about 0.5 to about 25 mg / kg body weight per patient, or about 5 to 15 mg / kg body weight per patient, or about 8 to about 12 mg / kg body weight per patient, or about 10 mg / kg body weight per patient. In particular, when administering drugs to anatomically isolated sites such as the cerebrospinal fluid (CSF) space, lower doses can be used, in contrast to administration orally, into the bloodstream, body cavities, or organ lumens. Practical methods for preparing parenterally administered compound formulations are known or obvious to those skilled in the art and are described in detail in publications such as Remington's mentioned above. See also Nieman, "Receptor-Mediated Antisteroid Action," in Agarwal et al. (eds.), De Gruyter, New York, 1987.

[0197] The activator can be present in the composition of the present invention in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). The activator can be present in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w).

[0198] In certain embodiments of the present invention, a patient diagnosed with TBI may be administered a therapeutically effective amount of the compound (including its embodiments, examples, and / or pharmaceutical compositions) immediately after TBI, i.e., within 0 hours of TBI, at the above-mentioned dosage. In some embodiments, a therapeutically effective amount of the compound can be administered to a patient with TBI within approximately 10 minutes of receiving the TBI, or within approximately 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, or 72 hours of receiving the TBI. In some embodiments, a therapeutically effective amount of the compound can be administered to a patient with TBI within approximately 0 to 72 hours of receiving the TBI, or within approximately 10 minutes to 48 hours, or within approximately 20 minutes to 36 hours, or within approximately 30 minutes to 30 hours, or within approximately 45 minutes to 24 hours, or within approximately 1 to 18 hours, or within approximately 2 to 12 hours, or within approximately 4 to 7 hours. In certain other embodiments of the present invention, a therapeutically effective amount of the compound can be administered to a patient with TBI within approximately 0 to 24 hours of receiving the TBI. In another embodiment of the present invention, a therapeutically effective amount of the compound can be administered to a patient with TBI within approximately 18 hours of receiving the TBI. In yet another embodiment of the present invention, a therapeutically effective amount of the compound can be administered to a patient with TBI within 18 hours or less of receiving the TBI. In certain embodiments of the present invention, a therapeutically effective amount of the compound can be administered to a patient with TBI within 4 hours of receiving the TBI. In some other certain embodiments of the present invention, a therapeutically effective amount of the compound can be administered to a patient with TBI within 1 hour of receiving the TBI.

[0199] In some embodiments of the present invention, a patient having TBI may be administered a therapeutically effective amount of the compound (including its embodiments, examples, and / or pharmaceutical compositions) in the above-mentioned dosage at least once every 30 minutes, or every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, or 24 hours. In other embodiments, a patient having TBI may be administered a pharmaceutical composition of the compound in a certain dose once every 30 minutes to 24 hours, or at least once every 1 hour to 18 hours, or at least once every 2 to 12 hours, or at least once every 3 to 8 hours, or at least once every 4 to 6 hours.

[0200] In some embodiments of the present invention, a patient with TBI can receive the above treatment regimen (i.e., a therapeutically effective dose and frequency of administration of the compound of formula (VII) or formula (VIIa)) for any appropriate length of time. In other embodiments, a patient with TBI can receive the treatment regimen for about 1 day, or 2, 3, 5, 7, 10, 14, 20, 25, 30, 35, 45, 60, or about 90 days. In some embodiments, a patient with TBI can receive the treatment regimen for about 1 to about 90 days, or about 2 to about 60 days, or about 3 to about 45 days, or about 5 to about 35 days, or about 7 to about 30 days, or about 10 to about 25 days, or about 14 to about 20 days. In yet another embodiment, a patient with TBI can receive the treatment regimen for about 35 days. VI. Measuring the effectiveness of TBI treatment

[0201] Patients diagnosed with traumatic brain injury (i.e., those receiving therapeutically effective doses of the compound) who have received treatment to alleviate the symptoms of traumatic brain injury as described above are periodically evaluated throughout the patient's treatment regimen to determine the effectiveness of the treatment. Patients receiving therapeutically effective doses of the compound can be evaluated for improvements in performance in one or more functional domains (i.e., physical, visual, auditory, neurobehavioral, cognitive communication, and sleep). In some embodiments, patients being treated for TBI can be evaluated for improvements in one or more functional domains using any one or any combination of methods used to diagnose patients with TBI (as described herein or known in the art). For example, TBI patients receiving the above treatment regimen can be evaluated for improvements in one or more functional domains by monitoring the levels of GFAP and UCH-L1 biomarkers in the patient's blood, and / or by using any of the following evaluations. The following can be used for evaluation: GCS, RPQ, MACE, ImPACT, SCAT, ANAM, and / or Cogstate. In some embodiments of the present invention, TBI patients receiving a treatment regimen can be evaluated for improvement in one or more functional domains using GCS, RPQ, and / or MACE. In other embodiments of the present invention, TBI patients receiving a treatment regimen can be evaluated for improvement in one or more functional domains using GCS and RPQ. In certain embodiments of the present invention, TBI patients receiving a treatment regimen can be evaluated for improvement in one or more functional domains using RPQ.

[0202] In certain embodiments of the present invention, a TBI patient undergoing treatment can be evaluated for improvement in the performance of one or more functional domains at any appropriate number of times during the duration of the TBI treatment regimen. In some embodiments of the present invention, a TBI patient undergoing treatment can be evaluated for improvement in the performance of one or more functional domains at least once per treatment regimen, or about two, three, six, twelve, fifteen, eighteen, 20, 25, 30, forty, fifty, sixty, eighty, 100, or fifteen times per treatment regimen. In other embodiments of the present invention, a TBI patient undergoing treatment can be evaluated for improvement in the performance of one or more functional domains approximately 1 to 150 times per treatment regimen, or approximately 2 to 100 times, or approximately 3 to 80 times, or approximately 6 to 60 times, or approximately 12 to 50 times, or approximately 15 to 40 times, or approximately 18 to 30 times, or approximately 20 to 25 times. In certain embodiments, a TBI patient undergoing treatment can be evaluated for improvement in the performance of one or more functional domains approximately 3 to 80 times per treatment regimen. For example, a TBI patient undergoing a treatment regimen of approximately 35 days can be evaluated for improvement in the performance of one or more functional domains 3 to 80 times at any point during the 35-day period of the treatment regimen.

[0203] In embodiments of the present invention, the reduction of symptoms of traumatic brain injury in TBI patients can be observed as an improvement in the performance of one or more functional domains in TBI patients. Alternatively, an improvement in the performance of one or more functional domains in TBI patients can be observed as a reduction of symptoms of traumatic brain injury in TBI patients.

[0204] After treatment for TBI, the measured performance of one or more functional domains in a patient improves by a certain percentage (%) compared to the performance of one or more functional domains measured before treatment but after injury. In some embodiments of the present invention, the performance of one or more functional domains may improve by at least 1% compared to the performance of one or more functional domains measured before treatment but after injury, or by at least 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, or 80% compared to the performance of one or more functional domains measured before treatment but after injury. In other embodiments, the measured performance of one or more functional domains in a patient may improve by at least 1% to 80% compared to the performance of one or more functional domains measured before treatment but after injury, or by at least 1% to 80%, at least 5% to 70%, at least 10% to 60%, at least 15% to 50%, at least 20% to 40%, or at least 25% to 35% compared to the performance of one or more functional domains measured before treatment but after injury. In certain embodiments, the performance of one or more functional domains may improve by at least 20% to 30% compared to the performance of one or more functional domains measured before treatment but after injury.

[0205] In some embodiments of the present invention, the performance of one or more functional domains can be improved within any appropriate treatment time. In other embodiments, one or more functional domains The main performance may improve within approximately 24 hours of treatment, or within approximately 48 hours, 72 hours, 5 days, 7 days, 14 days, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, or 20 weeks of treatment. In some embodiments of the present invention, the performance of one or more functional domains may improve within approximately 24 hours to approximately 20 weeks of treatment, or within approximately 48 hours to approximately 16 weeks, or within approximately 72 hours to approximately 12 weeks, or within approximately 5 days to approximately 8 weeks, or within approximately 7 days to approximately 6 weeks, or within approximately 14 days to approximately 4 weeks. In certain embodiments, the performance of one or more functional domains may improve within approximately 7 days to approximately 4 weeks of treatment. In other specific embodiments, the performance of one or more functional domains may improve within approximately 7 days of treatment. [Examples]

[0206] VII. Examples The following examples are provided for illustrative purposes only and are not intended to limit the claimed invention. Example 1. Synthesis of 2-(2-(2-(2-(4-(benzo[d]thiazole-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethane-1-ol (3, "benzothiazole-IIIB") Scheme 4 [ka]

[0207] Step A.): Preparation of 4-(benzo[d]thiazole-2-yl)phenol(1). All reagents were obtained from Sigma Aldrich and used as is. Scandium triflate (Sc(OTf)3, 1 g, 2 mmol), 2-aminobenzenethiol (1.2, 3.6 g, 28.8 mmol), and 4-hydroxybenzaldehyde (1.1, 3.6 g, 29.5 mmol) were added to 40 mL of a 1:1 ethanol / water solvent mixture. The reaction mixture was stirred overnight in an open flask at 50°C. After the oxidation reaction was complete, the reaction product was cooled to room temperature (rt) and filtered. The isolated solid was washed with ether and dried to obtain 4-(benzo[d]thiazole-2-yl)phenol(1) in 70-80% yield.

[0208] Step B.): Preparation of tetraethylene glycol p-toluenesulfonate (2). All reagents were obtained from Sigma Aldrich and used as is. To 100 mL of tetraethylene glycol (2.2, 3.88 g, 20 mmol) in dichloromethane, tosyl chloride (2.1, 3.8 g, 20 mmol) was added. The reaction mixture was then cooled to -78°C, and triethylamine (2.01 g, 20 mM) was slowly added dropwise. Further addition was made and the mixture was stirred overnight. The reaction mixture was slowly heated in rt, washed with 1 L of water, and dried to obtain the crude product. After purification using an ISCO CombiFlash® 80 g silica cartridge and 0-100% ethyl acetate / hexane, pure tetraethylene glycol p-toluenesulfonate (2) was isolated in 40-50% yield.

[0209] Step C.): Preparation of 2-(2-(2-(2-(4-(benzo[d]thiazole-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (3). All reagents were obtained from Sigma Aldrich and used as is. To a 30 mL solution of 1 (2.27 g, 10 mmol) in DMF, cesium carbonate (3.26 g, 10 mmol) and 2 (4.05 g, 11.6 mmol) were added. The reaction mixture was stirred overnight at 60°C. The reaction mixture was then cooled to rt, washed with 1 L of a 1:1 water / ethyl acetate solvent mixture, dried, and the crude product was obtained. Using ISCO CombiFlash® and 0-100% dichloromethane / ethyl acetate, pure 2-(2-(2-(2-(4-(benzo[d]thiazole-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (3) was obtained. The pure fractions were combined, dried, washed with ether, filtered, and dried again to obtain 4 g of 3 (72% yield). Purity was determined by HPLC with 0-100% acetonitrile / water containing 1 g of ammonium acetate per liter. 1 H NMR (600MHz, DMSO-d6): δ8.15(d,1H), 8.05-8.15(m,3H), 7.6(d,1H), 7.4(d,1H), 7.1(d,2H), 4.6(m,1H), 4.25(m,2H), 3.3-3.8(m,14H). APCI(LCQ):m / z[M+H] + C 21 H 25 Calculated value for NO5S: 403.49; Measured value: 404.1. Example 2. In vitro spine formation using a benzothiazole compound.

[0210] The compounds of the present invention bind to fascin, an actin bundling protein, preventing the formation of long, rigid actin cytoskeletons, thereby promoting dendritic spine formation. (See Sedeh, RS et al. J.Mol.Biol.400, 589-604 (2010); Chen, L. et al. Nature 464, 1062-1066 (2010); Jansen, S. et al. J.Biol.Chem.286, 30087-30096 (2011); Yang, S. et al. J.Biol.Chem.288, 274-284 (2013); Zheng, S. et al. J.Med.Chem.57, 6653-6667 (2014)). To demonstrate the efficacy of the compounds of the present invention in promoting spine formation, the effects of benzothiazole compounds on synaptic puncta and synapses of mouse cortical neurons were investigated. Specifically, the benzothiazole-IIIA and benzothiazole-IIIB compounds of the present invention, as well as the benzothiazole-I compound described in International Application No. PCT / US2017 / 012139, were used in this test (Figure 1).

[0211] Primary mouse cortical neurons were treated with 5 μM benzothiazole-I, benzothiazole-IIIA, or benzothiazole-IIIB in DIV 15. As a control, primary mouse cortical neurons were treated with vehicle alone (10% DMSO, 90% phosphate-buffered saline (PBS)). After 24 hours, DIV 16 neurons were fixed, immunostained with the presynaptic vesicle protein synaptophysin (P38), counterstained with the nuclear dye DAPI (4',6-diamidino-2-phenylindole), and counted. Immunolabeled neurons were imaged with a Leica confocal microscope. The number of P38 immunopositive spots was analyzed using FIJI with the Squash plugin (Figure 2). As shown in Figure 2, benzothiazole-I, benzothiazole-IIIA, and benzothiazole-IIIB all resulted in an increase in the number of synaptic spots compared to the vehicle control.

[0212] In a similar experiment, primary mouse cortical neurons were treated with 1 μM benzothiazole-I or benzothiazole-IIIB in DIV 15, using the same DMSO / PBS buffer as the control vehicle. After 24 hours, DIV 16 neurons were fixed, immunolabeled with synaptophysin, stained with DAPI, and counted as described above. Figure 3 shows that after 24 hours, benzothiazole-I and benzothiazole-IIIB promoted approximately 100% increase in the number of synapses compared to the control. Example 3. In silicofacin binding of a benzothiazole compound.

[0213] In silico studies were performed using benzothiazole compounds and available human facin 1 crystal structures to evaluate the ability of benzothiazole compounds to bind to facin and thereby inhibit the formation of bundled actin fibrils. Binding sites were identified on the surface of each facin crystal structure, and subsequently, virtual docking of benzothiazole-I, benzothiazole-II, benzothiazole-IIIA, and benzothiazole-IIIB (Figure 1) within each pocket was performed to determine the preferred binding conformation. Analysis and preparation of fascin crystal structure

[0214] All available Fascin crystal structures were downloaded from the PDB and prepared for structural analysis (see Sedeh, RS et al. J.Mol.Biol.400, 589-604 (2010); Chen, L. et al. Nature 464, 1062-1066 (2010); Jansen, S. et al. J.Biol.Chem.286, 30087-30096 (2011); Yang, S. et al. J.Biol.Chem.288, 274-284 (2013)). Structures were analyzed visually and using standard automated protocols incorporated into MolSoft's ICM-Pro software. Hydrogen atoms were added to the structures, and consideration was given to the correct orientation of Asn and Gln side chains, ligand and protein charges, histidine orientation and protonation state, and any crystallographic quality flags such as high b-factor or low occupancy. Pocket identification

[0215] Using MolSoft's ICMPocketFinder algorithm, potential ligand-binding pockets and cavities were identified within all available Fascin crystal structures (see An, J. et al. Genome Inform. Int Conf. Genome Inform. 15, 31-41 (2004); Kufareva, I. et al. Nucleic Acids Res. 40, D535-540 (2012)). Initially, the pockets of the active chain A in crystal structure 3LLP were searched because this structure offered the best resolution (1.8 Å). Four “drug-like” pockets were identified as having properties suitable for small molecule binding (Figure 4). Ligand docking and scoring

[0216] The head groups and head+tails of benzothiazole-I, benzothiazole-II, and benzothiazole-IIIA were docked to each of the four pockets shown in Figure 4 using MolSoft's ICM-Docking software, version 3.8-6a (Abagyan, R. & Totrov, MJMol. Biol. 235, 983-1002 (1994)). The docking scores for each pocket are shown in Table 6. A lower docking score indicates a better "compound-fasin binding pocket" interaction. [Table 6]

[0217] Pocket B, located at actin-binding site 1, yielded the lowest docking score in almost all cases, with one exception being benzothiazole-I (head) with a docking score of -25 in pocket D. Binding pocket B was further investigated in other Fascin crystal structures. It was noted that pocket B was close to the pentaethylene glycol binding site of PDB 3P53. Docking the head group to pocket B of PDB 3P53 resulted in significantly better docking scores using the head group of each benzothiazole compound (Table 7). Then, as shown in Figure 8, the tail group was docked using the docked head group as an anchor point to ultimately generate energetically favorable compound poses. [Table 7]

[0218] All three compounds, benzothiazole-I, benzothiazole-II, and benzothiazole-IIIA, form a hydrogen bond from the nitrogen of the benzothiazole ring to ARG 389, and the first ethylene glycol forms a hydrogen bond with LYS 460. These interactions are shown in Figure 9, using benzothiazole-I as an example.

[0219] In a similar docking experiment, when the head-tail group of benzothiazole-IIIB (Figure 1) was docked to binding pocket B, the docking score was -41. Based on this docking score of benzothiazole-IIIB, and considering the above findings, additional docking tests were conducted using structural modifications of benzothiazole-IIIB within pocket B of Fascin. The docking scores for each modified benzothiazole-IIIB are shown in Table 8 below. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] Example 4. Treatment of TBI symptoms in adult males with a benzothiazole compound.

[0220] A 17-year-old male patient with no prior history of traumatic brain injury experienced disorientation, dizziness, and headache after being tackled during a football game, resulting in approximately 30 seconds of unconsciousness. Observation of the patient's symptoms suggested a possible diagnosis of TBI (traumatic brain injury). Within approximately 30 minutes of the head injury, on-site medical professionals confirmed the patient's diagnosis of moderate to mild traumatic brain injury using the Rivermead Postconcussion Questionnaire (RPQ) with a score of 32. The RPQ assessment also indicated the patient experienced photosensitivity, irritability, and aphasia. The patient was treated for traumatic brain injury.

[0221] Patients are treated with benzothiazole-IIIB, a benzothiazole compound, administered once daily in capsule form at a dose of approximately 15 mg / kg over several weeks. Therefore, a daily dose of benzothiazole-IIIB ranging from 1155 mg over approximately 14 to 35 days is used as an effective treatment for TBI.

[0222] During the course of treatment, the patient's progress is monitored by performing RPQ assessments, providing a barometer of the patient's overall improvement from treatment using the method of the present invention. RPQ assessments are performed both before administration of benzothiazole-IIIB (i.e., to diagnose the patient) and after administration of benzothiazole-IIIB. RPQ assessments are performed on days 1, 7, 14, 21, 28, and 35.

[0223] Patients will be orally administered 1155 mg of benzothiazole-IIIB once daily for 35 days. By day 7 of the treatment, patients are expected to see a decrease in their Rivermead Post-Concussion Questionnaire score from approximately 32 to approximately 24. This represents a 25% improvement in performance in one or more functional domains, particularly physical, visual, cognitive communication, and neurobehavioral domains. When the RPQ results are assessed after the 35-day period, patients will show improvement in traumatic brain injury. In fact, patients will see an improvement of approximately 30%–7% in performance in the affected domains after 35 days of treatment. A 0% improvement is expected.

[0224] This example shows how a relatively short-term dose (approximately 35 days) of a benzothiazole compound, administered once daily at a range of approximately 1155 mg per day, is expected to alleviate symptoms of traumatic brain injury in human patients.

[0225] While the above is described in some detail as examples and illustrations for clarity and understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims (e.g., substitution of equivalents for the compounds of the present invention or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures as described herein, and other kinds of modifications). Each aspect and embodiment described herein may include or incorporate variations or embodiments disclosed in relation to any or all of the other aspects and embodiments. Furthermore, each reference provided herein is incorporated by reference as collectively as each individual reference is incorporated by reference.

[0226] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds according to formula VII: [ka] [In the formula, The subscripts n and p are independently selected from 0, 1, or 2; The subscript q is an integer selected from 2 to 8; Each R 1 and R 2 [These are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.] or a pharmaceutically acceptable salt or solvate thereof. (Section 2) The subscript q is an integer selected from 3 to 6; R 1 However, it is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3, and -SO2NH2; R 2 The group is selected from halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH2)2OCH3, -CONH2, -CON(CH3)2, -CH2SO2N(CH3)2, -OCH3, -OCF3, -OCH(CH3)2, -N(CH3)2, -NHCOCH3, -NO2, -SCH3, -SO2CH3 and -SO2N(CH3)2. The compounds described in item 1 above, or their pharmaceutically acceptable salts or solvates. (Section 3) The compounds described in item 1 or 2 above, or their pharmaceutically acceptable compounds, wherein the subscripts n and p are independently selected from 0 or 1, provided that neither subscript n nor p is 1. A possible salt or solvate. (Section 4) [ka] [ka] [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof, according to any one of items 1 to 3 above. (Section 5) R 1 The group is selected from halo, -CH3, -OCH3, phenyl, and -CN; R 2 The group is selected from halo, -CH3, -CF3, -OCH3, -OCF3, -CHCH2, -CH2CHCH2, phenyl, and -NO2. A compound described in any one of items 1 to 3 above, or a pharmaceutically acceptable salt or solvate thereof. (Section 6) Formula VIIa: [ka] [In the formula, The subscript q is an integer selected from 4 or 6; R 3 , R 4 , R 5 and R 6 This is independently selected from the group consisting of hydrogen, halo, -CH3, and -OCH3; R 7 , R 8 , R 9 and R 10 It is independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; At least six of the aforementioned R groups are hydrogen atoms. The compounds described in item 1 above, or their pharmaceutically acceptable salts or solvates. (Section 7) [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof, according to any one of items 1 to 6 above. (Section 8) formula: [ka] A compound as described in item 7 above, or a pharmaceutically acceptable salt or solvate thereof, having the above. (Section 9) A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of items 1 to 8 above, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. (Section 10) The aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof, [ka] A pharmaceutical composition according to item 9 above, selected from the group consisting of the following: (Section 11) The aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof, [ka] The pharmaceutical composition described in item 10 above. (Section 12) A method for increasing the dendritic spine density of a neuron, comprising the step of contacting the neuron with a therapeutically effective amount of a compound described in any one of items 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, under conditions sufficient to increase the dendritic spine density of the neuron. (Section 13) A method for increasing the dendritic spine density of a neuron, comprising the step of contacting the neuron with a pharmaceutical composition according to any one of items 9 to 11 under conditions sufficient to increase the dendritic spine density of the neuron. (Section 14) The method described in item 12 or 13 above, wherein the method is performed after the patient has suffered traumatic brain injury. (Section 15) A method for reducing the neurotoxicity of a β-amyloid peptide to neurons, comprising the step of contacting the β-amyloid peptide with a therapeutically effective amount of a compound described in any one of the above items 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, under conditions sufficient to reduce the neurotoxicity of the β-amyloid peptide. (Section 16) A method for reducing the neurotoxicity of a β-amyloid peptide to neurons, comprising the step of contacting the β-amyloid peptide with a pharmaceutical composition according to any one of items 9 to 11 under conditions sufficient to reduce the neurotoxicity of the β-amyloid peptide. (Section 17) A method for alleviating the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury by administering a therapeutically effective amount of a compound described in any one of the above items 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof, is sufficient to alleviate the symptoms of traumatic brain injury. (Section 18) A method for alleviating the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury, by administering the pharmaceutical composition described in any one of items 9 to 11 above, under conditions sufficient to alleviate the symptoms of traumatic brain injury. (Section 19) The method according to item 17 or 18, wherein the method is performed within approximately 0 to 72 hours of the traumatic brain injury. (Section 20) The method according to paragraph 17 or 18, wherein the reduction of the aforementioned symptoms of trauma is measured by an improvement of at least 20% to 30% in the performance of one or more functional domains within approximately 7 days of treatment, compared to the performance of one or more functional domains measured before treatment but after injury.

Claims

1. A pharmaceutical composition, (i) Compounds according to formula VII: 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof [in the formula, The subscripts n and p are independently selected from 0, 1, or 2; The subscript q is an integer selected from 2 to 8; and Each R １ and R ２ [is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl and nitro]; and (ii) One or more pharmaceutically acceptable excipients Including; Here, the pharmaceutical composition is formulated for intravenous administration. Pharmaceutical composition.

2. A pharmaceutical composition according to claim 1, wherein, The subscript q is an integer selected from 3 to 6; R １ is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH ２ , -COCH ３ , -COOCH ３ , -CH ２ SO ２ NH ２ , -NHCOCH ３ , -N(CH ３ ) ２ , -SCH ３ , and -SO ２ NH ２ ; and R ２ Hello, -CH ３ ien-CH ２ CH ３ Cyclopentyl, -CF ３ , -CN, -CHCH ２ ien-CH ２ CHCH ２ phenyl, -CO ２ H, -CH ２ CO ２ H, -CH ２ CONH ２ , -COOCH ３ , -COCH ３ ,-(CH ２ ) ２ OCH ３ , -CONH ２ , -CON(CH ３ ) ２ ien-CH ２ SO ２ N(CH ３ ) ２ , -OCH ３ , -OCF ３ , -OCH(CH ３ ) ２ , -N(CH ３ ) ２ ,-NHCOCH ３ , -NO ２ , -SCH ３ , -SO ２ CH ３ , and -SO ２ N(CH ３ ) ２ Selected from the group consisting of, Pharmaceutical composition.

3. A pharmaceutical composition according to claim 1 or claim 2, wherein the subscripts n and p are independently selected from 0 or 1, provided that both subscripts n and p are not 1.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the compound according to formula VII or a pharmaceutically acceptable salt or solvate thereof is as follows: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 A pharmaceutical composition selected from the group consisting of the following.

5. A pharmaceutical composition according to any one of claims 1 to 3, wherein, R １ Hello, -CH ３ , -OCH ３ Selected from the group consisting of phenyl and -CN; and R ２ Hello, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ ien-CHCH ２ ien-CH ２ CHCH ２ phenyl and -NO ２ Selected from the group consisting of, Pharmaceutical composition.

6. A pharmaceutical composition according to claim 1, wherein the compound according to formula VII or a pharmaceutically acceptable salt or solvate thereof is a compound according to formula VIIa: 【Transformation 6】 or a pharmaceutically acceptable salt or solvate thereof [in the formula, The subscript q is an integer selected from 4 or 6; R ３ , R ４ , R ５ , and R ６ is hydrogen, halo, -CH ３ , and -OCH ３ Independently selected from the group consisting of; and R ７ , R ８ , R ９ and R １０ This is hydrogen, halo, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ phenyl, -NO ２ Independently selected from the group consisting of; Here, at least six of R3, R4, R5, R6, R7, R8, R9, and R10 are hydrogen. Pharmaceutical composition.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the compound according to VII or a pharmaceutically acceptable salt or solvate thereof is 【Transformation 7】 Selected from the group consisting of, Pharmaceutical composition.

8. A pharmaceutical composition according to claim 7, wherein the compound according to VII or a pharmaceutically acceptable salt or solvate thereof is of formula: 【Transformation 8】 A pharmaceutical composition which is a compound having [a certain property].

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition comprises a sterile aqueous solution containing one or more pharmaceutically acceptable excipients.

10. A pharmaceutical composition according to any one of claims 1 to 9, used for a method of increasing the dendritic spine density of a neuron, wherein the method comprises the step of bringing the neuron into contact with the pharmaceutical composition under conditions sufficient to increase the dendritic spine density of the neuron.

11. A pharmaceutical composition according to any one of claims 1 to 9, used for a method of reducing the neurotoxicity of a β-amyloid peptide to neurons, wherein the method comprises the step of contacting the β-amyloid peptide with the pharmaceutical composition under conditions sufficient to reduce the neurotoxicity of the β-amyloid peptide.

12. A pharmaceutical composition according to any one of claims 1 to 9, used for a method of alleviating the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury.

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