Fascin binding compounds for spinogenesis

Abstract

To provide a method for promoting spine formation in a patient, the method comprising administering to a patient in need of spine formation a therapeutically effective amount of a compound that binds to fascin at least at a binding site 2 or a binding site 3.SOLUTION: In some embodiments, a method for promoting spinogenesis or treating a neuronal disease or disorder in a patient is provided, the method comprising contacting fascin with an agent that inhibits activity of fascin. In some embodiments, a method for promoting spinogenesis in a patient is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound that binds to fascin at least at a binding site 2 or a binding site 3.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 723,381, filed August 27, 2018, No. 62 / 726,904, filed September 4, 2018, and No. 62 / 785,435, filed December 27, 2018, each of which is incorporated by reference in its entirety herein.

[0002] Provided herein are methods for promoting spine formation and for treating neuronal diseases or disorders. [Background technology]

[0003] Neurological disorders are diseases of the brain, spinal cord, and peripheral nervous system. In terms of epidemiology and human morbidity, the greatest societal costs are caused by neurodegenerative conditions, which result in damage or loss of neurons and the synaptic connections between them. The most well-known of these are Alzheimer's disease and Parkinson's disease. Other neurodegenerative conditions include age-related conditions (e.g., Parkinson's dementia, vascular dementia, amyotrophic lateral sclerosis), genetic syndromes (e.g., Down's syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic encephalopathy), as well as conditions that are usually considered purely psychiatric in nature, such as schizophrenia and depression.

[0004] Researchers have classified hundreds of diseases of the nervous system, such as brain tumors, epilepsy, Alzheimer's disease, Parkinson's disease, and stroke, as well as conditions associated with old age, such as dementia. Some such conditions result from the progressive loss of synapses (the junctions between two different neurons) and ultimately the loss of neurons (neurodegeneration). Unfortunately, neurodegenerative diseases are almost completely resistant to treatment. Neurons in the brain communicate with each other by the sending neuron releasing chemicals (neurotransmitters) into the synapse, which changes the electrical potential of the receiving neuron. The part of the neuron that releases the neurotransmitter is the axon (the presynaptic side of the synapse), and the part of the synapse that is affected by the neurotransmitter is called the dendritic spine (the postsynaptic side of the synapse). Changes in the number, location, and even shape of synaptic junctions form the basis of memory, learning, thinking, and our personality. A part of the brain called the hippocampus is intimately involved in the formation of memories and suffers a noticeable loss of synapses and neurons in neurodegenerative diseases. The development of new methods to restore hippocampal spine density may have important implications for the treatment of a host of neurodegenerative and developmental cognitive disorders.

[0005] Dendritic complexity, synaptogenesis, and proper development and function of neurons are endogenously regulated by growth factors such as brain-derived neurotrophic factor (BDNF). Although several small molecules have been reported in recent years to exhibit neurotrophin-like activity, these molecules have not been demonstrated to promote dendritic spine formation. Identification of new intracellular targets for small molecules may lead to the treatment of many neurodegenerative and psychiatric developmental disorders and may also provide improved memory and learning. Thus, small molecules that promote spine formation may be used to ameliorate cognitive impairment in neurodegenerative diseases such as Alzheimer's disease and may also find use as general cognitive enhancers. However, there is a need for pharmacologic acceptable compounds with such activity. Summary of the Invention [Problem to be solved by the invention]

[0006] Provided herein are methods for promoting spine formation and for treating neuronal diseases or disorders. [Means for solving the problem]

[0007] In some embodiments, a method of promoting spine formation or treating a neuronal disease or disorder in a patient is provided, the method comprising contacting fascin with an agent that inhibits the activity of fascin.

[0008] In some embodiments, a method for promoting spine formation in a patient is provided, the method comprising administering a therapeutically effective amount of a compound that binds to fascin at least binding site 2 or binding site 3 to a patient in need thereof.

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

[0010] In some embodiments, a method of promoting spine formation in a patient is provided, the method comprising administering a therapeutically effective amount of a compound that binds to fascin at least binding site 3 to a patient in need thereof.

[0011] In some embodiments, there is provided a method of promoting spine formation in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , CH, CR 3 and N, where A 1 , A2 , A 3 , A 4 , A 5 , and A 6 4 or less is N, R 1 is selected from the group consisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by L 2 is a covalent bond, -NR 8 -, -C(O)NR 8 -, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -C(O)CR 8 2-, -CR 8 2C(O)-, -NR 8 CR 8 2-, and -CR 8 2NR 8 - selected from the group consisting of R 2 , H, C 1-6 alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, and the 6- to 10-membered aryl or 5- to 10-membered heteroaryl may optionally be one to four R 4 Each R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl (in some cases, C 1-6 Alkyl, halo, C 1-6 haloalkyl, or substituted with -OH, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: Each R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: q is 1, 2, or 3; Each R 6 Cyano, halo, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of haloalkyl, and -CHOH; R 7 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 8 is hydrogen or C 1-6 is alkyl, Each R 10 are independently hydrogen or C 1-6Alkyl or two R 10 forms a 4- to 6-membered ring together with the atoms attached to it, R 11 is hydrogen or R 3 (It is.)

[0012] In some embodiments, there is provided a method of treating depression, the method comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof.

[0013] In some embodiments, the compound is a compound described in U.S. Patent Application Publication No. 2015 / 0299191. In some embodiments, the compound is a compound described in U.S. Patent Application Publication No. 2014 / 0080843.

[0014] In some embodiments, the compound is a compound described in International Patent Publication No. WO2013 / 013240. In some embodiments, the compound is a compound described in U.S. Patent Application Publication No. 2014 / 0024705.

[0015] In some embodiments, a method for treating or preventing a neuronal disease or disorder is provided, the method comprising administering a therapeutically effective amount of a compound that binds to fascin at least binding site 2 to a patient in need thereof.

[0016] In some embodiments, a method for treating or preventing a neuronal disease or disorder is provided, the method comprising administering a therapeutically effective amount of a compound that binds to fascin at least binding site 3 to a patient in need thereof.

[0017] In some embodiments, a method for treating or preventing a neuronal disease or disorder is provided, comprising administering a therapeutically effective amount of a compound as described herein to a patient in need thereof.The compound is, for example, a compound selected from the compounds of formula I provided herein or a pharma- ceutically acceptable salt thereof, a compound selected from the compounds of formula II provided herein or a pharma- ceutically acceptable salt thereof, a compound selected from the compounds of formula IV provided herein or a pharma- ceutically acceptable salt thereof, a compound selected from the compounds of formula V provided herein or a pharma- ceutically acceptable salt thereof, a compound selected from the compounds of formula VII provided herein or a pharma- ceutically acceptable salt thereof, or compound 1, compound 8, compound 9, compound 10, or compound 11, or a pharma- ceutically acceptable salt thereof.

[0018] In some embodiments, the neuronal disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, depression, and traumatic brain injury.

[0019] In some embodiments, the neuronal disease or disorder is a mood disorder, e.g., depression.

[0020] In some embodiments, provided herein are methods of promoting spine formation in a patient, the methods comprising administering to a patient in need thereof a therapeutically effective amount of an agent described herein, e.g., a compound selected from Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, there is provided a method of promoting spine formation in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide (Compound 1), having the following structure, or a pharma- ceutical acceptable salt thereof. [ka]

[0022] In some embodiments, compounds are provided that inhibit fascin, wherein the compound does not bind to fascin at binding site 1.

[0023] In some embodiments, a method of promoting spine formation in a patient is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound that binds to fascin, provided that the compound is not a compound of formula III: [ka] (Wherein, Y is -NR 33 -, O, or -S-, and R 31 are independently halogen, -CX 31 , -CHX 31 , -CH2X 31 , -OCX 31 3. -OCHX 31 2, -OCH2X 31 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -HNC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 32 are independently halogen, -CX 32 3. -CHX 32 2, -CH2X32 , -OCX 32 3. -OCHX 32 2, -OCH2X 32 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is 31 and X 32 each independently represents a halogen; each of z1 and z2 independently represents an integer of 0 to 4; z3 represents an integer of 1 to 12; R 33 is hydrogen or substituted or unsubstituted C 1-6 In some embodiments, Y of formula III is -NR 33 -or -S-. In certain embodiments, for example, the following are provided: (Item 1) A method for promoting spine formation in a patient, comprising administering to a patient in need of spine formation a therapeutically effective amount of a compound that binds to fascin at least binding site 2. (Item 2) A method for promoting spine formation in a patient, comprising administering to a patient in need of spine formation a therapeutically effective amount of a compound that binds to fascin at least binding site 3. (Item 3) 1. A method of promoting spine formation in a patient, comprising administering to a patient in need of spine formation a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 , A 2 , A 3 , A 4, A 5 , and A 6 , CH, CR 3 and N, where A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 4 or less is N, R 1 is selected from the group consisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by L 2 is a covalent bond, -NR 8 -, -C(O)NR 8 -, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -C(O)CR 8 2-, -CR 8 2C(O)-, -NR 8 CR 8 2-, and -CR 8 2NR 8 - selected from the group consisting of R 2 , H, C 1-6 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is optionally selected from 1 to 4 R 4 Each R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl (in some cases, C 1-6 Alkyl, halo, C 1-6 haloalkyl, or substituted with -OH, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of Each R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of q is 1, 2, or 3; Each R 6 Cyano, halo, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of haloalkyl, and -CHOH; R 7 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 8 is hydrogen or C 1-6 is alkyl, Each R 10 are independently hydrogen or C 1-6 Alkyl or two R 10 forms a 4- to 6-membered ring together with the atoms attached to it, R 11 is hydrogen or R 3 (It is.) (Item 4) A method of promoting spine formation in a patient, comprising administering to a patient in need of spine formation a therapeutically effective amount of a compound of Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI, or a pharma- ceutically acceptable salt thereof, or a compound selected from Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. (Item 5) A method for treating or preventing a neuronal disease or disorder, comprising administering a therapeutically effective amount of a compound that binds to fascin at least at binding site 2 to a patient in need of treatment or prevention. (Item 6) A method for treating or preventing a neuronal disease or disorder, comprising administering a therapeutically effective amount of a compound that binds to fascin at least binding site 3 to a patient in need of treatment or prevention. (Item 7) 7. The method of claim 5 or 6, wherein the compound is selected from a compound of formula I, formula II, formula IV, formula V, formula VII, formula VIII, formula IX, formula X, or formula XI, or a pharma- ceutically acceptable salt thereof, or compound 1, compound 8, compound 9, compound 10, or compound 11, or a pharma- ceutically acceptable salt thereof. (Item 8) A method for treating or preventing a neuronal disease or disorder, comprising administering to a patient in need of treatment or prevention a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , CH, CR 3 and N, where A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 Four or less of is N, R 1 is selected from the group consisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by L 2 is a covalent bond, -NR 8 -, -C(O)NR 8 -, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -C(O)CR 8 2-, -CR 8 2C(O)-, -NR 8 CR 8 2-, and -CR 8 2NR 8 - selected from the group consisting of R 2 , H, C 1-6 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is optionally selected from 1 to 4 R 4 Each R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl (in some cases, C 1-6 Alkyl, halo, C 1-6 haloalkyl, or substituted with -OH, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: Each R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: q is 1, 2, or 3; Each R 6 are independently cyano, halo, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of haloalkyl, and -CHOH; R 7 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 8 is hydrogen or C 1-6 is alkyl, Each R 10 are independently hydrogen or C 1-6 Alkyl or two R 10 forms a 4- to 6-membered ring together with the atoms attached to it, R 11 is hydrogen or R 3 (It is.) (Item 9) 8. The method according to any one of items 5 to 7, wherein the neuronal disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, depression, and traumatic brain injury. (Item 10) 8. The method according to any one of items 5 to 7, wherein the neuronal disease or disorder is Alzheimer's disease. (Item 11) 8. The method according to any one of items 5 to 7, wherein the neuronal disease or disorder is depression. (Item 12) 1. A method of promoting spine formation in a patient, comprising administering to a patient in need of spine formation a therapeutically effective amount of N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide (Compound 1), having the following structure, or a pharma- ceutical acceptable salt thereof: [ka] (Item 13) A method of treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI, or a pharma- ceutically acceptable salt thereof, or a compound selected from Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. (Item 14) 1. A method for treating depression, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , CH, CR 3 and N, where A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 4 or less is N, R 1 is selected from the group consisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by L 2 is a covalent bond, -NR 8 -, -C(O)NR 8 -, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -C(O)CR 8 2-, -CR 8 2C(O)-, -NR 8 CR 8 2-, and -CR 8 2NR 8 - selected from the group consisting of R2 , H, C 1-6 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is optionally selected from 1 to 4 R 4 Each R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl (in some cases, C 1-6 Alkyl, halo, C 1-6 haloalkyl, or substituted with -OH, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of Each R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: q is 1, 2, or 3; Each R 6 are independently cyano, halo, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of haloalkyl, and -CHOH; R 7 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 8 is hydrogen or C 1-6 is alkyl, Each R 10 are independently hydrogen or C 1-6 Alkyl or two R 10 forms a 4- to 6-membered ring together with the atoms attached to it, R 11 is hydrogen or R 3 (It is.) [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 shows, in one embodiment, the three known actin-binding sites of fascin.

[0025] [Figure 2A] FIG. 2A provides, in one embodiment, a front view of fascin, based on the available crystal structure. [Figure 2B] FIG. 2B provides, in one embodiment, a bottom view of fascin based on the available crystal structure. [Figure 2C] FIG. 2C provides, in one embodiment, a top view of fascin, based on the available crystal structure. [Figure 2D] FIG. 2D provides, in one embodiment, a back view of fascin, based on the available crystal structure.

[0026] [Figure 3A-3C] Figure 3A shows, in one embodiment, a complex in which human fascin 1 is docked with comparative compound 2. Figure 3B shows, in one embodiment, a complex in which human fascin 1 is docked with comparative compound 3. Figure 3C shows, in one embodiment, a complex in which human fascin 1 is docked with comparative compound 4.

[0027] [Figure 4] FIG. 4 shows, in one embodiment, a 2D interaction diagram of the complex of Comparative Compound 2 and human Fascin 1.

[0028] [Diagram 5] FIG. 5 shows the phasin apo structure superimposed on the phasin structure with compound 1 bound, with binding site 1 and binding site 2 as shown in one embodiment.

[0029] [Figure 6] FIG. 6 shows, in one embodiment, synaptic growth results for Comparative Compound 2, Comparative Compound 7, and Compound 1 compared to vehicle control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] In general, the compositions and methods described herein are for administering a compound that binds to fascin at binding site 2 or binding site 3 to promote spine formation. In some embodiments, the compositions and methods are useful for treating neuronal diseases or disorders. In general, the active or primary ingredient comprises an agent such as a compound or a pharma- ceutically acceptable salt of a compound described herein. The active or primary ingredient may also include one or more additional pharma- ceutical active materials.

[0031] I. Definition The following description describes exemplary embodiments of the present technology, but it should be appreciated that such description is not intended to limit the scope of the disclosure, but rather is provided as a description of exemplary embodiments.

[0032] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0033] The term "fascin" refers to a 54-58 kDa protein that is an actin cross-linking protein. The term "fascin" may refer to the amino acid sequence of human fascin 1. The term "fascin" includes both the wild-type nucleotide sequence or protein, and any mutants thereof. In some embodiments, "fascin" is wild-type fascin. In some embodiments, "fascin" is one or more mutant forms. In some embodiments, fascin is human fascin 1. In some embodiments, the fascin protein is encoded by a nucleotide sequence corresponding to reference number GI:347360903. In some embodiments, the fascin protein is encoded by a nucleotide sequence in RefSeq M_003088. In some embodiments, fascin corresponds to an amino acid sequence in RefSeq NP_003079.1.

[0034] Terms such as "spine formation" refer in their normal accustomed sense to the development (e.g., growth and / or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote spine formation without affecting spine morphology. Promotion is relative to the absence of administration of the compound.

[0035] As used herein, the term "dendrite" refers to the branched extension of a neuronal cell. Dendrites are usually responsible for receiving electrochemical signals transmitted from the axons of adjacent neurons. The term "dendritic spines" or "dendrite spines" refers to the protoplasmic protuberances on a neuronal cell (e.g., dendrites). In some embodiments, dendritic spines may be described as having a membranous neck that may terminate in a small head (e.g., head). Dendritic spines are classified as headless, thin, stubby, mushroom, or branched depending on their shape. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuronal cell. For example, dendritic spine density may be given as the number of dendritic spines per micron.

[0036] Terms such as "dendritic spine formation" refer in their normal, customary sense to a 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 in their normal, customary sense to the physical characteristics (e.g., shape and structure) of dendritic spines. Improving dendritic spine morphology is a change in morphology (e.g., an increase in length or an increase in width) that results in improved function (e.g., an increase in the number of contacts between neurons or a decrease in the space (e.g., synaptic cleft) between adjacent neurons). As known in the art and disclosed herein, exemplary methods for such characterization include measuring the dimensions (i.e., length and width) of dendritic spines. Thus, the term "improving dendritic spine morphology" generally refers to an increase in the length, width, or both length and width of dendritic spines.

[0037] "Binding" refers to at least two different species (e.g., compounds or cells, including biomolecules) coming into sufficient proximity to react or interact, thereby resulting in the formation of a complex. For example, binding of two different species (e.g., a protein and a compound described herein) can result in the formation of a complex in which the species interact through non-covalent or covalent bonds. In some embodiments, the resulting complex is formed when two different species (e.g., a protein and a compound described herein) interact through non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).

[0038] As defined herein, the terms "activation," "activate," "activating," and the like, in reference to protein-activator (e.g., agonist) interaction, mean a positive effect (e.g., an increase) on the activity or function of the protein compared to the activity or function in the absence of the activator (e.g., a compound described herein).

[0039] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subjects or agents are treated as in a parallel experiment, except for the omission of an experimental procedure, agent, or variable. In some cases, a control is used as a standard of comparison in evaluating the effect of an experiment.

[0040] "Contacting" is used according to its plain and ordinary meaning and refers to a process by which at least two different species (e.g., compounds including biomolecules or cells) can come into sufficient proximity to interact. The term "contacting" can include allowing two molecular species to react or come into physical contact, where the two species can be, for example, compounds, biomolecules, proteins, or enzymes described herein. In some embodiments, contacting includes allowing a compound described herein to interact with a protein (e.g., phasin) or enzyme. In some embodiments, contacting can include protein binding.

[0041] As defined herein, the terms "inhibit," "inhibit," "inhibiting," and the like should be given their accustomed meaning to one of skill in the art. The terms "inhibit," "inhibit," and "inhibiting," in reference to protein-inhibitor (e.g., antagonist) interactions, refer to a negative effect (e.g., a decrease) on the functional activity of the protein compared to the functional activity of the protein in the absence of the inhibitor.

[0042] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes before or at the end of a chemical group are for convenience, and chemical groups may be represented with or without one or more dashes without loss of ordinary meaning. A wavy line through a line in a structure indicates the point of attachment of the group. No directionality is given or implied by the order of writing or naming chemical groups unless chemically or structurally necessary.

[0043] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0044] References herein to "about" a value or parameter include (and describe) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Additionally, the term "about X" includes the statement "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0045] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a hydrocarbon chain having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be encompassed. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2). In some embodiments, the term "lower alkyl" includes C 1-6 Refers to alkyl.

[0046] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl refers to an alkyl group having the radical 1,2- or 2-alkyl groups. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0047] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" refers to an alkyl group having one triple bond and one double bond.

[0048] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0049] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen.

[0050] "Alkylthio" refers to the group "alkyl-S--".

[0051] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0052] "Amide" is -C(O)NR y R z -C-amide, which refers to the -NR group, y C(O)R z The "N-amide" group refers to both the y and R zis independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0053] "Amino" is -NR y R z R refers to the group y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, each of which may be optionally substituted.

[0054] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or in any way overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0055] "Aralkyl" refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0056] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the -NR y C(O)OR z The "N-carbamoyl" group refers to both the y and R zis independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0057] "Carboxyl" refers to -C(O)OH.

[0058] "Carboxyl ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0059] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to cyclic alkyl groups having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0060] "Imino" refers to the group -C(NR)R, where each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0061] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced with halogens. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0062] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like. Wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CHOCH3, -SCH3, -CHSCH3, -NRCH3, and -CHNRCH3. Wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0063] "Heteroaryl" refers to an aromatic group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, and having a single ring, multiple rings, or multiple fused rings. As used herein, heteroaryl includes 5-20 ring atoms (i.e., 5-20 membered heteroaryl), or 5-10 ring atoms (i.e., 5-10 membered heteroaryl), and 1-5 heteroatoms, 1-4 heteroatoms, 1-3 heteroatoms, 1-2 heteroatoms, or 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl. Here, heteroaryl can be bonded via any ring of the fused system. Any aromatic ring with single or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of the attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0064] "Heterocyclyl" and "heterocycloalkyl" refer to saturated or unsaturated cyclic alkyl groups having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The terms "heterocyclyl" and "heterocycloalkyl" include heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls can be single rings or multiple rings, and multiple rings can be fused, bridged, or spiro. Non-aromatic rings containing at least one heteroatom are considered heterocyclyls, regardless of attachment (i.e., can be attached through a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, regardless of attachment to the remainder of the molecule, which ring can be fused to an aryl or heteroaryl ring. As used herein, a heterocyclyl has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), or 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4-10 membered cyclic moiety connected by two non-adjacent atoms of a heterocyclyl having at least one heteroatom and having one or more (e.g., one or two) 4-10 membered cyclic moieties. wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings.wherein the one or more additional rings are 3-10 membered cycloalkyl or 3-10 membered heterocyclyl, and one atom of the one or more additional rings is also an atom of the 3-10 membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl. wherein the heterocyclyl can be attached via either ring of the fused system.

[0065] "Oxo" refers to the (=O) or (O) group.

[0066] "Sulfonyl" refers to the group -S(O)R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0067] "Alkylsulfonyl" refers to the group -S(O)R where R is alkyl.

[0068] "Alkylsulfinyl" refers to the group -S(O)R where R is alkyl.

[0069] "Thiocyanate" refers to the group -SCN.

[0070] "Thioxo" or "thione" refers to the (=S) or (S) group.

[0071] As used herein, the term "carbohydrate" refers to a sugar, such as a monosaccharide, disaccharide, oligosaccharide, or polysaccharide. Monosaccharides include, but are not limited to, glucose, ribose, and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides refer to 2-10 sugars linked together, preferably via alpha bonds. Examples of oligosaccharides include, but are not limited to, maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose, lignocellulose, or starch. Carbohydrates or sugars may 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, sialic acid, and the like, including their aldol and pyranose forms, and their D and L isomers.

[0072] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless otherwise indicated, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl, the last-mentioned group includes the atom by which the moiety is attached to the remainder of the molecule.

[0073] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0074] The protecting groups are any of those known in the art, for example, as described in Peter G. M. Huts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007). In some embodiments, the oxygen protecting groups can be selected from benzyl ethers, silyl ethers, esters, carbonates, cyclic acetals and ketals.

[0075] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, the compound is understood by those skilled in the art to include all tautomers.

[0076] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure, or their counterions, include: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 These include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as I. Under the present disclosure, various isotopically labeled compounds are contemplated, such as 3 H, 13 C, and 14Radioactive isotopes, such as C, can be incorporated. Such isotopically labeled compounds can be useful in detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0077] The present disclosure also includes "deuterated analogs" of compounds and their counterions in which one to n hydrogens attached to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of the compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0078] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from higher metabolic stability, such as extended in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F labeled compound can be useful for PET or SPECT research.The isotopically labeled compounds of the present disclosure and their prodrugs can be prepared by generally replacing nonisotopically labeled reagent with readily available isotopically labeled reagent and carrying out the procedures disclosed in the scheme or in the examples and preparations described below.It is understood that deuterium in this context is considered as a substituent in the compound.

[0079] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to contain hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0080] The compounds described herein may exist as salts, such as pharma- ceutically acceptable salts. The compounds can form salts, such as acid and / or base salts. Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Salts of the compounds described herein can be prepared according to the procedures described herein as known in the art.

[0081] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise unsuitable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be made by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharma-ceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkyl amines (i.e., N(substituted alkenyl)3 ... Examples of suitable amines include, but are not limited to, salts of primary, secondary and tertiary amines such as monoalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Methods of preparing salts also include mixing compounds, for example, by redox reaction with active metals or by exchange of ions, due to the different solubilities of the salts.

[0082] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, aryl, -N3, carbamoyl, carboxyl, carboxyl ester, -CN, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, -OH, imino, oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thione, or combinations thereof. It is not intended herein to include polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents added (e.g., a substituted aryl having a substituted alkyl, itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, the substituents of the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0083] A "solvate" is a solid form of a compound in which solvent molecules are incorporated. A solvate is formed by the interaction of a solvent and a compound. A hydrate is a solvate in which the solvent is water. Solvates of the salts of the compounds described herein are also provided.

[0084] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents as pharmaceutically active substances is well known in the art. Except where a conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Auxiliary active ingredients can also be incorporated into the composition.

[0085] "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) treating a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of the disease or condition); b) delaying or preventing the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or delaying the worsening or progression of a disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of a disease or condition; and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the condition, providing partial or complete remission of a disease or condition, enhancing the effect of another medication, delaying disease progression, improving quality of life, and / or prolonging survival).

[0086] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition to develop. The compounds, in some embodiments, may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0087] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. When the subject is a human, the subject may be referred to as a "patient."

[0088] The term "therapeutically effective amount" or "effective amount" of a compound or its pharma- ceutically acceptable salt described herein means an amount sufficient to exert a therapeutic effect when administered to a subject, resulting in a therapeutic benefit such as ameliorating symptoms or delaying disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a neuronal disease. The therapeutically effective amount may vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, but can be easily determined by those skilled in the art.

[0089] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used to set up in vivo treatment protocols, either for experimental purposes or in the clinic. Other ex vivo applications for which the compounds and compositions described herein may be suitable are described below and will be apparent to those skilled in the art. Selected compounds may be further characterized to determine safety or tolerated dosage in human or non-human subjects. Such properties may be determined using methods commonly known to those of skill in the art. [Table 5]

[0090] compound Provided herein is an agent that promotes spine formation. Such an agent is useful for treating neuronal diseases and disorders. The agent can be a compound provided herein. The compound can be a compound described in U.S. Patent Application Publication No. 2015 / 0299191. The compound can be a compound of Formula I or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , CH, CR 3 and N, where A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 Four or less of is N, R 1 is selected from the group consisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by L 2 is a covalent bond, -NR 8 -, -C(O)NR 8 -, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -C(O)CR 8 2-, -CR 8 2C(O)-, -NR 8 CR 8 2-, and -CR 8 2NR 8 - selected from the group consisting of R 2 , H, C 1-6 alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, and the 6- to 10-membered aryl or 5- to 10-membered heteroaryl may optionally be one to four R 4 Each R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl (in some cases, C 1-6 Alkyl, halo, C 1-6 haloalkyl, or substituted with -OH, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10, halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of Each R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 7 , -NR 10 CO2R 7 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of q is 1, 2, or 3; Each R 6 Cyano, halo, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of haloalkyl, and -CHOH; R7 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 8 is hydrogen or C 1-6 is alkyl, Each R 10 are independently hydrogen or C 1-6 Alkyl or two R 10 forms a 4- to 6-membered ring together with the atoms attached to it, R 11 is hydrogen or R 3 (It is.)

[0091] The compound can be a compound described in International Patent Publication No. WO2013 / 013240. The compound can be a compound of Formula II, or a pharma- ceutically acceptable salt thereof: [ka] (wherein n and m are each independently 0, 1, 2, 3, or 4; X 1 -O-, -NR 7a -, -CR 9a R 9b -, -C(O)-NR 7a -, -NR 7a -C(O)-, -NR 8a -S(O)2- or -S(O)2-NR 8a - and X 2 -NR 8a -, -CR 9a R 9b -, -S-, -O-, -S(O)-, -S(O)2-, -C(O)-NR 8a -, -NR 8a -C(O)-, -NR 8a -S(O)2-, or -S(O)2-NR-; R 1a Halo, C 1-6 Alkyl, or C 1-6 is an alkoxy; Each R 2a and R 2b are independently hydrogen or C1-6 is alkyl, Each R 4a and R 4b are independently hydrogen, hydroxyl, C 1-6 Alkyl, or C 1-6 is an alkoxy; Each R 5a and R 5b are independently hydrogen, halo, amino, amido, C 1-6 Alkyl, or C 1-6 is an alkoxy; Each R 6a and R 6b are independently hydrogen, halo, amino, amido, C 1-6 Alkyl, or C 1-6 is an alkoxy; R 7a is hydrogen, C 1-6 alkyl, acyl, aryl, or aralkyl; R 8a is hydrogen, C 1-6 is alkyl, acyl, aryl or aralkyl; Each R 9a and R 9b are independently hydrogen, C 1-6 Alkyl, C 1-6 alkoxy, halo, amino, amido, aryl, or heteroaryl).

[0092] The compound can be a compound described in U.S. Patent Application Publication No. 2014 / 0024705. The compound can be a compound of Formula IV or a pharma- ceutically acceptable salt thereof: [ka] R 21 is hydrogen or optionally substituted C 1-6 is alkyl, R 22 is an oxygen protecting group, hydrogen, or an optionally substituted C 1-6 is alkyl, R 23 and R 25 each independently represents an optionally substituted C1-6 is alkyl, R 24 is hydrogen or -TY, -T- is an optionally substituted C 1-8 A divalent saturated or unsaturated, linear or branched, hydrocarbon chain in which one or more methylene units are optionally independently -NR 26 -, -N(R 26 )C(O)-, -C(O)N(R 26 )-, -N(R 26 )SO2-, -SO2N(R 26 )-, -O-, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, -OC(O)N(R 26 )-, -S-, -SO-, or -SO2-, Each R 26 are independently hydrogen or C 1-20 Alkyl, C 1-20 selected from the group consisting of heteroalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 12-membered heterocyclyl; -Y is hydrogen or acyl.

[0093] The compound can be a compound described in U.S. Patent Application Publication No. 2014 / 0080843. The compound can be a compound of Formula V, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, L 5 is -(C(R 58 )2) q -, -(C(R 58 )2) q -C(O)-(C(R 58 )2) r -, -(C(R 58 )2) q -C(O)N(R 58 )-(C(R 58 )2) r -, -(C(R 58 )2) q-N(R 58 )C(O)-(C(R 58 )2) r -, -(C(R 58 )2) q -N(R 58 )S(O)2-(C(R 58 )2) r , -(CH2) q -S(O)2N(R 58 )-(CH2) r -, -S-, -O-, and -NR 58 - selected from the group consisting of Each R 51 is halo and C optionally substituted with 1 to 3 halo 1-6 alkyl, or two adjacent R on a phenyl ring; 51 forms a 5- or 6-membered cycloalkyl or heterocyclyl fused to a phenyl ring; Each R 58 are independently hydrogen or C 1-6 is alkyl, q is 0 or 1; r is 0 or 1; u5 can be 1, 2, or 3).

[0094] In some embodiments, the compound can be a compound described in U.S. Patent Application Publication No. 2014 / 0080843. In some embodiments, the compound is a compound of Formula Ia or Ib: [ka] Q of formula Ia or formula Ib 1 and Q 2 are independently phenyl, 5-membered heteroaryl, or 6-membered heteroaryl and are fused together in formula Ia; Q of formula Ib 3 is a 6-membered unsaturated ring; (1) Y 1 and Y 2 The bond between Y and Y is a double bond. 2 or (2) Y1 and Y 2 The bond between Y 3 and Y 2 In formula Ib, the bond between Q 3 Q 2 It is condensed with In formula Ia or formula Ib, s is 0 or 1; In formula Ia or formula Ib, t is 1 or 2; Y of formula Ia or formula Ib 1 , Y 3 , and Y 4 is independently C or N, and Y of formula Ia or formula Ib 2 , Y 4 , and Y 6 are independently CH, CR 3 or N, with the proviso that Y of formula Ia or formula Ib 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 Four or less of is N, R of formula Ia or formula Ib 1 is phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl, and the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to three R 6 is replaced by R and R of formula Ia or formula Ib 4 is absent, hydrogen, halo, or lower alkyl (preferably methyl or ethyl), and R and R 4 The other is L 2 -R 5 Or L 3 -R 3 or R is absent and R 4 is -(CH2) j -R 11a and R of formula Ia or Ib 11a -OH, -OR 7 , -SH, -SR 7 , -NR 10 R10 , cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 10 , -NR 10 CO2R 10 , -SOR 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 is selected from the group consisting of X of formula Ia or formula Ib 1 OR 8 , N.H.R. 8 , and S.R. 8 is selected from the group consisting of X of formula Ia or formula Ib 2 , O, NR 8 and S, L of formula Ia or formula Ib 1 is -(C(R 8 )2) j -, -(C(R 8 )2) q -C(O)-(C(R 8 )2) r -, -(C(R 8 )2) q -C(O)N(R 8 )-(C(R 8 )2) r -, -(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -, -(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -, -(CH2) q -S(O)2N(R8 )-(CH2) r -, -S-, -O-, and -NR 8 - selected from the group consisting of j in formula Ia or formula Ib is 1, 2, or 3; In formula Ia or formula Ib, q is 0 or 1; r in formula Ia or formula Ib is 0 or 1; L of formula Ia or formula Ib 2 is a covalent bond, -C(O)N(R 8 )-, -N(R 8 )C(O)-, -N(R 8 )S(O)2-, and -S(O)2N(R 8 )-, L of formula Ia or formula Ib 3 is =NC(O)- or =NS(O)2-, Each R of formula Ia or formula Ib 3 is independently selected from the group consisting of lower alkyl (preferably methyl or ethyl) and halo; R of formula Ia or formula Ib 5 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, and the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally selected from one to four R 2 and each R of formula Ia or formula Ib is substituted with 2 is lower alkyl, lower haloalkyl, -OH, -OR 7 , -SH, -SR 7 , -NR 10 R 10 , halo, cyano, nitro, -COH, -COR 7 , -CO2H, -CO2R 7 , -CONR 10 R 10 , -OCOR 7 , -OCO2R 7 , -OCONR 10 R 10 , -NR 10 COR 10 , -NR 10 CO2R10 , -S(O)R 7 , -SO2R 7 , -SO2NR 10 R 10 , and -NR 10 SO2R 7 are independently selected from the group consisting of: Each R of formula Ia or formula Ib 6 are independently selected from the group consisting of halo and lower alkyl (preferably methyl or ethyl) optionally substituted with 1 to 3 halo, or two adjacent R 6 forms a 5- or 6-membered cycloalkyl or heterocycloalkyl fused to a phenyl ring; R of formula Ia or formula Ib 7 is lower alkyl (preferably methyl or ethyl), R of formula Ia or formula Ib 8 is hydrogen or lower alkyl (preferably methyl or ethyl), Each R of formula Ia or formula Ib 10 are independently hydrogen or lower alkyl (preferably methyl or ethyl), or two R 10 forms a 4- to 6-membered ring together with the atoms to which it is bonded.

[0095] In some embodiments, there is provided a compound according to formula VII or a pharma- ceutically acceptable salt thereof: [ka] wherein the nitro group is ortho or meta, R in formula VII is methyl or ethyl, and X in formula VII is O or S.

[0096] In some embodiments, there is provided a compound according to formula VIII or a pharma- ceutically acceptable salt thereof: [ka]

[0097] In some embodiments, there is provided a compound according to formula IX or a pharma- ceutically acceptable salt thereof: [ka]

[0098] In some embodiments, there is provided a compound according to formula X, or a pharma- ceutically acceptable salt thereof: [ka]

[0099] In some embodiments, there is provided a compound according to formula XI or a pharma- ceutically acceptable salt thereof: [ka]

[0100] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0101] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from

[0102] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the compound is [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the compound is [ka]

[0105] In some embodiments, the compound is N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the compound is not Comparative Compound 2, Comparative Compound 3, or Comparative Compound 4. [ka] In some embodiments, comparative compound 2, comparative compound 3, or comparative compound 4 is present as a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the compound is Compound 5 or Compound 6, [ka] or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, the compound is [ka] is selected from.

[0109] In some embodiments, the compound is migrastatin (compound 8) or isomigrastatin (compound 9). [ka] In some embodiments, compound 8 or compound 9 is present as a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the compound is compound 10. [ka] In some embodiments, compound 10 is present as a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the compound is compound 11. [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the compound is BDP-00010834 or BDP-00013544, as disclosed in Abstract LB-228:Identifying small molecule inhibitors of Fascin 1 using fragment-based drug discovery, Cancer Research 77(Suppl 13):LB-228-LB-228, July 2017, DOI:10.1158 / 1538-7445.AM2017-LB-228.

[0113] In some embodiments, the agent is a fascin antibody that binds to fascin at least at binding site 2 or binding site 3.

[0114] In some embodiments, the compound is not a compound of formula III: [ka] (Wherein, Y is -NR 33 - or -S-, R 31 are independently halogen, -CX 31 , -CHX 31 , -CH2X 31 , -OCX 31 3. -OCHX 31 2, -OCH2X 31 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -HNC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 32 are independently halogen, -CX 32 3. -CHX 32 2, -CH2X 32 , -OCX 32 3. -OCHX 32 2, -OCH2X 32 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is31 and X 32 each of z1 and z2 is independently an integer of 0 to 4, z3 is an integer of 1 to 12, R 33 is hydrogen or a substituted or unsubstituted C 1-6 (It is alkyl).

[0115] The compounds described herein can be prepared according to methods known to those skilled in the art. Where available, the compounds can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0116] The synthesis can be carried out by known procedures or modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0117] Treatment Methods and Uses Fashin Described herein are methods for regenerating spine synapses lost to neurodegenerative conditions by targeting cytoskeletal proteins with agents such as the compounds described herein. Unexpectedly, inhibition of the cytoskeletal protein Fascin 1 (FSCN1) was observed to rapidly upregulate dendritic spines in vivo and in vitro. Dendritic spines contain filamentous actin (F-actin), a cytoskeletal polymer that provides structure to cells and their subcellular specialization. The elongation of F-actin filaments and their changes in tissue are believed to be important for the formation, maturation, and plasticity of dendritic spines. Prior to the present disclosure, Fascin 1's ability to bundle F-actin filaments into parallel arrays was believed to be essential for the formation of a wide range of cellular processes, such as invadopodia, filopodia, and possibly dendritic spines. Fascin 1 is believed to facilitate the process of cell migration and associated cancer metastasis by such processes. Small molecule inhibitors of fascin1, which inhibit its ability to bundle F-actin, have been observed to reduce F-actin-rich cellular processes. Thus, previous studies have suggested that fascin inhibitors also inhibit the formation of dendritic spines, which are F-actin-rich cellular processes. However, contrary to expectations, the present disclosure demonstrates that the opposite is true; that is, structurally distinct inhibitors of fascin1, as well as genetic knockdown of fascin1, can result in a rapid increase in dendritic spine density. Without wishing to be limited by theory, it is believed that dendritic spines require the formation of highly branched assemblies of F-actin, and that the formation of such assemblies may be prevented or greatly reduced by bundling into parallel arrays by fascin1.

[0118] In some embodiments, a method is provided for binding to site 2 or site 3 of fascin protein, the method comprising contacting an effective amount of a compound described herein with the fascin protein. The compound is, for example, a compound of formula I provided herein, or a phasic acid salt thereof, or a compound of formula II provided herein, or a phasic acid salt thereof, or a compound selected from a compound of formula IV provided herein, or a phasic acid salt thereof, or a compound selected from a compound of formula V provided herein, or a phasic acid salt thereof, or a compound selected from a compound of formula VII provided herein, or a phasic acid salt thereof, or a compound 1, a compound 8, a compound 9, a compound 10, or a compound 11, or a phasic acid salt thereof. In some embodiments, the method inhibits fascin. A compound of formula I, formula II, formula IV, formula V, formula VII, formula VIII, formula IX, formula X, or formula XI provided herein, or a phasic acid salt thereof, or a compound 1, a compound 8, a compound 9, a compound 10, or a compound 11, or a phasic acid salt thereof, promotes dendritic spine formation by inhibiting fascin.

[0119] Fascin is an important actin cross-linker that has no amino acid sequence homology to other actin-binding proteins. Three forms of fascin are found in vertebrates: fascin 1 in the nervous system and elsewhere, fascin 2 in retinal photoreceptor cells, and fascin 3 only in the testis. In some embodiments, the fascin is human fascin 1. Fascin has a molecular weight of 55 kDa and functions as a monomer, cross-linking actin filaments into straight, compact, and rigid bundles, providing mechanical rigidity to actin bundles. Fascin is thought to hold parallel actin filaments together to form filopodia with diameters of approximately 60-200 nm. The structure of fascin, along with the actin-binding sites, is shown in Figure 1.

[0120] During neuronal development, long bundles of f-actin are believed to extrude neuronal membranes to form structures such as axons, dendrites, filopodia, and lamellipodia. Fascin is thought to be involved in cytoskeletal rearrangements in nascent dendrite protrusions. Thus, actin bundling by fascin is generally believed to be required for the formation and elongation of axons and dendrites. Surprisingly, the present results show that inhibiting the activity of fascin in the formation of actin bundles promotes the formation of dendritic spines, protrusions of the cytoplasmic membrane of dendrites.

[0121] Fascin is believed to have at least three binding sites, binding site 1, binding site 2, and binding site 3. Thus, with reference to FIG. 1, fascin appears to have three sites to which actin may bind. Binding site 2 was not seen in the initial apo (ligand-free) crystal structure of fascin, likely due to movement of the protein structure upon ligand binding. The compounds disclosed in International Patent Publication No. WO2017 / 120198 are believed to bind to fascin at binding site 1.

[0122] It has been observed that upon binding of compound 1, actin-binding site 2 opens and actin-binding site 1 closes, at least partially preventing the bundling of actin filaments. As shown in Figure 5, compound 1 has been found to bind to fascin at binding site 2. Furthermore, it was discovered that compound 1 could increase spine density compared to the control. Figure 6. In particular, compound 1 was found to increase spine density more than comparative compounds 1 and 7. Figure 6. Thus, by inhibiting fascin at least by binding at binding site 2, a new molecular pathway for increasing dendritic spine density is expected.

[0123] In some embodiments, phasin binding site 1 is defined, at least in part, by V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and / or Y493. In some embodiments, an agent described herein, e.g., a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a phasic acid salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a phasic acid salt thereof, does not bind to any of the phasin residues selected from V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and / or Y493. In some embodiments, an agent described herein, such as a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma- ceutically acceptable salt thereof, does not bind to phasin binding site 1 and binding site 2. In some embodiments, an agent described herein, such as a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma- ceutically acceptable salt thereof, does not bind to phasin binding site 1 and binding site 3. In some embodiments, an agent described herein, e.g., a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, does not bind to fascin binding site 1, binding site 2, and binding site 3.

[0124] Fascin binding site 2 is believed to be defined, at least in part, by F14, L16, L48, Q50, L62, W101, L103, E215, and / or S218. In some embodiments, an agent described herein, such as a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a phascin residue selected from F14, L16, L48, Q50, L62, W101, L103, E215, and S218, binds to at least one phascin residue selected from F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, an agent described herein, e.g., a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a phasic acid salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a phasic acid salt thereof, binds to two, three, four, five, six, seven, or eight phasic acid residues selected from F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, an agent described herein, such as a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, binds to at least one Group I phasin residue selected from F14 and L16. In some embodiments, an agent described herein, such as a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, binds to at least one Group II phasin residue selected from L48, Q50, and L62.In some embodiments, an agent described herein, such as a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, binds to at least one Group III phasin residue selected from W101 and L103. In some embodiments, an agent described herein, such as a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, binds to at least one Group IV phasin residue selected from E215 and S218. In some embodiments, fascin binding site 2 is defined, at least in part, by F14, L16, L48, A58, V60, L62, I93, A95, W101, L103, V134, T213, L214, E215, F216, and / or R217.

[0125] In some embodiments, fascin binding site 3 is defined, at least in part, by Q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and / or K379. In some embodiments, an agent described herein, e.g., a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of Q291, R308, H310, T311, G312, K313, Y314, L317, T318, T319, T320, T321, T322, T323, T324, T325, T326, T327, T328, T329, T330, T331, T332, T333, T334, T335, T336, T337, T338, T339, T340, T341, T342, T343, T344, T345, T346, T347, T348, T349, T350, T351, T352, T353, T354, T355, T356, T357, T358, T359, T360, T361, T362, T363, T364, T365, T366, T367, T368, T369, T370, T371, T372, T373, T374, T375, T376, T377, T378, T379, T380, T381, T382, T383, T384, T385, T386, T387, T388, T389, 18, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379.In some embodiments, an agent described herein, e.g., a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of Q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, and binding to two, three, four, five, six, seven, or eight phasin residues selected from T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379.

[0126] In some embodiments, the binding site of an agent, such as a compound described herein, can be determined by site-directed mutagenesis. For example, the amino acid residues of a mutant fascin can be altered compared to wild-type fascin. For example, if a decrease in binding affinity of an agent is measured between wild-type fascin and a mutant fascin in which an amino acid residue in binding site 1, binding site 2, or binding site 3 is replaced with a non-natural residue (e.g., an alanine residue), the decrease can be due to a loss of binding affinity at the replacement site. Site-directed mutagenesis can be performed by known methods, such as the Kunkel method, cassette mutagenesis, PCR site-directed mutagenesis, or CRISPR.

[0127] In some embodiments, the agents described herein have a K of at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 20 μM, at least about 50 μM, at least about 100 μM, or at least about 500 μM as measured by isothermal titration calorimetry. d binds to fascin.

[0128] Various small molecule compounds disclosed herein can bind to binding site 2 or phasin binding site 3 of phasin, and variants and additional compounds thereof can be identified by methods known in the art. For example, antibodies can be identified that bind to amino acid residues within phasin binding site 2 or 3 that serve as epitopes for antibodies.

[0129] Methods for generating antibodies are well known in the art and are described herein. For example, antibodies against specific epitopes on a protein can be prepared by administering the protein or epitope fragments to animals. Humanized, primatized, deimmunized, or chimeric antibodies can be generated. These types of antibodies are derived from non-human antibodies (typically murine or primate antibodies) that retain or substantially retain the antigen-binding properties of the parent antibody, but are less immunogenic in humans.

[0130] The binding specificity of an antigen-binding polypeptide of the disclosure can be determined by in vitro assays, such as immunoprecipitation, radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

[0131] A humanized antibody is an antibody molecule derived from a non-human species antibody that binds to a desired antigen with one or more complementarity determining regions (CDRs) of the non-human species and framework regions of a human immunoglobulin molecule. Fully human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be produced by a variety of methods known in the art, including phage display methods using antibody libraries derived from human immunoglobulin sequences. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins but can express human immunoglobulin genes.

[0132] Neuronal Diseases and Conditions and Their Treatment A unifying feature of neurodegenerative conditions associated with cognitive components is the loss of synapses that utilize the amino acid glutamate as a neurotransmitter ("glutamatergic" synapses), which are thought to be the most abundant type of synapse in humans and other mammals. Importantly, approximately 90% of glutamatergic synapses involve postsynaptic dendritic spines. The majority of synapses lost in neurodegenerative conditions are synapses where an axon contacts a dendritic spine, so-called "axon-spine synapses." Under normal conditions, changes in the density, shape, and protein composition of dendritic spines affect the strength of synaptic communication and underlie several forms of synaptic change (i.e., "plasticity") involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes. These changes in axon-spine synapses are thought to be important for the memory encoding function of structures such as the hippocampus. Thus, early and progressive loss of dendritic spines in the hippocampus and other regions is thought to be a driving force behind memory loss and cognitive decline in Alzheimer's disease and other dementias. The development of new methods to regenerate spine density may have important implications for the treatment of a host of neurodegenerative and developmental cognitive disorders.

[0133] Dendritic spines are specialized protrusions involved in receiving synaptic inputs and provide important functions in communication between neurons. The morphology of dendritic spines and their overall density are correlated with synaptic function and are strongly implicated in memory and learning. Cellular changes in brain cells may contribute to the pathogenesis of neuronal diseases. For example, abnormal levels (e.g., reductions) of dendritic spine density in the brain may contribute to the pathogenesis of neuronal diseases. As a result, alterations or misregulation of dendritic spines affect synaptic function and are thought to play a major role in various neurological and psychiatric disorders, such as autism, fragile X syndrome, Parkinson's disease (PD), and Alzheimer's disease (AD). For example, in AD, increasing evidence suggests that loss begins with alterations in hippocampal synaptic function caused by amyloid-β (Aβ) protein, prior to neuronal loss. Thus, therapeutic strategies targeting early synapse loss rather than later disease interventions may offer better prognosis for the treatment of AD. Moreover, because most cognitive disorders induce abnormalities in dendritic spine morphology and function, it would be desirable to directly target them using small molecules to alter or mitigate these spine changes. For example, fragile X syndrome is characterized by an excess of immature spines.

[0134] In some embodiments, the agents described herein, such as the compounds of formula I, formula II, formula IV, formula V, formula VII, formula VIII, formula IX, formula X, or formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, compound 8, compound 9, compound 10, or compound 11, or a pharma- ceutically acceptable salt thereof, are useful for treating mood disorders. Mood disorders are primarily mental disorders in which the patient's general emotional state or mood is distorted or inconsistent with the situation, interfering with the patient's ability to perform daily life. Subjects may feel sad, empty, or irritable, or have periods of negative emotions alternating with excessive euphoria (mania).

[0135] In some embodiments, the mood disorder may be depression. Depression, sometimes called major depressive disorder or clinical depression, is a common but serious mood disorder. People suffering from depression may experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. Besides the emotional problems caused by depression, individuals may also exhibit physical symptoms such as chronic pain or digestive problems. To be diagnosed with depression, symptoms must generally be present for at least two weeks. Depression may be diagnosed by those skilled in the art, for example, according to the guidelines of the Diagnostic and Statistical Manual of Mental Disorders ("DSM"). The DSM outlines the following criteria to make a diagnosis of depression. Currently, according to the diagnostic criteria of DSM-5, a diagnosis of depression requires an individual to have experienced five or more symptoms in the same two-week period, with at least one of the symptoms being either (1) a depressed mood, or (2) a loss of interest or pleasure. The symptoms identified in the DSM are: 1. Feeling depressed most of the time, almost every day. 2. Markedly decreased interest or pleasure in all or almost all activities for most of the day, on most days of the day. 3. Significant weight loss or significant weight gain when not dieting, or decreased or increased appetite almost every day. 4. Slowing of thinking and reduced bodily movements (observable by others, not just subjective restlessness or slowing). 5. Fatigue or loss of energy almost every day. 6. Feelings of worthlessness or excessive or inappropriate guilt almost every day. 7. Poor thinking or concentration, or indecisiveness nearly every day. 8. Recurrent thoughts of death, recurrent suicidal thoughts without a specific plan, or suicide attempts or specific plans for suicide.

[0136] To receive a diagnosis of depression, these symptoms must cause an individual clinically significant distress or impairment in social, occupational, or other important areas of functioning. The DSM also provides specifiers for diagnosed depression: (1) Mixed Features - This specifier allows for the presence of manic symptoms as part of a depression diagnosis in patients who do not meet all criteria for a manic episode. (2) Anxiety Distress - The presence of anxiety in a patient may affect prognosis, treatment options, and the patient's response to them.

[0137] Depression has many causes. Contributing factors to depression include stressors such as physical abuse, psychological abuse, traumatic events, personal conflicts, loss of relationships with loved ones, social isolation, illness, substance abuse, or use of certain medications. The subject may have a genetic predisposition to depression. The subject may have suffered a physical trauma that affects the brain, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). In some cases, depression is idiopathic. Classes of depression include: major depressive disorder - prolonged and persistent periods of extreme sadness; bipolar disorder - also called manic depression or bipolar affective disorder, depression that involves alternating periods of depression and mania; seasonal affective disorder (SAD) - a form of depression most often associated with less daylight hours in the far northern and southern latitudes from late fall to early spring; cyclothymic disorder - a disorder that causes emotional ups and downs that are less extreme than bipolar disorder; premenstrual dysphoric disorder - mood changes and irritability that occur during the premenstrual phase of a woman's cycle and disappear with the onset of menstruation; persistent depressive disorder (dysthymia) - long-term (chronic) but mild depression; severe mood dysregulation disorder - a chronic, severe, persistent disorder of irritability in children that often includes frequent temper tantrums that do not coincide with the child's developmental age; depression associated with a medical illness - a persistent depressed mood and a significant loss of pleasure in most or all activities that are directly related to the physical effects of another medical condition; and substance use or medication-induced depression - symptoms of depression that develop during or shortly after substance use, or after withdrawal from or exposure to a medication.

[0138] In some embodiments, a method of treating a mood disorder in a patient in need of treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound described herein. In some embodiments, the mood disorder is depression. In some embodiments, the patient may be resistant to treatment with an antidepressant. The antidepressant may be an antidepressant described herein.

[0139] In further embodiments, compositions and methods are provided for relieving, alleviating or reversing the symptoms of mood disorders.The symptoms can be any of the symptoms described herein, or any of the symptoms known to practitioners, for example, as described in DSM.

[0140] Symptoms of depression may include anxiety, loss of interest in daily activities, pessimism, persistent feelings of negativity, sadness, emptiness or depression, feelings of worthlessness, helplessness, hopelessness, fatigue, tiredness or lack of energy, low self-esteem, self-criticism and / or feelings of incompetence, poor concentration, difficulty remembering details and / or difficulty making decisions, persistent irritability, hostility and / or excessive anger, decreased activity, effectiveness and / or productivity, avoidance of social activities, guilt and / or worry about the past, loss of appetite or overeating, suicidal thoughts, decreased libido and / or loss of interest in sex, sleep disorders, insomnia, early morning awakenings or hypersomnia, restlessness, loss of interest in pleasurable activities, overeating or loss of appetite, dull pain of unknown cause, severe pain of unknown cause, headaches of unknown cause, persistent cramps, persistent digestive problems, suicidal thoughts, and suicidal behaviors.

[0141] Provided herein are methods useful for promoting spine formation. In some embodiments, the methods include administering to a subject an effective amount of an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma- ceutically acceptable salt thereof, as described herein, including embodiments. Spine formation may be observed as an increase in the average number of spines per neuron, or an increase in unit length of a neuron, which may be referred to as an increase in dendritic spine density. Spine formation may be observed as an improvement in dendritic spine morphology. For example, an improvement in dendritic spine morphology may be observed as an increase in the average size of spine heads. Spine formation may be observed as an improvement in dendritic spine size, spine plasticity, spine motility, spine density, and / or synaptic function. Spine formation may be observed as a localized, spatially averaged increase in membrane potential. 2+The increase in dendritic spine density may be observed as an increase in the postsynaptic concentration (e.g., volume average) of fascin. Spine formation may be observed as an increase in the average ratio of mature to immature spines. In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma-ceutically acceptable salt thereof, increases dendritic spine density compared to a control. In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma-ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma-ceutically acceptable salt thereof, increases dendritic spine density compared to that observed at the start of treatment. In some embodiments, the increase in dendritic spine density results in a reduction in symptoms of a neuronal disease or disorder in a subject or patient. In some embodiments, the increase in dendritic spine density is explained by anatomical observations. In some embodiments, the increase in dendritic spine density is observed in primary hippocampal neurons.

[0142] In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, increases average dendritic spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two numbers (including the endpoints), compared to when treatment was initiated with the agent. In some embodiments, the average dendritic spine density is increased by about 50% to about 500% compared to when treatment was initiated with an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the average dendritic spine density is increased by about 100% to about 300% compared to when treatment was initiated with an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutical acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutical acceptable salt thereof, increases average dendritic spine density by about 200% to about 300% compared to when treatment was initiated.In some embodiments, the duration of treatment with an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0143] In some embodiments, the method increases spine density by promoting the formation of new spines. In some embodiments, the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two numbers (including the endpoints), compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases the average spine density by about 50% to about 500% compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 100% to about 300% as compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 200% to about 300% as compared to a control (e.g., spine density in the absence of the compound).

[0144] In some embodiments, the method increases spine density by increasing neuronal length. In some embodiments, the method increases the average neuronal length by about 100 nm, 300 nm, 500 nm, 700 nm, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 7 microns, 10 microns, 15 microns, 20 microns, 25 microns, or any range between any two numbers (including endpoints) compared to when treatment was initiated with an agent that binds to fascin at least binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the method increases the average neuronal length by about 500 nm to about 25 microns compared to a control (e.g., neuronal length in the absence of the compound). In some embodiments, the method increases neuron length by about 10% to about 300% compared to a control (e.g., neuron length in the absence of the compound). In some embodiments, the method increases neuron length by about 200% to about 300% compared to a control (e.g., neuron length in the absence of the compound).

[0145] In some embodiments, the method increases the average number of spines per neuron compared to when treatment was initiated with an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the average number of spines per unit length of the neuron is increased by at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 or more, or any range between any two numerical values ​​(including the endpoints). In some embodiments, the time period is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0146] In some embodiments, the compound is useful for treating neuronal diseases and disorders. Neuronal diseases are diseases or conditions that impair the function of the nervous system of a subject. Neuronal diseases or disorders can be neurological diseases or disorders. Neuronal diseases or disorders can be related to neurodegenerative diseases or disorders.

[0147] In one aspect, a method of treating a neuronal disease in a patient in need of treatment is provided, the method comprising administering to the patient a therapeutically effective amount of an agent that binds to fascin at least binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is fragile X syndrome. In some embodiments, the disease or disorder is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the neuronal disease is traumatic brain injury. In some embodiments, the patient with the neuronal disease suffers from traumatic brain injury before, during, or after the onset of the neuronal disease. In some embodiments, neuronal disease comprises neuronal dysfunction.Neuron dysfunction can comprise atrophy or other decline in effective neuronal function.For example, Alzheimer's disease is known to exhibit neuronal dysfunction, especially in cortical neurons, such as hippocampal neurons and neurons adjacent to the hippocampus.Synaptic loss can be correlated with dendritic spine loss and neurodegeneration.

[0148] In some embodiments, the neuronal disease is associated with abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density, and / or abnormal synaptic function. In some embodiments, the neuronal disease is associated with abnormal (e.g., reduced) levels of dendritic spine density.

[0149] In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's disease with dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is stroke. In some embodiments, the neuronal disease is post-traumatic stress disorder (PTSD). In some embodiments, the neuronal disease is traumatic brain disorder (TBD). In some embodiments, the neuronal disease is chronic traumatic encephalopathy (CTE). In some embodiments, the neuronal disease is schizophrenia. In some embodiments, the neuronal disease is dementia (e.g., general dementia). In some embodiments, the neuronal disease is attention deficit / hyperactivity disorder (ADHD). In some embodiments, the neuronal disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neuronal disease is frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS). In some embodiments, the neuronal disease is memory loss. In some embodiments, the neuronal disease comprises memory loss. In some embodiments, the neuronal disease is age-associated memory loss. In some embodiments, the neuronal disease comprises age-associated memory loss. In some embodiments, the neuronal disease is hypertensive encephalopathy. In some embodiments, the neuronal disease is chronic stress. In some embodiments, the neuronal disease comprises chronic stress. In some embodiments, the neuronal disease is FTLD-TDP type A. In some embodiments, the neuronal disease is FTLD-TDP type B. In some embodiments, the neuronal disease is FTLD-TDP type C. In some embodiments, the neuronal disease is FTLD-TDP type D.

[0150] Examples of neuronal diseases that may be treated with the compounds or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, depression, perinatal asphyxia, Parkinson's disease dementia ("PD dementia"), amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Speelmeyer-Voigt-Sjogren-Batten disease), spongiform encephalopathies (e.g., bovine spongiform encephalopathy (mad cow disease), kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, Canavan disease, moss disease, and the like). Syndrome of the cerebrospinal fluid, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, secondary to pernicious anemia Subacute combined spinal cord degeneration associated with cerebrospinal fluid dysfunction, schizophrenia, spinocerebellar ataxia (multiple types with various features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord laryngeal stenosis, drug-induced parkinsonism, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial, type 1 (PARK1), Parkinson's disease 3, autosomal dominant with Lewy bodies (PARK3), Parkinson's disease 4, autosomal dominant with Lewy bodies (PARK4), Parkinson's disease 5, autosomal dominant with Lewy bodies (PARK5), Parkinson's disease 6, autosomal dominant with Lewy bodies (PARK6), Parkinson's disease 7, autosomal dominant with Lewy bodies (PARK7), Parkinson's disease 8, autosomal dominant with Lewy bodies (PARK8), Parkinson's disease 9, autosomal dominant with Lewy bodies (PARK9), Parkinson's disease 10, Parkinson's disease 11, Parkinson's disease 12, Parkinson's disease 13, Parkinson's disease 14, Parkinson's disease 15, Parkinson's disease 16, Parkinson's disease 17, Parkinson's disease 18, Parkinson's disease 19, Parkinson's disease 20, Parkinson's disease 21, Parkinson's disease 22, Parkinson's disease 23, Parkinson's disease 24, Parkinson's disease 25, Parkinson's disease 26, Parkinson's disease 27, Parkinson's disease 28, Parkinson's disease 29, Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive juvenile (PARK2), Parkinson's disease 7, autosomal recessive early-onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), or mitochondrial Parkinson's disease.In some embodiments, the neuronal disease includes Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, stroke, post-traumatic stress disorder (PTSD), traumatic brain injury (TBD), chronic traumatic encephalopathy (CTE), schizophrenia, dementia (e.g., general dementia), attention-deficit / hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS), memory loss (e.g., age-associated memory loss), hypertensive encephalopathy, or chronic stress.

[0151] In some embodiments, the neuronal disease is Alzheimer's disease (AD). Alzheimer's disease is characterized by symptoms of memory loss in the early stages of the disease. Apoε4 carriers are at increased risk of developing AD. APOε4 is believed to be less efficient than other isoforms in removing Aε, and thus may correlate with increased amyloid burden, tau phosphorylation, synaptic toxicity, and decreased synaptic density. Experiencing traumatic brain injury (TBI) is another risk factor for developing AD, and studies have shown that people who have experienced TBI have a significantly increased risk of AD. Cognitive decline is correlated with progressive synaptic loss. As the disease progresses, symptoms include confusion, loss of long-term memory, paraphasia, loss of vocabulary, aggression, irritability, and / or mood swings. In more advanced stages of the disease, there is loss of physical function. Patients with Alzheimer's disease (AD) exhibit many characteristic neurological disorders, including increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. Without wishing to be bound by theory, both the cause and the consequence of these neurological disorders are believed to be the accumulation of harmful forms of aggregated amyloid beta (Aβ) peptides in the brain. AD-related disorders include senile dementia of the AD type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-associated memory impairment (AAMI). In some embodiments, a method of treating or preventing Alzheimer's disease is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound described herein (such as compound 1). In some embodiments, the patient is an Apoε2 or Apoε3 carrier. In some embodiments, the patient has suffered from TBI. In some embodiments, the patient is an Apoε4 carrier. In some embodiments, the patient is an Apoε4 carrier who has suffered a TBI.

[0152] In some embodiments, the neuronal disease is fragile X syndrome (FXS). As known in the art, FXS is a genetic syndrome that is associated with various disorders (e.g., autism and hereditary intellectual disability). Physical disability can range from mild to severe. It has been observed that men with FXS, usually from age 40 onwards, begin to develop gradually more severe problems in performing tasks that require working memory. This is especially observed with respect to verbal working memory. In some embodiments, the neuronal disease is autism. As known in the art, autism is a neurodevelopmental disorder. Without wishing to be bound by theory, it is believed that autism affects information processing in the brain by changing how nerves and synapses connect and organize.

[0153] In further embodiments, compositions and methods are provided for alleviating, reducing, or reversing a symptom of a neuronal disease or disorder. The symptom may be any of the symptoms described herein.

[0154] Terms such as "memory" refer in their normal and customary sense to the process by which information is encoded, stored, and retrieved by a subject. Terms such as "encode" and "register" in the context of memory refer in their normal and customary sense to the reception, processing, and combination of information that affects the senses as chemical or physical stimuli. Terms such as "stored" in this context refer in their normal and customary sense to the creation of a record of encoded information. Terms such as "retrieve" and "recall" in this context refer in their normal and customary sense to the recall of stored information. As known in the art, retrieval can be in response to a cue. In some embodiments, memory loss refers to a reduced ability to encode, store, or retrieve information. In some embodiments, memory can be recognition memory or recall memory. In this context, "recognition memory" refers to the recollection of a previously encountered stimulus. The stimulus can be, for example, a word, a scene, a sound, a smell, etc., as known in the art. A broader class of memory is "recall memory," which involves the retrieval of previously learned information, such as a sequence of actions, a list of words or numbers that the subject previously encountered. Methods for evaluating the level of memory encoding, storage and retrieval performed by a subject are well known in the art, including the methods disclosed herein.For example, in some embodiments, the method improves memory in a subject suffering from a neuronal disease, in a subject in need of memory improvement.In some embodiments, the method improves memory in a subject.In some embodiments, the method treats neuronal or cognitive dysfunction in a subject.In some embodiments, the method treats neuronal dysfunction in a subject.In some embodiments, the method treats cognitive dysfunction in a subject.

[0155] In addition to any aspect disclosed herein, in some embodiments, the subject suffers from brain injury. Types of brain injury include brain damage (i.e., destruction or degeneration of brain cells), traumatic brain injury (i.e., damage resulting from external force to the brain), stroke (i.e., vascular injury, e.g., anoxia, that temporarily or permanently damages the brain), and acquired brain injury (i.e., brain damage not present at birth). In some embodiments, the method improves memory in the subject. In some embodiments, the method improves learning in the subject. In some embodiments, the method treats neuronal or cognitive dysfunction in the subject. In some embodiments, the method treats neuronal dysfunction in the subject. In some embodiments, the method treats cognitive dysfunction in the subject.

[0156] In some embodiments, a method is provided for promoting spine formation in a patient in need thereof, comprising administering to the patient a compound that inhibits fascin. In some embodiments, a method is provided for treating or preventing a neuronal disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of an agent that binds to fascin at least binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma-ceutically acceptable salt thereof. In some embodiments, a compound is provided for use in treating a neuronal disease or disorder, the compound being a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma-ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma-ceutically acceptable salt thereof. In some embodiments, a compound is provided for use in the manufacture of a medicament for the treatment of a neuronal disease or disorder, the compound being a compound of formula I, formula II, formula IV, formula V, formula VII, formula VIII, formula IX, formula X, or formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, compound 8, compound 9, compound 10, or compound 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the neuronal disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or disorder is Alzheimer's disease. In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, inhibits cross-linking of f-actin.In some embodiments, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of Formula I, Formula II, Formula IV, Formula V, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI provided herein, or a pharma- ceutically acceptable salt thereof, or Compound 1, Compound 8, Compound 9, Compound 10, or Compound 11, or a pharma- ceutically acceptable salt thereof, is anti-metastatic.

[0157] Combination therapy In one embodiment, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents used and / or developed to treat a neuronal disease or disorder.

[0158] When used to treat or prevent the above diseases and disorders, an agent that binds to fascin at least at binding site 2 or binding site 3, or a compound of formula I, II, IV, V, VII, VIII, IX, X, or XI provided herein, or a pharma- ceutically acceptable salt thereof, or compound 1, 8, 9, 10, or 11, or a pharma- ceutically acceptable salt thereof, can be administered together with one or more additional therapeutic agents, such as additional therapeutic agents approved for use in the treatment or prevention of a particular disease or disorder, more particularly, agents that are considered to constitute the current standard of care. When combination therapy is contemplated, the active agents can be administered simultaneously, separately, or sequentially in one or more pharmaceutical compositions.

[0159] Thus, recent strategies for the treatment of AD include controlling the production or aggregation state of specific isoforms of Aβ peptides. Additional strategies include the prevention, reduction, or elimination of toxic forms of phosphorylated tau. Other strategies include small molecule targeting of enzymes that play a role in the production of Aβ peptides through the processing of amyloid precursor proteins to lower the abundance of Aβ peptides in the brain. In addition, information is accumulating regarding the role of nonamyloid neuropathy, such as tauopathies or sporadic inheritance of specific mutations in the apolipoprotein E gene, which encourages additional strategies to combat neurodegeneration.

[0160] The one or more additional therapeutic agents may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, lisuride, rasagiline, tolcapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, rivastigmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omigapil, CEP-1347, isradipine, DOPA, lithium, riluzole, levetiracetam, ezogabine, pregabalin, rufinamide, felbamate, carbamazepine ... It may be zepine, valproic acid, sodium valproate, lamotrigine, phenytoin, oxcarbazepine, ethosuximide, gabapentin, tiagabine, topiramate, vigabatrin, phenobarbital, pyrimidone, clonazepam, interferon beta-la, interferon beta-lb, mitoxantrone, natalizumab, fingolimod, natalizumab, teriflunomide, dimethyl fumarate, glatiramer, ATOH1 gene therapy, ozanezumab, arimoclomol, tiracemtib, dexpramipexole, pridopidine, or galantamine, or phosphoglycerate kinase (PGK) as described in US2018 / 0147263. In some embodiments, the one or more additional therapeutic agents can be an acetylcholinesterase inhibitor (AChEI), such as acotiamide, alpha pinene, ambenonium, demecarium, DFP (diisopropylfluorophosphate), donepezil, edrophonium, galantamine, huperzine A, lactucopicrin, ladostigil, neostigmine, physostigmine, pyridostigmine, diflos, echothiopate, rivastigmine, rosmarinic acid, tacrine, ungeremine, zanapezil, ganstigmine, phenserine, phenethylnorcymserine (PENC), cymserine, thiacymserine, SPH1371 (galantamine plus), ER127528, RS1259, or F3796.In some embodiments, the one or more additional therapeutic agents may be an amyloid-clearing antibody, such as bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, BAN2401, or aducanumab.

[0161] The one or more additional therapeutic agents may be selected from the group consisting of chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, hypnotic sedatives such as temazepam, triazolam, zaleplon, or zolpidem tartrate, acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximide, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, Anticonvulsants such as thal, phenobarbital sodium, phenytoin, phenytoin sodium, pyrimidones, tiagabine hydrochloride, topiramate, sodium valproate, or valproic acid, amitriptyline hydrochloride, amitriptyline pamoate, amoxapine, bupropion hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine hydrochloride, imipramine hydrochloride, imipramine pamoate, mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phene sulfate Antidepressants such as ludine, sertraline hydrochloride, tranylcypromine sulfate, trimipramine maleate, or venlafaxine hydrochloride; antianxiety drugs such as alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, meprobamate, midazolam hydrochloride, or oxazepam; chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluphenazine antipsychotics such as fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, or trifluoperazine hydrochloride, amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride,Central nervous system stimulants such as methylphenidate hydrochloride, modafinil, pemoline, or phentermine hydrochloride; antiparkinsonian drugs such as amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, or trihexyphenidyl hydrochloride; bupropion hydrochloride, donepezil hydrochloride, droperidol, and fluvoxamine maleate. Central nervous system drugs such as triptan, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan; cholinergic agents (e.g., parasympathomimetics) such as bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, or pyridostigmine bromide; astropine sulfate, dicyclopentasiloxane, or cyclohexasiloxane; anticholinergics such as scopolamine hydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate, propantheline bromide, scopolamine, butylscopolamine bromide, or scopolamine hydrobromide; adrenergic agonists (sympathomimetics) such as dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, or pseudoephedrine sulfate; dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, or propranolol salts adrenergic blockers (sympatholytics) such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, or tizanidine hydrochloride; skeletal muscle relaxants such as atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, or vecuronium bromide; or betamethasone,It may be a corticosteroid such as betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, or triamcinolone acetate.

[0162] The one or more additional therapeutic agents may be levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, bicifadine, tesofensine, brasofensine, isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine, desic In some embodiments, the antidepressant may be selected from fluoxetine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, trimipramine, fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, sertraline, ketamine, esketamine, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, and St. John's wort.

[0163] kit Also provided herein is a kit comprising the compound described herein, or its pharmaceutically acceptable salt, optionally a second active ingredient, and suitable packaging.In one embodiment, the kit further comprises instructions for use.In one aspect, the kit comprises the compound or its pharmaceutically acceptable salt, and a label and / or instructions for use of the pharmaceutical composition in treating indications, including diseases or conditions described herein.

[0164] Also provided herein is an article of manufacture comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, nebulizer, aerosol dispensing device, dropper, or intravenous bag.

[0165] Pharmaceutical Compositions and Modes of Administration The compounds provided herein are usually administered in the form of pharmaceutical compositions.Therefore, the present invention also provides pharmaceutical compositions that generally comprise the compounds described herein, or their pharma-ceutically acceptable salts, and one or more pharma-ceutically acceptable vehicles selected from carriers, adjuvants and excipients, and contain one or more of the compounds described herein.Suitable pharma-ceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.Such compositions are prepared in a manner well known in the pharmaceutical field.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Edition (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Edition (edited by G.S. Banker & C.T. Rhodes).

[0166] The pharmaceutical composition can be administered either in a single dose or multiple doses.The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal and transdermal routes.In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenously, intraperitoneally ("ip"), parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0167] One mode of administration is parenteral, for example, by injection.The form in which the pharmaceutical composition described herein can be incorporated for administration by injection includes, for example, aqueous or oily suspension or emulsion, including sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0168] Oral administration may be another route for administering the compositions described herein. Administration may be, for example, via capsules or enteric coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein or its pharma- ceutically acceptable salts, the active ingredient is usually diluted by an excipient and / or enclosed in a carrier, such as may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it serves as a vehicle, carrier or medium for the active ingredient and may be in the form of a solid, semi-solid, or liquid material. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solution, and sterile packaged powder.

[0169] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation can additionally include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents.

[0170] The pharmaceutical composition and any container into which it is dispensed may be sterilized.The pharmaceutical composition may also contain adjuvants such as preservatives, stabilizers, emulsifying or suspending agents, wetting agents, salts for changing the osmotic pressure, viscosity agents, or buffers.

[0171] Compositions comprising at least one compound described herein, such as the compounds described herein or pharma- ceutically acceptable salts thereof, can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems comprising polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches include those constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0172] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compound described herein or a pharma- ceutically acceptable salt thereof. When these preformulation compositions are referred to as homogenous, the active ingredient is evenly dispersed throughout the composition, and the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, capsules, and the like.

[0173] The tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter in the form of an envelope covering the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0174] The pharmaceutical composition can be formulated for nasal administration. Such pharmaceutical composition can include one or more active ingredients, such as the compounds described herein or their pharmaceutically acceptable salts, in various physical states. For example, the active ingredient can be dissolved or suspended in a liquid carrier. The active ingredient can be in a dry form. The dry form can be a powder. The active ingredient in the powder can be amorphous or crystalline. For example, the compounds described herein or their pharmaceutically acceptable salts can be amorphous or crystalline. The crystalline active material can be a hydrate or solvate.

[0175] The solid compound, or its salt or crystal, may be present in the formulation with a selected average particle size. The particles have an average particle size (longest dimension) of 10 nm, 100 nm, 300 nm, 500 nm, 1 μm, 10 μm, 50 μm, 100 μm, 300 μm, or 500 μm, or a range between any two values.

[0176] Administration may be by inhalation or insufflation. Compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by oral or nasal respiratory routes. The effect may be local or systemic. In certain embodiments, the effect is local to the cranial tissues. In other embodiments, the compositions in pharma- ceutically acceptable solvents may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner. Pharmaceutical compositions for inhalation or insufflation may be aerosols.

[0177] The pharmaceutical composition may include a liquid suspension or solution containing about 0.05%, about 0.1%, about 0.3%, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, or about 5% w / w of the active ingredient. The liquid may include water and / or alcohol. The liquid may include a pH adjuster such that the pH is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range of values ​​therebetween.

[0178] The pharmaceutical composition may include a pharma- ceutically acceptable preservative. Preservatives suitable for use herein include those that protect the solution from contamination with pathogenic particles, including, but not limited to, phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. In certain embodiments, the pharmaceutical composition includes about 0.01% to about 1.0% w / w benzalkonium chloride, or about 0.01% to about 1% v / w phenylethyl alcohol. The preservative may also be present in an amount of about 0.01% to about 1%, preferably about 0.002% to about 0.02%, of the total weight or volume of the composition.

[0179] The pharmaceutical compositions may also contain one or more emulsifying agents, wetting agents or suspending agents, at about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1% w / w. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, lecithin, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-diol alginate, agar, carrageenan, locust bean gum, guar gum, tragacanth, acacia, xanthan gum, karaya gum, pectin, amidated pectin, phosphatidic acid ammonium salts of fatty acids, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl methylcellulose, carboxymethylcellulose, sodium, potassium and calcium salts of fatty acids, mono- and diglycerides of fatty acids, acetate esters of mono- and diglycerides of fatty acids, lactate esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, monoacetyl tartaric acid and diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate and tartaric acid esters of mono- and diglycerides of fatty acids, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol esters of polycondensed fatty acids of castor oil, propane-1,2-diol esters, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearoyl tartrate, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, extract of Quillaja japonica, polyglycerol esters of dimerized fatty acids of soybean oil, oxidatively polymerized soybean oil, and pectin extract.

[0180] In a further embodiment, the pharmaceutical composition for nasal administration may be provided in the form of a powder. For example, the powdered nasal composition may be used directly as a powder unit dosage form. If necessary, the powder may be filled into a capsule, such as a hard gelatin capsule. The contents of the capsule or single dose device may be administered, for example, using an insufflator.

[0181] Thus, a method for treating a neuronal disorder may comprise the step of intranasally administering to a subject in need thereof a pharmaceutical composition comprising a compound described herein or a salt thereof. Administration

[0182] The specific dosage level of the active ingredients of the present application (e.g., a compound described herein or a salt thereof) for a specific subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, as well as the excretion rate in the subject being treated, the drug combination, and the severity of the particular disease. For example, dosages can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, between about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, as occurs when using drugs in both children and adults, or when translating effective dosages for non-human subjects, such as dogs, to dosages appropriate for human subjects.

[0183] A daily dose may also be described as the total amount of a compound described herein administered per dose or per day. The daily dose of a compound described herein or a salt thereof may be between about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0184] When administered intranasally, the total daily dosage for a human subject can be between 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In various embodiments, the daily dosage is about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range of values ​​therebetween.

[0185] The active ingredient of the present application or a pharmaceutical composition thereof can be administered once, twice, three times, or four times a day using any suitable mode described above. Also, administration or treatment can continue for several days. For example, treatment usually continues for at least 7 days, 14 days, or 28 days in one cycle of treatment. Treatment cycles are well known and often alternate with a rest period of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycles can also be continuous. Administration or treatment can be continued indefinitely.

[0186] In certain embodiments, the method includes administering to a subject an initial daily dose of about 1-800 mg of a compound described herein, and gradually increasing the dose until a clinical response is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week. EXAMPLES

[0187] Working Example Example 1 Analysis and preparation of phasin crystal structure All available phasin crystal structures were downloaded from the PDB and prepared for structure analysis. Structures were solved by eye and by standard automated protocols implemented in MolSoft's ICM-Pro software. Hydrogen atoms were added to the structures and consideration was given to crystallographic quality flags such as correct orientation of Asn and Gln side chains, ligand and protein charges, histidine orientation and protonation state, and high b-factors or low occupancy.

[0188] MolSoft's ICMPocketFinder algorithm was used to identify potential ligand-binding pockets and cavities in all available fascin crystal structures. Pockets were searched in active chain A of crystal structure 3LLP. This structure has the highest resolution (1.8 Å). Figure 2A-D provide the "front", "bottom", "top", and "back" views of fascin, respectively, with pockets A-D shown.

[0189] Four "drug-like" pockets (Pockets AD) that appear to have suitable properties for small molecule binding were identified.

[0190] Ligand docking and scoring Using MolSoft's ICM-Docking software (version 3.8-6a), the headgroup and head+tail of comparative compound 2, comparative compound 3, and comparative compound 4 were docked into each of the four pockets shown in Figure 1. The docking scores into each pocket are shown in Table 1. The lower the docking score, the better the interaction with the ligand.

[0191] Comparative compound 2 has the following structure: [ka] Comparative compound 3 has the following structure: [ka] Comparative compound 4 has the following structure: [ka] [Table 1]

[0192] As shown in Figure 1, pocket B, which is located in actin-binding site 1, yielded the lowest docking score. This site was further investigated in other fascin crystal structures. This pocket is in close proximity to the pentaethylene glycol binding site in PDB 3P53. The head group was docked into pocket B of PDB 3P53, which gave a significantly better score. [Table 2]

[0193] The docked headgroup was then used as an anchor point to dock the tail, and the final energetically favorable ligand poses are shown in Figures 3A-C.

[0194] Figures 3A-C show docked complexes of human fascin 1 with comparative compound 2, comparative compound 3, and comparative compound 4. All three ligands form hydrogen bonds from the nitrogen of the benzothiazole ring to ARG389, and the first ethylene glycol forms a hydrogen bond with LYS460.

[0195] Figure 4 shows a 2D interaction diagram of the complex of comparative compound 2 with human fascin 1. The dashed arrows represent hydrogen bonds. The thick lines surrounding the ligand shape indicate the accessible surface. The residue ellipse size represents the strength of the contact. The 2D distance between the residue label and the ligand represents the proximity.

[0196] Example 2 The crystal structure of phasin bound to compound 1 (Protein Data Bank (PDB) 6B0T) was prepared for structure analysis, as shown in Figure 5. The structure was solved by eye and by a standard automated protocol built into MolSoft's ICM-Pro software. Hydrogen atoms were added to the structure and consideration was given to correct orientation of Asn and Gln side chains, ligand and protein charges, histidine orientation and protonation state, and crystallographic quality flags such as high b-factor or low occupancy. MolSoft's ICMPocketFinder algorithm was used to define the binding pocket for docking. The phasin binding site was described by the closest neighboring residues to the ligand (residues within a distance of 3 Å). Referring to Figure 5, fascin binding site 1 was defined by V10, Q11, L40, K41, A137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and Y493, and binding site 2 was defined by F14, L16, L48, Q50, L62, W101, L103, E215, and S218. Ligand docking and scoring

[0197] The comparative compound 2, the comparative compound 3, and the comparative compound 4 were docked into each binding site to determine the most favorable binding site for each compound. The predicted energetically favorable binding conformations of the comparative compound 2, the comparative compound 3, and the comparative compound 4 are as shown above.

[0198] The headgroup and head+tail of Comparative Compound 2, Comparative Compound 3, and Comparative Compound 4 were docked into binding site 2 (see rows in Table 3). The docking scores into each pocket are shown in Table 3. The lower the docking score, the better the interaction with the ligand. When Comparative Compounds 2, 3, and 4 were docked into binding site 2, the scores were significantly higher, indicating less favorable binding. [Table 3]

[0199] The two compounds docked into binding site 1 and binding site 2 (compound 5 and compound 6) have the following structures: [ka] The docking scores are shown in Table 4. Based on the results, both compound 5 and compound 6 are unlikely to bind to binding site 1 and binding site 2. [Table 4]

[0200] Example 3 The effect of the indicated compounds on synaptic density of mouse cortical primary neurons was determined 24 hours after treatment. Figure 6. Mouse cortical primary neurons were treated with 1 uM of fascin-inhibiting small molecules or vehicle (DMSO) in vitro on day 15. After 24 hours of treatment, neurons were fixed and immunolabeled for protein components of synapses (synaptophysin (P38), a presynaptic vesicle protein) and then stained with the nuclear dye DAPI. Immunolabeled neurons were imaged with a Leica confocal microscope. The number of P38 immunopositive puncta was analyzed using FIJI with the Squash plugin. Data was analyzed and plotted in Graphpad Prism (** p<0.0001, * p=0.0012, two-tailed T-test). Figure 6 shows the synaptic growth results of Comparative Compound 2, Comparative Compound 7, and Compound 1 compared to vehicle control in one embodiment. Comparative Compound 7 has the following structure: [ka]

[0201] Example 4 Efficacy Testing Procedures We selected female APOe4-TR mice because several studies have shown that females with APOe4 have poorer memory, greater brain atrophy, and lower brain metabolism than males. Females with APOe4 are also more likely to develop mild cognitive impairment or Alzheimer's disease than males with the allele. Mice expressing the APOe3 allele (APOe3-TR) serve as controls. Additionally, controlled cortical impact (CCI) was administered to APOe4-TR and APOe3 mice to produce a reliable and regulated TBI event. Anesthetized mice subjected to CCI receive an impact with a velocity of 5.0 m / s, a depth of 1.0 mm, and a dwell time of 50 ms. Control animals undergo the same approximately 20-25 min procedure without receiving the impact.

[0202] Determining that CCI exacerbates cognitive decline in APOe4-TR mice. It is hypothesized that cognitive and motor performance in APOe4 mice is exacerbated by a synergistic effect of TBI and APOe4 genotype on dendritic spine synapses. To test this, CCI (or a control procedure without impact) is administered to 8-month-old APOe4-TR and APOe3-TR mice (12 mice per group), followed by behavioral testing at 10 and 12 months of age. Behavioral testing is scheduled from least stressful to most stressful tasks (i.e., aversive tasks involving restraint versus minimal handling) as follows (behavioral phenotyping is performed using Ethovision Xt (Noldus)). Open field test (day 1): Using video tracking, the time and frequency that mice spend in the center and periphery of the arena can be used to assess anxiety. Increased time in the periphery indicates increased anxiety, while distance traveled and speed indicate locomotor activity / spontaneous activity. New place and object recognition (days 6–7): After 4 days of habituation (day 6), mice explore two identical objects in the arena, then are returned to the arena the next day (day 7). One of the objects is replaced with a new object. Increased time exploring the familiar object in the new location, or the new object, indicates improved memory. Y-maze (day 8): Spontaneous alternation behavior in the Y-maze is performed to measure rodents' willingness to explore a new environment. Mice prefer to explore new arms over returning to previously visited arms. Each mouse is placed at the end of one arm and allowed to move freely through the maze during an 8-min session. Alternation behavior is defined as consecutive entries into three arms in three overlapping sets of trials. Barnes maze (days 9–13): This test assesses hippocampus-dependent spatial learning and memory. During acquisition, mice are trained to use extramaze visual cues to find an escape hole hidden in a circular table. Mice are tested in two trials per day with approximately 30 minutes between trials. If a mouse does not enter the escape cage within 5 minutes, it is guided to the correct escape location. Tail Suspension (Day 14): In the tail suspension test, mice are suspended above the ground by their tails.The time of immobility (seconds) is used as a measure of stress. Contextual fear conditioning (days 15-16): Mice are placed in a new chamber where an electric shock is administered. After 24 hours, mice are returned to the chamber and the amount of freezing behavior is recorded. Increased freezing indicates improved memory for the context.

[0203] Expected and Alternative Outcomes: The effects of TBI and APOe4 genotype on synapse loss and cognition will be characterized. The combination of these AD risk factors is expected to lead to further (beyond APOe4 alone) impairments in the measured tasks, especially spatial memory, as this combination relies on structures that are hit hard by synapse loss during AD and TBI. Although unlikely, it is possible that no performance decline will be observed in either task with the addition of TBI. In this case, we will consider optimizing the CCI framework to induce more robust synapse loss. Some functional impairments may not correspond to detectable synapse loss. Adding TBI can make it difficult to reverse the occurring functional impairments, thus providing a valid test of SPG ability to treat common gene X-environment interactions in AD.

[0204] To determine compounds that improve TBI-induced cognitive decline in APOe4-TR mice. The spine forming effects of compounds may counteract synaptic loss induced by the APOe4 genotype and additional TBI, leading to improved functional recovery. As in Aim 1, 8-month-old APOe4-TR and APOe3-TR mice subjected to CCI will be treated with compounds (30 mg / kg / day, i.p.) or vehicle starting immediately after the CCI procedure and continuing with behavioral testing at 10 and 12 months of age (as described in Aim 1). For daily administration in rodents over a long period of time, the intraperitoneal route of administration will be used.

[0205] Expected and alternative outcomes: Both cognitive and motor functions improve in APOe4-TR mice exposed to CCI. In some cases, only one symptom domain is restored (e.g., spatial memory but not motor skills) due to a synergistic effect between APOe4 status and TBI on neuronal viability in specific brain regions. When neuronal death exceeds a certain level, recovery of synaptic density may not be possible. Evaluation of histological data calibrates neuronal loss, taking into account the CCI protocol.

[0206] Aim 3: Evaluate the effect of compounds on dendritic spine density and Alzheimer's-related molecular biomarkers in APOe4-TR mice. In Aim 2 (APOe4-TR+ / -CCI), we hypothesize that mice treated with compounds will show improved spine density and reduced Ab-initiated dephosphorylation of cofilin. We further hypothesize that by inhibiting fascin, microglial migration and activation may be reduced, and thus active compounds will reduce synapse pruning by microglia. Attributes to be measured include (i) synapse density, (ii) phospho-cofilin, and (iii) synapse-associated activated microglia. Additionally, we will assess levels of phospho-tau and Ab.

[0207] Mice are anesthetized and perfused transcardially with paraformaldehyde, and brains are collected for histological and dendritic spine analysis. Neuronal loss in the hippocampus, entorhinal cortex, and several neocortical regions (e.g., insula, prefrontal cortex) is assessed via unbiased stereology (Stereo Investigator System, MBF Biosciences) using cresyl violet and NeuN stained sections. Brain volume, especially within the hippocampal formation, is measured by the Cavalier method. Synaptic puncta are labeled with antibodies against synaptophysin (presynaptic terminals) and PSD95 (postsynaptic density) and counted with Bitplane Imaris. Fascin levels and distribution to synapses are determined as well. Glial cell density and activation state are also assessed. Microglia are detected by immunohistochemistry for IBA1, and microglial cell bodies are automatically counted by Bitplane Imaris. Additional tests include stratifying microglia into synapse-associated and extrasynaptic IBA+ cells based on their proximity to PSD95 staining. Microglia are further stratified as plaque-associated and non-plaque-associated IBA1+ cells. Microglial activation state is assessed using antibodies against a set of known microglial surface markers, including CD45 and CD68. Astrocyte number and activation state, as well as distribution relative to synapses, are similarly assessed using antibodies against GFAP, BLPB, and S100b. Additionally, Aβ and tau pathology are measured using 3D volumetric Aβ / tau burden analysis via Imaris software and commercially available antibodies.

[0208] Stereoscopic quantification was performed using Microbrightfield Bioscience (MBF Stereo-investigator software from Microbrightfield Bioscience (MBF Bioscience, Williston, VT, USA) was used to determine the number of spines in the stratum radiatum (SR) and plexiform molecular layer of the hippocampal CA3 field. Briefly, stereological quantification was performed using every other section and Stereo-Investigator software from Microbrightfield Bioscience (MBF Bioscience, Williston, VT, USA) to determine the number of spines in the stratum radiatum (SR) and plexiform molecular layer of the hippocampal CA3 field. Briefly, stereological quantification was performed using every other section and Stereo-Investigator software from Microbrightfield Bioscience (MBF Bioscience, Williston, VT, USA) to determine the number of spines in the stratum radiatum (SR) and plexiform molecular layer of the hippocampal CA3 field. Briefly, every other section was used throughout to perform stereological quantification to determine spine number in the stratum radiatum (SR) and plexiform molecular layer of the hippocampal CA3 field by using Stereo-Investigator software from Microbrightfield Bioscience (MBF Bioscience, Williston, VT, USA). Briefly, every other section was used throughout. Dendritic spine density and dendritic morphology were measured stereologically using Neurolucida software (MBF Bioscience, Williston, VT, USA) to determine spine number in the stratum radiatum (SR) and dentate gyrus (DG) of the hippocampus. Mouse brains were processed using the superGolgi kit (Bioenno Tech LLC, Santa Ana, CA) as previously described. The CA1 stratum radiatum and dentate gyrus regions of the hippocampus, as well as layer 2 of the entorhinal cortex and layers 2 / 3 of the insula and medial prefrontal cortex, are defined using a 5x objective and spines are counted using a 100x / 1.4 objective.For dendritic spine length and spine volume, a 100x / 1.4 objective is used to trace and data is analyzed via Neurolucida Explorer software. Spine density is correlated with behavioral recovery measures in Objective 2. For dendritic morphology analysis, for the CA1 hippocampal region, 5 neurons per animal (n=6) are traced using Neurolucida software and assessed using Sholl analysis.

[0209] Expected and Alternative Results: Treatment increases hippocampal dendritic spine density by approximately 20% or more, nearly offsetting the losses caused by the APOe4 genotype and APOe4 X CCI, and increases levels of phospho-cofilin. In some cases, treatment reduces microglial phagocytosis of synapses.

[0210] Example 5 Spine formation test To determine whether small molecule inhibitors of fascin 1 induce the formation of new dendritic spine synapses in the prefrontal cortex, mice are treated with fascin 1 inhibitors Compound 1 and Compound 11, and then dendritic spine density and morphology are analyzed by Golgi staining. Specifically, 15 C57BL / 6J mice, aged 26 weeks, are acclimated to housing and handling conditions for 3 days and then randomly assigned to three treatment groups (5 mice / group): (1) vehicle (7% DMSO, 14% Tween 80, H2O) control, (2) Compound 1 at 10 mg / kg, (3) Compound 11 at 10 mg / kg. Mice are then intraperitoneally injected daily for 26 days with vehicle, Compound 1, or Compound 11. Two hours after the last injection, mice are sacrificed and brains are rapidly removed for infiltration fixation followed by Golgi staining. After completion of Golgi staining, sections of the prefrontal cortex are cut in the coronal plane and mounted for imaging using a microscope. Dendritic spine density is analyzed on layer II / III prefrontal cortical neurons by the method described in Example 4 herein (n=X images / section, Y sections / mouse).

[0211] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0212] The disclosure illustratively described herein can suitably be practiced in the absence of any element(s), limitation(s) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc., should be read broadly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description and not of limitation. It should also be recognized that the terms and expressions are not used with the intention of excluding any equivalents of the features or portions thereof shown and described, and various modifications are possible.

[0213] Thus, although the present disclosure has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications, improvements, and variations of the disclosure embodied in the invention disclosed herein may be practiced by those skilled in the art, and such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended to limit the scope of the present disclosure.

[0214] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

Claims

[Claim 1] The invention described in this specification.

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