Methods for Treating Spinal Cord Injury or Damage

Abstract

In some embodiments, the present invention provides a method for treating spinal cord injury or damage or its complications in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of the compound of formula I, Ia, Ik or II.Generally, the compounds and methods described herein provide for the administration of compounds that provide benefits in treating spinal cord injury or damage or its complications.In some embodiments, the compositions and methods are useful for treating complications resulting from neuronal damage suffered in spinal cord injury.

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. 63 / 287,710, filed December 9, 2021, and U.S. Provisional Patent Application No. 63 / 152,174, filed February 22, 2021, each of which is hereby incorporated by reference in its entirety.

[0002] Field Provided herein are methods for treating spinal cord injury and promoting spine formation in patients suffering from spinal cord injury or damage. [Background technology]

[0003] background Spinal cord injury (SCI) is a serious cause of hospitalization, and many patients with such injuries require mid- or long-term care. The average length of stay for such patients in hospital acute care is 11 days, and rehabilitation is 31 days. Spinal cord injury is also a cause of significant morbidity. For example, 39.5% of individuals with spinal cord injuries are considered paraplegic, and 59.9% are considered quadriplegic. The cost of caring for such patients is significant. Researchers estimated that as of 2019, 17,730 new SCI cases occur annually, and that 249,000–363,000 individuals are currently surviving with SCI in the United States. Spinal cord injury can result from damage or loss of neurons and synaptic connections between them. Secondary pathologies that can result from spinal cord injury include diseases of the genitourinary system, diseases of the skin, respiratory diseases, gastrointestinal diseases, circulatory diseases, and musculoskeletal diseases. In some circumstances, hospital readmission may be required. Respiratory complications associated with SCI are a significant cause of morbidity and mortality, both in the acute and chronic phases.

[0004] Spinal cord injury may also involve loss of neuronal health. Neuronal degeneration may result from loss of synapses (the junctions between two different neurons) and ultimately loss of neurons (neurodegeneration). Neurons in the spinal cord receive excitatory input from axons, which use glutamate as a neurotransmitter, and the postsynaptic elements may be dendritic spines. Such junctions are often damaged or lost in spinal cord injury, leading to impairments in voluntary muscle control and autonomic function. The development of novel methods to restore spine density after SCI may have important implications for the treatment of many complications resulting from spinal cord injury, addressing the inherent damage to spines.

[0005] Identification of novel intracellular targets of small molecules may lead to the treatment of neuronal disorders and complications of spinal cord injury. Thus, small molecules that promote spine formation may be used to improve the complications resulting from SCI. However, pharmacologic acceptable compounds with such activity are needed. Summary of the Invention [Means for solving the problem]

[0006] overview Provided herein are methods for treating spinal cord injury or damage, or complications thereof, in a patient suffering from a spinal cord injury or damage.

[0007] In some embodiments, the disclosure provides a method for treating spinal cord injury or damage or a complication thereof comprising contacting with a compound described herein.

[0008] In some embodiments, the disclosure provides a method of treating spinal cord injury or damage or a complication thereof in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or Ia: [ka] [In the formula, subscripts n and p are independently selected from 0, 1, or 2; Each R 1 is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro; A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, wherein R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; X is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, with the proviso that A is arylene and Y is -S- or -NR 2 -, provided that X is not -S-; Y is -O-, -S-, -SO-, S(O)2-, and -NR 2 - selected from the group consisting of Z is -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R 3 )O) q -T, where the subscript q is an integer from 1 to 100, and R 3 is selected from the group consisting of hydrogen and methyl; T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharides and -L-oligosaccharides; and L is selected from the group consisting of a bond, phosphate, and sulfate. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0009] In some embodiments, the present disclosure provides a method of treating a spinal cord injury or damage or a complication thereof in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula II: [ka] [In the formula, Y is -NR 33 - or -S-, Each 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, -C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each 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, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 33 is H, alkyl, or substituted alkyl; X 31 and X 32 each is independently a halogen; Each of z1 and z2 independently represents an integer of 0 to 4. z3 is an integer from 1 to 12. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0010] In some embodiments, the complication of spinal cord injury or damage is respiratory complications, cardiovascular complications, hypotension, bradycardia, neurogenic shock, autonomic dysreflexia, secondary immune deficiency, syringomyelia, neuropathic arthropathy, Charcot arthropathy, loss of motor control, loss of sensory function, quadriplegia, paraplegia, loss of bladder control, spasms, loss of sexual function, anesthesia, loss of balance, deep vein thrombosis, spasticity, pain, neuropathic pain, syringomyelia, nerve heterotopic ossification, shock, bradycardial arrhythmia, hypotension, ectopic beats, abnormal thermoregulation, changes in sweat secretion, vasodilation, thromboembolism, pressure ulcers, or heterotopic ossification, or a combination thereof. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1A illustrates enhanced recovery from spinal cord injury in rats treated with compound 1 of the present disclosure as determined by diaphragm EMG, and FIG. 1B illustrates the extent of recovery in rats treated with compound 1 compared to vehicle (0.5% DMSO in phosphate buffered saline). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description In general, the compounds and methods described herein provide for the administration of compounds that provide benefits in the treatment of spinal cord injury or damage or its complications.In some embodiments, the compositions and methods are useful for the treatment of complications resulting from neuronal damage incurred in spinal cord injury.In general, the active or main component will comprise an agent, such as a compound, or a deuterated analogue, pharma-ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers of the compounds described herein.The compounds described herein may also be administered with one or more additional pharma-ceutically active materials, or in combination with one or more non-pharma-ceutical therapies. I. Definition

[0013] The following description describes exemplary embodiments of the present technology, however, it should be understood that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0014] As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used dictates otherwise.

[0015] A "pediatric patient" is a person under the age of 18. A "juvenile patient" is a person who has not reached physical maturity.

[0016] The term "spine formation" and the like commonly and conventionally refer 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 altering the normal distribution of spine morphology. Promotion is relative to the promotion in the absence of administration of the compound.

[0017] As used herein, the term "dendrite" refers to the branching extension of a neuron. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axons of adjacent neurons. The term "dendritic spine" or "dendritic spine" refers to a protoplasmic projection on a neuron (e.g., on a dendrite). In some embodiments, a dendritic spine may be described as having a membranous neck that may terminate in a capitellum (e.g., a capitellum). Dendritic spines are classified according to their shape: e.g., thin, stubby, or mushroom. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuron. For example, dendritic spine density can be obtained as the number of dendritic spines per micron.

[0018] The term "dendritic spine formation" and the like usually and conventionally refer to a process that results in an increase in the number of dendritic spines or enhanced development of dendritic spines. The term "dendritic spine morphology" and the like usually and conventionally refer to the physical characterization (e.g., shape and structure) of dendritic spines. Improvement of dendritic spine morphology is a change in morphology (e.g., length or width) that results in enhanced functionality, which may occur with, but is not limited to, an increase in the number of synaptic connections between neurons, an increase in the volume of the spine head and an increase in the area of ​​the associated postsynaptic density (PSD), "maturation" of spines to become more mushroom-shaped than thin, better alignment of PSDs with presynaptic sites of glutamate release (i.e., active areas), an increase in the width of the spine neck, and clustering of dendritic spines within an area of ​​the dendritic membrane. As known in the art and disclosed herein, an exemplary method of such characterization includes measuring the dimensions (i.e., length and width) of dendritic spines. Accordingly, the term "improved dendritic spine morphology" generally refers to an increase in the length, width, or both the length and width of dendritic spines.

[0019] "Binding" refers to the closeness of at least two specific species (e.g., chemical compounds, including biomolecules, or cells) to react or interact with each other, resulting in the formation of a complex. For example, binding of two specific species (e.g., a protein and a compound described herein) can result in the formation of a complex, where each species interacts via a non-covalent or covalent bond. In some embodiments, the resulting complex is formed when two specific species (e.g., a protein and a compound described herein) interact with each other via a non-covalent bond (e.g., electrostatic, van der Waals, or hydrophobic).

[0020] As defined herein, the terms "activation," "activate," "activating," and the like, in relation to protein-activator (e.g., agonist) interactions, mean to favorably affect (e.g., enhance) the activity or function of the protein compared to the activity or function of the protein without the activator (e.g., a compound described herein).

[0021] As defined herein, the terms "inhibit," "inhibit," "inhibiting," and the like are given their customary meaning to one of ordinary skill in the art. In the context of protein-inhibitor (e.g., antagonist) interactions, the terms "inhibit," "inhibit," and "inhibiting" refer to adversely affecting (e.g., decreasing) the functional activity of a protein compared to the functional activity of the protein without the inhibitor.

[0022] A dash symbol ("-") 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 the carbon atom. Dash symbols at the front or end of a chemical group are for convenience, and the chemical group may be depicted with or without one or more dash symbols without loss of ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. No directionality is indicated or implied by the order in which chemical groups are described or named, unless chemically or structurally required.

[0023] 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.

[0024] References to "about" with respect to a value or parameter herein include (and describe) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the specified amount. In other embodiments, the term "about" includes ±5% of the specified amount. In certain other embodiments, the term "about" includes ±1% of the specified amount. Also, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural references 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 than one assay and equivalents thereof known to those of skill in the art.

[0025] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0026] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably from 1 to 3, or more preferably from 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy nitro, -SOH, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0027] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl can be any number of carbons, e.g., C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6, and C6. Alkenyl groups can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0028] "Substituted alkenyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cyclo refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of alkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SOH, substituted sulfonyl, substituted sulfonyloxy, and thiol, provided that any hydroxyl or thiol substituents are not attached to a vinyl (unsaturated) carbon atom.

[0029] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Acyl includes the "acetyl" group, CHC(O)-.

[0030] "Acylamino" is -NR 47 C(O)alkyl, -NR 47 C(O) substituted alkyl, -NR 47 C(O)cycloalkyl, -NR 47 C(O)-substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O)alkenyl, -NR 47 C(O) substituted alkenyl, -NR 47 C(O)aryl, -NR 47 C(O) substituted aryl, -NR 47 C(O)heteroaryl, -NR 47 C(O)-substituted heteroaryl, -NR 47 C(O) heterocyclic, and -NR 47 C(O)-substituted heterocyclic rings, 47 is hydrogen or alkyl.

[0031] "Acyloxy" refers to alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- groups.

[0032] "Alkynyl" refers to an alkynyl 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 unbranched or branched hydrocarbon group having at least one carbon-carbon triple bond and at least one carbon-carbon double bond.

[0033] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. "Substituted alkoxy" refers to an -O-(substituted alkyl) group, where substituted alkyl is as defined herein.

[0034] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced with halogen.

[0035] "Alkylthio" refers to the group "alkyl-S--".

[0036] "Amide" is -C(O)NR y R z -C-amide groups and -NR y C(O)R z "N-amide" refers to both the "N-amino" and "N-aryl" groups, y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which is optionally substituted.

[0037] "Amino" refers to the group -NH. "Substituted amino" refers to the group -NR 48 R 49 R48 and R 49 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic; R 48 and R 49 optionally form, together with the nitrogen to which they are attached, a heterocyclic or substituted heterocyclic group, with the proviso that R 48 and R 49 and (b) are not both hydrogen.

[0038] "Aminocarbonyl" is -C(O)NR 50 R 51 R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen to which they are attached. "Aminocarbonylamino" refers to -NR 47 C(O)NR 50 R 51 R 47 is hydrogen or alkyl, and R 50 and R 51is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0039] "Aminocarbonyloxy" is -OC(O)NR 50 R 51 R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0040] "Aminosulfonyl" is -SONR 50 R 51 R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0041] "Aminosulfonyloxy" is -O-SONR 50 R 51 R 50 and R 51is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0042] "Aminosulfonylamino" is -NR 47 SO2NR 50 R 51 R 47 is hydrogen or alkyl, and R 50 and R 51 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0043] "Amidino" is -C(=NR 52 )NR 50 R 51 R 50 , R 51 and R 52 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 50 and R 51 optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group.

[0044] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). The condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.), provided that the point of attachment is to an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. "Substituted aryl" refers to one to five, preferably one to three, or more preferably one to two alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester) "aryl" refers to an aryl group substituted with a substituent selected from the group consisting of oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SOH, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0045] "Arylene" refers to a divalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings. "Substituted arylene" refers to an arylene having one to five, preferably one to three, or more preferably one to two, substituents as defined for an aryl group.

[0046] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy. "Substituted aryloxy" refers to the group -O-(substituted aryl).

[0047] "Carbonyl" refers to the divalent group -C(O)- (i.e., -C(=O)-).

[0048] "Aralkyl" refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0049] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the -NR group y C(O)OR z "N-carbamoyl" refers to both the "N-carbamoyl" group and the "N-carbamoyl" group, y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which is optionally substituted.

[0050] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.

[0051] "Carboxyl ester" or "carboxy ester" refers to the groups -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)(O)-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic. "(carboxyl ester)amino" refers to -NR 47C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl, -NR 47 C(O)(O)-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-aryl, -NR 47 C(O)(O)-substituted aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -NR 47 C(O)(O)-heterocyclic, and -NR 47 "(Carboxyl ester)oxy" refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic groups.

[0052] "Cyano" refers to the radical -CN.

[0053] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the indicated number of atoms. Cycloalkyl is defined as any of the C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10, C 3~11 , and C 3~12 Cycloalkyl groups may contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. "Cycloalkenyl" refers to a partially unsaturated cycloalkyl group having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl groups may be saturated monocyclic C 3~8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3~6When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted. "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl groups that have one to five, or preferably one to three, oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino ...

[0036] This refers to a cycloalkyl or cycloalkenyl group having a substituent selected from the group consisting of aryl, aryloxy ...

[0054] "Cycloalkyloxy" refers to -O-cycloalkyl. "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl). "Cycloalkenyloxy" refers to -O-cycloalkenyl. "Substituted cycloalkenyloxy" refers to -O-(substituted cycloalkenyl).

[0055] "Guanidino" refers to the group -NHC(=NH)NH.

[0056] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0057] "Imino" refers to the group -C(NR)R, where each R is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0058] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, where one or more hydrogen atoms are replaced with halogen. For example, if a residue is replaced 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).

[0059] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are replaced, independently of one another, with the same or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. Examples include one, two, or three carbon atoms may be replaced, independently, with the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where 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, where 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.

[0060] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5-16 ring atoms, with 1-5 of the ring atoms being heteroatoms such as N, O, or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, including but not limited to -S(O)- and -S(O)2-. Heteroaryl groups can contain any number of ring atoms, for example, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms may be included in the heteroaryl group, for example, 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems, such as phenyl rings, which may or may not contain heteroatoms, forming ring members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine, or benzothienes. Heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. For example, the nitrogen and / or sulfur ring atoms of the heteroaryl group can be optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties.Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thiazolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. "Substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents selected from the group consisting of the same substituents defined for substituted aryl.

[0061] "Heteroarylene" refers to a divalent heteroaryl. "Substituted heteroarylene" refers to a heteroarylene having 1 to 5, preferably 1 to 3, or more preferably 1 to 2, substituents as defined for the heteroaryl group.

[0062] "Heteroaryloxy" refers to the group -O-heteroaryl. "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[0063] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a ring system that is saturated or partially saturated, having 3-12 ring members and 1-4 N, O, and S heteroatoms. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, including but not limited to -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring atoms, such as 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms may be included in the heterocycloalkyl group, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members, including but not limited to indoline. In fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups are particularly well known in the art, including C 1~6It may be substituted with alkyl, oxo (=O), nitro (-NO2), or sulfonyl (-S(O)2-). "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group that is substituted with one to five, or preferably one to three, of the same substituents as specified for substituted cycloalkyl.

[0064] "Heterocyclyloxy" refers to the group -O-heterocyclyl. "Substituted heterocyclyloxy" refers to the group -O-(substituted heterocyclyl).

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

[0066] "Spirocycloalkyl" and "spiro ring system" refer to a divalent cyclic group of 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro bond (a bond formed by a single atom that is only a normal member of the ring), as exemplified by the following structure: [ka]

[0067] "Sulfonyl" refers to the -S(O)R group, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. "Substituted sulfonyl" refers to -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic groups. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. "Substituted sulfonyloxy" refers to -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic groups.

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

[0069] "Alkylsulfinyl" refers to the group -S(O)R where R is alkyl.

[0070] As used herein, the term "saccharide" 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, preferably linked together through alpha bonds. Examples of oligosaccharides include maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose, and lignocellulose or starch. Saccharides or sugars useful in the present invention include any and all naturally occurring sugars, such as, but are not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, sialic acid, (including aldol and pyranose forms thereof), and D and L isomers thereof.

[0071] "Thiocyanate" refers to the group -SCN.

[0072] "Thioxo" or "thione" refers to the (=S) or (S) group.

[0073] The substituted rings may be substituted with one or more fused rings and / or spiro rings. Such fused rings include fused cycloalkyl, fused heterocyclyl, fused aryl, and fused heteroaryl rings, each of which may be unsubstituted or substituted. Such spiro rings include fused cycloalkyl and fused heterocyclyl, each of which may be unsubstituted or substituted.

[0074] The above-defined groups may be optionally substituted with any suitable number and type of substituents. Representative substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, haloalkyl, haloalkoxy, -OR', =O, -OC(O)R', -(O)R', -OR', -ONR'R'', -OC(O)NR'R'', =NR', =N-OR', -NR'R'', -NR''C(O)R', -NR'-(O)NR''R'', -NR''C(O)OR', -NH-(NH2)=NH, -NR'C(NH2)=NH, -NH-(NH2)=NR', -SR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3 and -NO2. R', R'' and R''' are each independently hydrogen, unsubstituted alkyl, e.g., unsubstituted C 1~6 Alternatively, R' and R'', or R'' and R''', when attached to the same nitrogen, combine with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring as defined above.

[0075] It should be understood that in all of the above defined substituents, polymers arrived at by defining the substituents to have further substituents thereon (e.g., substituted aryls having substituted aryl groups as substituents themselves substituted with substituted aryl groups, etc.) are not intended to be encompassed herein. In such cases, the maximum number of such substituents is 3. In other words, each of the above definitions is constrained by the restriction that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0076] 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" groups, "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly specified otherwise, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last-mentioned group contains the atom that connects the moiety to the remainder of the molecule.

[0077] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when said event or circumstance occurs and instances when said event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms at a specified atom or group that may or may not be replaced with a moiety other than hydrogen. The term "optionally substituted" in reference to a group is intended to be interpreted as describing both unsubstituted and those groups that are substituted with the indicated or specified substituents.

[0078] The protecting groups can be any known in the art, for example, as described in Peter GM Wuts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007).

[0079] Some compounds exist as tautomers. For example, amide-containing compounds may exist in equilibrium with imidic acid tautomers. It is understood by those skilled in the art that whichever tautomer is shown, and notwithstanding the properties of equilibrium among the tautomers, the compound includes all tautomers.

[0080] Formulas or structures described herein are also intended to represent the compounds in isotopically labeled and unlabeled form.Isotopically labeled compounds have the structure depicted by the formulas described herein, except that one or more atoms are replaced with the isotope having the atomic mass or mass number indicated.Examples of isotopes or counterions to said isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, including but not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds, e.g. 3 H and 14 Incorporating radioactive isotopes such as C is possible under the present disclosure. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0081] The present disclosure also includes "deuterated analogs" of compounds and counterions to said analogs in which one to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit enhanced resistance to metabolism and thus may be useful in 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, using starting materials in which one or more hydrogens have been replaced with deuterium.

[0082] 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 heavy isotopes such as deuterium can provide certain therapeutic advantages resulting from greater metabolic stability, for example increased 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 compound and its prodrug of the present disclosure can generally be prepared by carrying out the procedure disclosed in scheme or example and the following preparation method by replacing non-isotopically labeled reagent with easily available isotopically labeled reagent.It should be understood that deuterium in this context is regarded as a substituent in the compound.

[0083] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. Any atom not specifically designated as a specific isotope in the compounds of the present disclosure is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, any atom specifically designated as deuterium (D) in the compounds of the present disclosure is meant to represent the deuterium enrichment at the indicated position above the naturally occurring level.

[0084] The compounds described herein may exist as salts, e.g., pharma- ceutically acceptable salts. The compounds may form salts, such as acid and / or base salts. Also provided are pharma- ceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful for the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Salts of the compounds described herein can be prepared according to procedures described herein and known in the art.

[0085] 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 undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts of inorganic acids and salts of 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 produced by dissolving the free base in a suitable 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 be aware of the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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, isobutyric acid, suberic acid, lactic acid, and the like. Similarly, pharmaceutically 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, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), ), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (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-cycloalkylamines (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(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Methods for preparing salts also include mixing compounds by redox reaction with active metals or by ion exchange (eg, due to different solubilities of the salts).

[0086] The term "substituted" means that one or more of any hydrogen atoms at the specified atom or group are replaced with one or more non-hydrogen substituents, provided that the normal valence of the specified atom is not exceeded. If not specified, 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. Polymers or similar unspecified structures obtained by defining a substituent with an unlimited number of additional substituents (e.g., substituted aryl with a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be encompassed herein. Unless otherwise stated, the maximum number of consecutive substituents in the compounds described herein is 3. For example, consecutive substituents of a substituted aryl group with two other substituted aryl groups are 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 5 fluorine atoms). Such impermissible substitution patterns are well known to those skilled 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 being optionally substituted, any of the substituents of the group are themselves not substituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more than one 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.

[0087] A "solvate" is a solid form of a compound that incorporates solvent molecules. 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.

[0088] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" includes any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, auxiliary active ingredients can also be incorporated into the composition.

[0089] "Treatment" or "treating" refers to providing a beneficial or desired result, e.g., amelioration, of one or more clinical signs of a disorder. The beneficial or desired result may include one or more of the following: reducing or ameliorating one or more symptoms of a disorder, and / or diminishing the severity of the disorder, (e.g., stabilizing the disorder, preventing or slowing the worsening or progression of the disorder), providing partial or total remission of the disorder, enhancing the effectiveness of another medication, improving quality of life, and / or extending survival in a patient population.

[0090] "Prevention" or "preventing" means blocking the onset of a disorder or its symptoms. The compounds may, in some embodiments, be administered to subjects (including humans) at risk of a disorder or who have a family history of the disorder. Prevention may include delaying the attainment of a given disease milestone or reducing the appearance or progression of a marker.

[0091] "Subject" refers to an animal, such as a mammal, e.g., a human, that can benefit from administration of a compound described herein. The methods described herein can be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. When the subject is a human, the subject may be referred to as a "patient."

[0092] The term "therapeutically effective amount" or "effective amount" of a compound described herein means an amount sufficient to exert treatment when administered to a subject to provide the benefits described herein.For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of mood disorders.The therapeutically effective amount may vary depending on the subject, the disorder to be treated, the weight and age of the subject, the severity of the disorder, and the method of administration, and can be easily determined by a physician.

[0093] The term "resistant" means that the subject with mood disorder has previously shown resistance to the treatment of the disorder.For example, after treatment, one or more symptoms of mood disorder continue.In some embodiments, the subject is resistant to the treatment with antidepressants as described herein.

[0094] The term "marker" refers to a characteristic of a subject that indicates the risk of developing a disorder. For example, a marker can be a genetic indicator associated with a disorder, a marker can be a personal history of a disorder, a marker can be a family history, e.g., a genetic relative(s) who has had the disorder or a related disorder, or a marker can be a physiological indicator, such as a test result. Treatment Methods and Uses

[0095] Herein, the method of treating spinal cord injury or damage or its complications is described by administering to a patient an effective amount of the compound described herein.The method described herein can also provide treatment with reduced side effects and / or treatment of subjects who are unresponsive or resistant to conventional treatment. Spinal cord injuries, their complications, and their treatment

[0096] In further embodiments, compositions and methods are provided for alleviating, reducing, or reversing spinal cord injury or damage or complications thereof. In further embodiments, compositions and methods are provided for alleviating, reducing, or reversing complications secondary to spinal cord injury or damage. The complications may be any of those described herein.

[0097] Spinal cord injury occurs when damage is sustained at the vertebrae, ligaments, or spinal discs, or to the spinal cord itself. Injury to the cauda equina is usually included in the definition, but injury to other single nerve roots is excluded. Physicians have the knowledge to diagnose and treat spinal cord injury (SCI). SCI can be any of those known in the art, such as those resulting from impact, incision, crush, puncture, blunt trauma, compression, stretching, tearing, fracture, degeneration due to infection or disease, autoimmune, or chemical injury. SCI can be incomplete or complete. SCI can be cervical, thoracic, lumbar, or sacral. SCI can include spinal cord concussion. The spinal cord can suffer more than one type of injury or damage.

[0098] SCI may be incomplete or complete. There are three common types of incomplete SCI: anterior cord syndrome, central cord syndrome, and Brown-Séquard syndrome. Complete SCI may result in quadriplegia, paraplegia, or triplegia. SCI may be graded according to the American Spinal Cord Injury Association (ASIA) rating scale, which describes the severity of the injury. The scale is graded as follows: ASIA A: The injury is a complete spinal cord injury with no preserved sensory or motor function. ASIA B: Incomplete sensory impairment with complete loss of motor function ASIA C: Some movement, but less than half of the muscle groups are antigravity (able to lift against gravity through a full range of motion), incomplete movement injury ASIA D: More than half of the muscles are antigravity, incomplete movement injury ASIA E: Normal

[0099] Spinal cord injury (SCI) may be accompanied by one or more acute complications. After SCI, instability of the cardiovascular, thermoregulatory and bronchopulmonary systems is common, in addition to motor and sensory disorders. Disturbances of the urinary and gastrointestinal systems as well as sexual dysfunction are typical. Common complications in cervical and upper thoracic SCI are neurogenic shock, bradyarrhythmias, hypotension, ectopic beats, abnormal thermoregulation and sweating disorders, vasodilation and autonomic dysreflexia. Autonomic dysreflexia is a sudden, uncontrolled sympathetic response elicited by stimuli below the level of injury. Symptoms may be mild, such as a skin rash or a mild headache, but can lead to severe hypertension, cerebral hemorrhage and death. Common complications in the acute phase are bradyarrhythmias and hypotension. Other complications are temperature instability (hyperthermia and hyperthermia), pain, spasticity and autonomic dysreflexia (AD). AD is associated with sudden, uncontrolled sympathetic responses elicited by stimuli below the level of injury, which can lead to severe hypertension, cerebral hemorrhage, and death. Ischemia and edema can exacerbate the injury during the first hours after injury. Complications can be thromboembolism, pressure ulcers, or heterotopic ossification.

[0100] Complications may be respiratory complications. Impaired respiratory function is frequent in tetraplegia, and the main cause of both short-term and long-term morbidity and mortality is pulmonary complications. Due to physical inactivity and altered hemostasis, SCI patients are at higher risk of venous thromboembolism and pressure ulcers. Spasticity and pain are common complications. Psychological stress associated with SCI can lead to anxiety and depression. Complications during the acute phase are important because they can be life-threatening and / or lead to prolonged rehabilitation. The early acute phase is generally defined as 2-48 hours after injury, the subacute phase as 2 days to 2 weeks, and the intermediate phase as 2 weeks to 6 months. The clinical acute phase is usually defined as the first 4-5 weeks after injury. Surgery may be indicated within hours to days after SCI.

[0101] Acute traumatic SCI typically begins with a sudden injury to the spine, leading to a fracture or dislocation of the vertebrae. Displaced fracture fragments and disc material cause immediate injury, leading to axonal damage and disrupted nervous system cell membranes. Vascular rupture can cause bleeding in the spinal cord, thereby increasing injury over the following hours. Several mechanisms may contribute to the overall injury of spinal cord tissue.

[0102] Respiratory complications include diaphragmatic motor unit dysfunction, diaphragm muscle lesions, phrenic motor neuron lesions, loss of phrenic motor neurons, loss of phrenic neuron spines (including typical thin, stubby and mushroom types, but also synapses that directly innervate dendritic shafts), loss of transdiaphragmatic pressure, loss of diaphragm muscle force generation, dysphagia, chest expansion failure, pneumonia, and respiratory failure.

[0103] Neurogenic shock may result from severe hypotension and bradycardia in cervical injuries due to the fall in blood pressure associated with acute SCI. Hypotension may be defined as a systolic blood pressure below 90 mmHg in the supine position, resulting from low intravascular volume (e.g., blood loss, dehydration). Neurogenic shock develops as a result of imbalance of autonomic regulation due to loss of sympathetic tone resulting from intact parasympathetic influences via the vagus nerve and disruption of supraspinal control. Depending on the severity of the SCI, prolonged severe hypotension requiring vasopressor therapy may persist for up to 5 weeks after injury. Some studies have put the percentage of neurogenic shock at 19.3% of cervical injuries. In patients with thoracic and lumbar injuries, the incidence was measured at 7.0% and 3.0%, respectively.

[0104] Injury to the autonomic nervous system is responsible for many cardiovascular complications after SCI. Cardiovascular dysfunction in patients with cervical and upper thoracic SCI can be life-threatening and may exacerbate the neurological impairment resulting from spinal cord injury. Patients have higher morbidity and mortality as a result of autonomic dysfunction. One study found that SCI is associated with increased odds of heart disease and stroke compared to healthy controls.

[0105] During the acute phase, many abnormalities of cardiac rhythm (sinus bradycardia and bradyarrhythmias including escape rhythms (14%–77%), supraventricular ectopic beats (19%), ventricular ectopic beats (18%–27%), orthostatic hypotension (33%–74%)), increased vasovagal reflexes, vasodilation and stasis may occur. One study found that orthostatic hypotension persisted during the first month after SCI in 74% of cervical and 20% of upper thoracic motor complete SCI patients. Both sinus bradycardia and arterial hypotension occur at high rates after cervical injury. Sinus bradycardia has been reported in 64%–77% of cervical SCI. Studies have found a peak incidence 4 days after injury followed by a gradual decrease in incidence. Arterial hypotension has been reported in 68% of patients with motor complete cervical SCI (ASIA A and B) who developed sinus bradycardia. Of these, 35% require vasopressors and 16% go into cardiac arrest. During the acute phase, arterial hypotension can be misinterpreted as volume loss. This can lead to fluid overload during the acute phase.

[0106] Common autonomic neuropathy (AD) 4-5 weeks after injury is autonomic dysreflexia, orthostatic hypotension (even in sitting position), reduced cardiovascular reflexes (which regulate blood pressure, blood volume, and temperature), and cardiac pain deficits. The prevalence of autonomic dysreflexia in SCI patients with injuries above Th6 ranges from 48% to 90%. One study found the incidence of early autonomic neuropathy to be 5.2% in an acute SCI population, with the first AD manifestations occurring 4 days after injury. Patients with cervical or thoracic injuries above Th4 may have disrupted sympathetic afferent fibers, including cardiac pain fibers, and the patient's sensation of ischemic cardiac pain may or may not be altered (referred pain). Secondary cardiac changes in tetraplegic patients are loss of muscle mass in the left ventricle (due to physiological adaptation to reduced myocardial work) and pseudoinfarction (elevated troponin with or without ECG changes).

[0107] Acute injury above the sixth thoracic vertebra (Th6) disrupts the descending pathways to neurons of the sympathetic trunk (in the intermediolateral cell column) from the first thoracic vertebra (Th1) to the second lumbar vertebra (L2). Resulting complications include ineffective supraspinal control of the sympathetic nervous system and a deficit in inhibition of the parasympathetic nervous system leading to increased sympathetic activity below the level of injury. In addition to motor and sensory disorders, instability of the cardiovascular, thermoregulatory and bronchopulmonary systems is common after SCI. Disturbances of the urinary and gastrointestinal systems as well as sexual dysfunction are typical. Patients with injuries below Th6 have intact sympathetic and parasympathetic regulation of the heart and lungs. Thus, responses from organ systems differ between tetraplegic and paraplegic patients.

[0108] Thermoregulatory abnormalities can include poikilothermy, the inability to maintain a constant core body temperature regardless of ambient temperature. Alterations in sweat secretion often occur after SCI, and excessive sweating (hyperhidrosis), non-sweating (anhidrosis), and reduced sweating (hypothidrosis) can all occur.

[0109] In some embodiments, the complication of spinal cord injury is respiratory complications, cardiovascular complications, hypotension, bradycardia, neurogenic shock, autonomic dysreflexia, secondary immunodeficiency, syringomyelia, neuropathic arthropathy, Charcot arthropathy, loss of motor control, loss of sensory function, quadriplegia, paraplegia, loss of bladder control, spasms, loss of sexual function, anesthesia, loss of balance, autonomic dysreflexia, deep vein thrombosis, spasticity, pain, neuropathic pain, syringomyelia, neural heterotopic ossification, shock, bradyarrhythmia, hypotension, ectopic beats, abnormal thermoregulation, changes in sweat secretion, vasodilation, autonomic dysreflexia, thromboembolism, pressure ulcers, or heterotopic ossification, or a combination thereof.

[0110] In further embodiments, compositions and methods are provided for alleviating, ameliorating, or reversing symptoms of spinal cord injury or damage or complications thereof, which may be any of the symptoms described herein. Dendritic spines

[0111] The role of spine density in the progression of SCI is not fully understood, therefore, the development of novel methods to increase spine density may have important implications for the treatment of secondary pathologies associated with spinal cord injury or damage and SCI.

[0112] In some embodiments, the methods provided herein include administering to a subject an effective amount of a compound described herein, thereby promoting spine formation. Spine formation may be observed as an increase in the average number of spines per neuron or 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 an increase in the local spatial average value of membrane potential. Spine formation may be observed as an increase in the postsynaptic concentration (e.g., volume-averaged) of Ca2+. In some embodiments, a compound described herein or a pharma- ceutically acceptable salt thereof increases dendritic spine density relative to that observed at the time treatment was initiated. In some embodiments, the increase in dendritic spine density reduces symptoms of spinal cord injury or damage or complications thereof in a subject or patient.

[0113] Fascin is an important actin cross-linking factor that has no amino acid sequence homology with other actin-binding proteins. Three forms of Fascin are found in vertebrates: Fascin 1, which is found widely in the nervous system, Fascin 2, which is found in photoreceptor cells in the retina, and Fascin 3, which is found only in the testes. In some embodiments, Fascin is human Fascin 1. Fascin has a molecular weight of 55 kDa and functions as a monomeric entity, cross-linking actin filaments into linear, compact, rigid bundles and imparting mechanical rigidity to actin bundles. Fascin is believed to hold parallel actin filaments together to form filopodia with diameters of approximately 60-200 nm.

[0114] During neuronal development, long bundles of f-actin are thought to push out the neuronal membrane to form structures such as axons, dendrites, filopodia and lamellipodia. Fascin is thought to be involved in cytoskeletal remodelling of early dendrites. Thus, actin bundling by Fascin is thought to be required in general for the formation and elongation of axons and dendrites. Surprisingly, the present results show that inhibition of Fascin activity, either its ability to bundle actin or its ability to bind other protein factors that may have a joint regulatory interaction, promotes the formation of dendritic spines, protrusions of the dendritic plasma membrane.

[0115] Dendritic spines are specialized protrusions responsible for receiving synaptic inputs and providing important functions in communication between neurons. The morphology of dendritic spines and their total density correlate with synaptic function. Cellular changes in neurons can contribute to the pathogenesis of nervous system diseases. For example, abnormal levels (e.g., reductions) in dendritic spine density can contribute to the pathogenesis of nervous system diseases. As a result, changes or misregulation of dendritic spines are believed to affect synaptic function and play a major role in various neurological and psychiatric disorders. Therefore, therapeutic strategies targeting early synapse loss rather than end-stage disease interventions may provide better prognosis for the treatment of disorders of some neurons.

[0116] In some embodiments, the average dendritic spine density is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100%, or any range between any two numbers, inclusive, relative to the time treatment with a compound described herein or a pharma- ceutically acceptable salt thereof is initiated. In some embodiments, the dendritic spine density is increased by about 10% to about 50% relative to the time treatment with a compound described herein or a pharma- ceutically acceptable salt thereof is initiated. In some embodiments, the dendritic spine density is increased by about 10% to about 40% relative to the time treatment with a compound described herein or a pharma- ceutically acceptable salt thereof is initiated. In some embodiments, the dendritic spine density is increased by about 10% to about 30% relative to the time treatment with a compound described herein or a pharma- ceutically acceptable salt thereof is initiated. In some embodiments, the duration of treatment with a compound described herein 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. In some embodiments, administration is not consecutive, e.g., separate administrations are administered on designated days.

[0117] 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%, or 100%, or any range between any two numbers, inclusive, relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 10% to about 50% relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 10% to about 40% relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 10% to about 30% relative to a control (e.g., spine density in the absence of the compound).

[0118] In some embodiments, the method increases the average number of spines per neuron relative to the time when treatment with a compound described herein or a pharma- ceutically acceptable salt thereof is initiated. In some embodiments, the average number of spines per unit length of a 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 more than about 1000, or any range between any two numbers, inclusive. In some embodiments, the time is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0119] In some embodiments, the time to achieve the changes in spine density or spine morphology described herein (e.g., average dendritic spine density, average spine density, average neuron length, or average number of spines per neuron) 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. In some embodiments, the time to achieve the changes in spine density or spine morphology described herein (e.g., average dendritic spine density, average spine density, average neuron length, or average number of spines per neuron) is 1 hour, 2 hours, 4 hours, 8 hours, or 1 day.

[0120] In some embodiments, the compound is useful in treating neurological diseases and disorders resulting from spinal cord injury or damage or its complications. Neuronal disease is a disease or condition that causes the function of the nervous system of a subject to be impaired. Neuronal disease or disorder can be a neurological disease or disorder. Neuronal disease or disorder can be associated with neurodegenerative disease or disorder, such as ALS. Neuronal disease or disorder or neurodegenerative disease or disorder can be acute (e.g., occurs at the time of injury or damage to spinal cord), but can also occur at a time after injury or damage to spinal cord. In some embodiments, the patient has a condition that involves nerve damage, such as, for example, Chiari malformation, radiculopathy, hydrocephalus, neuropathy caused by infection (e.g., all of which can be associated with spinal cord injury or damage).

[0121] In one aspect, a method for treating spinal cord injury or damage or a complication thereof in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound as described herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the complication is a complication as described herein.

[0122] In some embodiments, the neuronal disease comprises neuropathy, which may include atrophy or other decrease in the effective function of neurons.

[0123] 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.

[0124] Examples of diseases and disorders that can be treated by the compounds or methods described herein include Alexander disease, Alpers disease, Alzheimer's disease, depression, perinatal asphyxia, Parkinson's disease dementia ("PD dementia"), amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voigt-Sjogren-Batten disease), spongiform encephalopathies (e.g., bovine spongiform encephalopathy (mad cow disease)), kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, canavailability, and pulmonary circulation disorders. Diseases of the cerebrospinal fluid, Cockayne syndrome, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, sleeping sickness, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, and pernicious anemia. Subacute combined spinal cord degeneration following, Schizophrenia, Spinocerebellar ataxia (multiple types with variable characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, 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 Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive early onset (PARK2), Parkinson's disease 7, autosomal recessive early onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), or mitochondrial Parkinson's disease.In some embodiments, the neuronal disease is Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, stroke, post-traumatic stress disorder (PTSD), traumatic brain injury (TBD), chronic progressive 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 disorder (e.g., age-related memory disorder), hypertensive encephalopathy, or chronic stress. In some embodiments, the pathology to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the spinal cord injury is the result of amyotrophic lateral sclerosis (ALS). In some embodiments, the patient has ALS.

[0125] In some embodiments, the subject is found to suffer from abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density and / or abnormal synaptic function.In some embodiments, the complications resulting from SCI are accompanied by abnormal (e.g., reduced) levels of dendritic spine density.Abnormal spine density can be characterized as a decrease in number, changes in morphology, changes in the proportion or population of specific morphologies of dendritic spines, or a decrease in spine density.

[0126] In some embodiments, there is provided a method of promoting spine formation in a patient having a spinal cord injury or damage, the method comprising administering to the patient a compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, there is provided a compound for use in the manufacture of a medicament for the treatment of spinal cord injury or damage or complications thereof, the compound being a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the disclosure provides a method of treating spinal cord injury or damage or a complication thereof in a patient, comprising administering to a patient a therapeutically effective amount of a compound of Formula I or Ia: [ka] (In the formula, The subscripts n and p are independently selected from 0, 1, or 2; Each R 1 is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro; A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, wherein R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; X is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, with the proviso that A is arylene and Y is -S- or -NR 2 -, provided that X is not -S-; Y is -O-, -S-, -SO-, S(O)2-, and -NR 2 - selected from the group consisting of Z is -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R 3 )O) q -T, the subscript q is an integer selected from 1 to 100, R 3 is selected from the group consisting of hydrogen and methyl, T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharides, and -L-oligosaccharides, where L is selected from the group consisting of a bond, phosphate, and sulfate. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof to a patient in need thereof.

[0128] In some embodiments of the methods described herein, in the compound of formula I or Ia, A is phenylene or pyridylene. In some embodiments, in the compound of formula I, X is S. In some embodiments, in the compound of formula I or Ia, Y is -O-. In some embodiments, in the compound of formula I, X is S, Y is -O-, and A is phenylene.

[0129] In some embodiments of the methods described herein, the compound of formula I is a compound of formula Ik: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, The subscripts n and p are each independently 0, 1, or 2; The subscript q is an integer from 2 to 8; Each R 41 and each R 42 is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0130] In some embodiments of the methods described herein, in the compound of formula Ik, each subscript n and p is 0.

[0131] In some embodiments of the methods described herein, the compound of formula I is: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0132] In some embodiments, the disclosure provides a method of treating a spinal cord injury or damage or a complication thereof in a patient, comprising administering to a patient a therapeutically effective amount of a compound of formula II: [ka] (In the formula, Y is -NR 33 - or -S-, Each 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, -C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each 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, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 33 is H, alkyl, or substituted alkyl; X 31 and X 32 each is independently a halogen; Each of z1 and z2 independently represents an integer of 0 to 4. z3 is an integer from 1 to 12. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof to a patient in need thereof.

[0133] In some embodiments of the methods described herein, Y is S in the compound of formula II. In some embodiments, each of z1 and z2 is 0 in the compound of formula II.

[0134] In some embodiments of the methods described herein, the compound of formula II is: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0135] In some embodiments of the methods described herein, Y is NH in the compound of formula II. In some embodiments, z1 is 1, z2 is 0, and R 31 is alkyl.

[0136] In some embodiments of the methods described herein, the compound of formula II is: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0137] In some embodiments, the disclosure provides a method of treating a spinal cord injury or damage or a complication thereof in a patient, wherein the complication of the spinal cord injury or damage is a respiratory complication, a cardiovascular complication, hypotension, bradycardia, neurogenic shock, autonomic dysreflexia, secondary immune deficiency, syringomyelia, neuropathic arthropathy, Charcot arthropathy, loss of motor control, loss of sensory function, quadriplegia, paraplegia, loss of bladder control, spasms, loss of sexual function, anesthesia, loss of balance, autonomic dysreflexia, deep vein thrombosis, spasticity, pain, neuropathic pain, syringomyelia, neural heterotopic ossification, shock, bradycardia arrhythmia, hypotension, ectopic beats, abnormal thermoregulation, autonomic dysreflexia, changes in sweat secretion, vasodilation, thromboembolism, pressure ulcers, or heterotopic ossification, or a combination thereof.

[0138] In some embodiments, the present disclosure provides a method of treating spinal cord injury or damage or complications thereof in a patient, wherein the patient has a neuropathy due to Chiari malformation, radiculopathy, hydrocephalus, or infection. In some embodiments, the neuropathy due to infection is from Lyme disease. compound

[0139] Provided herein is an agent that promotes spine formation. Such an agent has surprisingly been found to be useful in treating mood disorders. The agent may be a compound provided herein.

[0140] The compound may be a compound described in International Patent Publication No. WO2019 / 028164. In some embodiments, the compound is a compound of Formula I or Formula Ia: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, The subscripts n and p are independently selected from 0, 1, or 2; Each R 1 is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro; A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, wherein R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; X is -O-, -S-, -SO-, -S(O)2-, and -NR 2 -, R 2 is as defined above, except that A is arylene and Y is -S- or -NR 2 -, provided that X is not -S-; Y is -O-, -S-, -SO-, S(O)2-, and -NR 2 -, wherein R 2 is as defined above, Z is -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R 3 )O) q -T, where the subscript q is an integer from 1 to 100, and R 3is selected from the group consisting of hydrogen and methyl, T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharides and -L-oligosaccharides, and L is selected from the group consisting of a bond, phosphate, and sulfate.

[0141] In some embodiments, the disclosure provides a compound of formula I or Ia, where A is phenylene or pyridylene. In some embodiments, in the compound of formula I, X is S. In some embodiments, in the compound of formula I or Ia, Y is -O-. In some embodiments, in the compound of formula I, X is S, Y is -O-, and A is phenylene.

[0142] In some embodiments, a compound according to formula Ib, formula Ic, formula Id, formula Ie, and / or formula Ig: [ka] (In the formula, R 1 , R 2 , A, Y, Z, n, and p are as defined above for Formula I and Formula Ia, and the subscript m is 0, 1, or 2. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0143] In some embodiments, [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0144] In some embodiments, the compound is a compound of formula Ik: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, The subscripts n and p are each independently 0, 1, or 2; The subscript q is an integer from 2 to 8; Each R 41 and each R 42 is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0145] In some embodiments, the disclosure provides compounds of formula Ik, where each of the subscripts n and p is 0.

[0146] In some embodiments, [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0147] In some embodiments, the compound according to formula Ij: [ka] (In the formula, The subscript q is an integer equal to 4 or 6; R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of hydrogen, halo, -CH3, and -OCH3; R 7 , R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; Here, R3 to R 10 at least six of which are hydrogen) or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0148] In some embodiments, [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0149] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0150] In some embodiments, the compound is a compound described in International Publication No. WO2017 / 120198. In some embodiments, the compound is a compound of formula II: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, 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, -C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each 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, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 33 is H, alkyl, or substituted alkyl; X 31 and X 32 each is independently a halogen; Each of z1 and z2 independently represents an integer of 0 to 4. z3 is an integer from 1 to 12.

[0151] In some embodiments, the disclosure provides a compound of formula II, where Y is S. In some embodiments, each of z1 and z2 is 0.

[0152] In some embodiments, the compound is a compound of formula IIa: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, Each R 1 are independently halogen, -CX 1 3. -CHX 1 2, -CH2X 1 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , -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, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each R 2 are independently halogen, -CX 2 3. -CHX 2 2, -CH2X 2 , -OCX 2 3. -OCHX 2 2, -OCH2X 2 , -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, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; X 1 and X 2 each is independently a halogen; Each of z1 and z2 independently represents an integer of 0 to 4. n is an integer from 1 to 12.

[0153] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0154] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0155] In some embodiments, the disclosure provides a compound of formula II, where Y is NH or NMe. In some embodiments, z1 is 1, z2 is 0, and R 31 is alkyl.

[0156] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0157] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

[0158] In some embodiments, the compound is a compound described in U.S. Patent No. 8,741,883. In some embodiments, the compound is a compound of formula III: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, R1-R8 are selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, where at least one of R5-R8 and one of R1-R4 is H; P is [ka] wherein: m is an integer from 1 to 20; n is 0, 1, or 2, and q is an integer from 1 to 20; R9~R 16 is selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, where R to R 12 At least one of and R 13 ~R 16 One of them is H, X is hydrogen, methyl, or ethyl.

[0159] In some embodiments, the compound of formula III is a compound of formula IIIa: [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, R1-R8 are selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, where at least one of R5-R8 and one of R1-R4 is H; P is [ka] where: m is an integer from 1 to 20; q is an integer from 1 to 20; R9~R 16 is selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, where R to R 12 At least one of and R 13 ~R 16 One of them is H, X is hydrogen, methyl, or ethyl.

[0160] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof. Combination therapy

[0161] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed to treat SCI.

[0162] When used to treat the above diseases and disorders, the compound described herein or its pharmacologic acceptable salts may be administered together with one or more additional therapeutic agents, for example, additional therapeutic agents approved for use in the treatment of a particular disease or disorder, more particularly, agents that are considered to form the current standard of care.When combined therapy is envisaged, the active agents may be administered simultaneously, separately or sequentially, and may be administered together in a single pharmaceutical composition or in more than one pharmaceutical composition.

[0163] The compounds described herein or their pharma- ceutically acceptable salts may be administered in combination with one or more additional therapies used in the treatment of spinal cord injury or damage or complications thereof. The one or more additional therapies may be drug therapies, non-drug therapies, or combinations thereof.

[0164] Non-pharmacological therapies include, for example, limb stabilization, alignment, traction, eg, cranial ring traction or Gardner-Wells Tongs traction, head and / or neck bracing, mechanical ventilation, physical therapy, and surgery. kit

[0165] Also provided herein is a kit comprising the compound or its pharmaceutically acceptable salt as described herein, a second active ingredient as needed, 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 the label and / or instructions for use of the pharmaceutical composition in treating symptoms, including disease or pathology, as described herein.

[0166] 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, bottle, ampoule, pre-filled syringe, nebulizer, aerosol dispensing device, dropper, or intravenous infusion bag. Pharmaceutical Compositions and Methods of Administration

[0167] The compound provided herein is usually administered in the form of a pharmaceutical composition.Therefore, the present invention also provides pharmaceutical compositions that contain the compound described herein or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable additives.Suitable pharmaceutically acceptable additives 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 by methods well known in the pharmaceutical industry.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0168] The pharmaceutical composition can be administered in a single dose or multiple doses.The pharmaceutical composition can be administered by various methods, including, for example, rectal, oral, intranasal and transdermal routes.In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal ("ip"), parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0169] One method of administration is parenterally, for example, by injection. Forms that can be incorporated to administer the pharmaceutical compositions described herein by injection include, for example, aqueous or oil suspensions or emulsions (including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose), or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0170] Oral administration can be another route of administration of the compositions described herein. Administration can be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one of the compounds described herein or pharma-ceutically acceptable salts thereof, the active ingredient is usually diluted with an additive and / or enclosed in such a carrier, which may be in the form of a capsule, sachet, paper or other container. When the additive serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0171] Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup, and methylcellulose.The formulation may 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.

[0172] 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 modifiers, or buffers.

[0173] 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 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 (containing 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 a controlled amount of the compounds described herein. The construction and use of transdermal patches for 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 may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0174] To prepare solid compositions such as tablets, the main active ingredient may be mixed with pharmaceutical excipients to form a solid preformulated composition containing a homogeneous mixture of the compound described herein or a pharma- ceutically acceptable salt thereof. When these preformulated compositions are considered homogeneous, the active ingredient may be evenly dispersed throughout the composition, and thus the composition may be easily subdivided into unit dosage forms of the same efficacy, such as tablets, pills, and capsules.

[0175] The tablet or pill of the compound described herein may be coated or otherwise compounded to obtain a dosage form that provides the benefit of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dosage form component and an outer dosage form component, the outer dosage form component being in the form of an envelope from the inner dosage form component.The two components may be separated by an enteric layer that resists disintegration in the stomach and acts to allow the inner component to pass intact into the duodenum or to delay release.Various materials may be used for such enteric layer or coating, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0176] 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 pharma- ceutically 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 powder active ingredient can be amorphous or crystalline. For example, the compounds described herein or their pharma- ceutically acceptable salts can be amorphous or crystalline. The crystalline active agent can be a hydrate or a solvate.

[0177] The solid compound or its salt or crystal can be present in the formulation with a selected average particle size. The particles can 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.

[0178] 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 additives 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 cranial tissues. In other embodiments, compositions in pharma- ceutically acceptable solvents may be nebulized using an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally. Pharmaceutical compositions for inhalation or insufflation may be aerosols.

[0179] The pharmaceutical composition may comprise 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 comprise water and / or alcohol. The liquid may comprise 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.

[0180] The pharmaceutical composition may include a pharma- ceutically acceptable preservative. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination with pathogenic particles, such as phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. In certain embodiments, the pharmaceutical composition comprises about 0.01% to about 1.0% w / w benzalkonium chloride, or about 0.01% to about 1% v / w phenylethyl alcohol. Preservatives 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.

[0181] The pharmaceutical compositions may also contain from about 0.01% to about 90%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10%, or from about 0.01% to about 1% w / w of one or more of an emulsifying agent, wetting agent or suspending agent. Such agents as used herein include, but are not limited to, polyoxyethylene sorbitan fatty acid esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan 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, agar, sorbitol, sorbitol glycerin ... Cassia, xanthan gum, karaya gum, pectin, amidated pectin, ammonium phosphatide, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl methylcellulose, carboxymethylcellulose, sodium, potassium and calcium salts of fatty acids, mono- and di-glycerides of fatty acids, acetate esters of mono- and di-glycerides of fatty acids, lactate esters of mono- and di-glycerides of fatty acids, citric acid esters of mono- and di-glycerides of fatty acids, tartaric acid esters of mono- and di-glycerides of fatty acids, mono- and diacetyl tartaric acid esters of mono- and di-glycerides of fatty acids, mixed acetate and tartaric acid esters of mono- and di-glycerides 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, Quillaja extract, polyglycerol esters of dimerized fatty acids of soybean oil, oxidatively polymerized soybean oil, and pectin extract.

[0182] In a further embodiment, the pharmaceutical composition for nasal administration can be provided in the form of powder.For example, the powdered nasal composition can be directly used as a powder of unit dosage form.If necessary, the powder can be filled into capsules such as hard gelatin capsules.The contents of the capsule or single-dose device can be administered, for example, by using an inhaler.

[0183] 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. dosage

[0184] The specific dosage level of the active ingredients of the present application, such as the compounds described herein or salts thereof, for any particular 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, and excretion rate, drug combinations, and the severity of the particular disease of the subject being treated. For example, dosages can be expressed as milligrams of the compounds described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.01 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. Normalization by subject body weight is particularly useful when adjusting dosages between subjects of widely disparate sizes (e.g., occurs when using drugs for both pediatric and adult humans, or when converting dosages effective for non-human subjects, such as dogs, to dosages suitable for human subjects).

[0185] Daily doses may also be described as the total amount of the compounds described herein administered per dose or per day. The daily dose of the compounds described herein or salts thereof may be between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, between about 1 and 1,000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0186] When administered intranasally, the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 1,000 and 2,000 mg / day, between about 10 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 100 and 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.

[0187] The active ingredient of the present application or its pharmaceutical composition can be administered once, twice, three times, or four times a day using any suitable method described above.Also, administration or treatment can continue for several days, for example, generally, for one cycle of treatment, the treatment will continue for at least 7 days, 14 days, or 28 days.The treatment cycle can be continuous.Administration or treatment can be continued indefinitely.

[0188] In certain embodiments, the method includes administering to the subject an initial daily dosage of about 1-800 mg of a compound described herein, and steadily increasing the dosage until a clinical effect is achieved. Dosage increases can be made using increments of about 5, 10, 25, 50, or 100 mg. Dosage can be increased daily, every other day, twice weekly, or once weekly.

[0189] As used herein and in the examples below, the following abbreviations have the following meanings. If not defined, these abbreviations have their art-recognized meaning. BDNF = brain-derived neurotrophic factor CTB = cholera toxin subunit beta DMSO = dimethyl sulfoxide EMG = electromyography NMJ = neuromuscular junction TrkB = tropomyosin receptor kinase B C2HS EXAMPLES

[0190] Example 1 Hypothesis: The compounds described herein will ameliorate functional and pathological diaphragm motor unit deficits following unilateral cervical spinal cord hemisection (C2HS) compared to vehicle-treated C2HS rats.

[0191] Outcome measures: Continuous diaphragmatic EMG, continuous ventilation transdiaphragmatic pressure (Pdi), terminal maximum Pdi, and ex vivo assessment of glutamatergic input onto phrenic motoneurons.

[0192] Experimental groups: this will entail three cohorts of animals (I - C2HS rats treated with vehicle (12), II - C2HS rats treated with compound (12) and III - Sham-operated + compound-treated rats (6)).

[0193] Statistical comparison: A powered sample size was used for functional recovery based on previous observations of spontaneous recovery of approximately 18% 14 days after SH. We expected a similar improvement in recovery to other neurotrophic agents tested in the laboratory (e.g., BDNF / TrkB), which increased recovery to approximately 67%. For ex vivo pathology assessment, differences in glutamatergic inputs (lesioned vs. nonlesioned sides) in SH rats would require 8 rats, whereas sham comparisons would require 6.

[0194] Phrenic motoneurons are identified via intrapleural labeling of both sides of the CTB. It is anticipated that any length-specific motoneuron loss in the SOD1 rodent model will be detected using this technique, similar to the loss observed in aged rats.

[0195] Diaphragm muscle (DIAm) EMG activity is recorded separately on either side of the diaphragm. Normal breathing (quiet breathing) is recorded along with the raw trace (burst) and RMS (root mean square - an estimate of EMG magnitude) for each burst. In cervical spinal cord hemisection models, EMG activity during normal breathing may disappear from the ipsilateral side to the lesion.

[0196] Transdiaphragmatic pressure (Pdi) is calculated from the sum of negative intrathoracic and positive intraabdominal pressures measured in the esophageal (Peso) and gastric (Pgas) spaces, respectively. Maximum Pdi (blue boxes) derived via bilateral phrenic nerve stimulation provides an upper limit for reliable prediction of phrenic nerve motor function in vivo. In conditions that result in motor unit-specific motor neuron loss (such as in ALS), we observe that ventilatory Pdi remains relatively unaffected, whereas maximum Pdi is impaired.

[0197] The number and density of glutamatergic inputs to labeled phrenic motoneurons are estimated. After the C2HS procedure, motoneurons receiving ipsilateral ventilatory drive from the medulla show a significant loss of glutamatergic input compared to the control (non-lesioned) side. After injury, treatment with the compounds described herein alleviates the deficit.

[0198] Neuromuscular transmission impairment (NMTF) is due to impaired axonal propagation and / or infidelity of NMJ synapses to muscle fatigue. NMTF contributed to a progressively diminishing force production over a 120 s period, while the force evoked by direct muscle stimulation remained stable. NMTF worsens with age due to both denervation (leading to impaired axonal propagation) and impaired NMJ morphology (reduced addition of pre- and postsynaptic elements at the NMJ). With age, impairment of presynaptic (synaptophysin and neurofilament) and postsynaptic regions (bungarotoxin) occurs only in fatigable (type Iix and / or IIb) fibers. It has been determined that a similar pattern of loss of function and lesions exists in SOD1 rats. Furthermore, it has been determined that type I, type IIa, and type IIx and / or IIb diaphragm muscle fibers show atrophy, but only type IIx and / or IIb fibers in aged rats compared to young rats. A similar lesion pattern has been determined to be obtained in the SOD1 ALS rat model. Example 2

[0199] To demonstrate the efficacy of the compounds for treating spinal cord injury or damage, the effects of the benzothiazole compounds on synaptic puncta and synapses of mouse cortical neurons were studied.

[0200] Primary mouse cortical neurons are treated with 5 μM of the compounds described herein at DIV15. As a control, primary mouse cortical neurons are treated with vehicle only (10% DMSO, 90% phosphate-buffered saline (PBS)). After 24 hours, DIV16 neurons are fixed, immunostained using the presynaptic vesicle protein synaptophysin (P38), counterstained with the nuclear dye DAPI (4',6-diamidino-2-phenylindole), and counted. Immunolabeled neurons are imaged with a Leica confocal microscope. The number of P38-immunopositive puncta is analyzed using FIJI with the Squash plugin. Compounds described herein are observed to increase the number of synaptic puncta compared to vehicle controls.

[0201] In a similar experiment, primary mouse cortical neurons are treated with 1 μM of compound at DIV15, using the same DMSO / PBS buffer as above as a control vehicle. After 24 hours, DIV16 neurons are fixed, immunolabeled with synaptophysin, stained with DAPI, and counted as above. After 24 hours, compounds are observed to promote approximately 100% increase in synapse number when compared to control. Example 3

[0202] Compound 1, which is a representative compound of the present disclosure, is used to treat spinal cord injury in rats.The rat C2 hemisection (C2HS) model of spinal cord injury is used in this experiment.Spinal cord injury is modeled in rats by hemisection at C2 level, followed by monitoring injury and performing recovery by one of the following methods: diaphragm EMG, transdiaphragm pressure, and ventilation behavior.

[0203] Seven rats were treated with Compound 1 (30 mg / kg) and eight rats were treated with vehicle (0.5% DMSO in phosphate-buffered saline) for 14 days and their recovery was monitored. 86% of the Compound 1-treated rats were found to have recovered by day 14 after injury as determined by diaphragmatic EMG. Also, the degree of recovery was an average of 54% among the compound-treated rats that recovered compared to vehicle-treated rats. Recovery was greater than that seen with the brain-derived neurotrophic factor approach. Results are shown in Figure 1A and Figure 1B.

[0204] Similar experiments were carried out separately using 4 rats, and similar results were obtained as above. In particular, higher recovery percentage and greater recovery were observed in rats treated with Compound 1 compared to vehicle-treated rats.

[0205] 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.

[0206] The present disclosure illustratively described herein may be practiced without any element(s) and limitation(s) not specifically disclosed herein, as appropriate. Thus, for example, the terms "comprising", "including", "containing", etc., shall be read broadly and without limitation. In addition, the terms and expressions used herein are used as conditions of description and are not intended to be used to exclude any equivalents or portions of the features shown and described, but rather, various modifications are possible.

[0207] Thus, although the present disclosure has been disclosed with particular reference to preferred embodiments and optional features, modifications, improvements and variations of the disclosed contents incorporated herein may be made 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 be limiting in scope of the present disclosure.

[0208] 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 the case of conflict, the present specification, including definitions, will control.

Claims

1. 1. A composition for treating spinal cord injury or damage or complications thereof in a patient, comprising a compound of formula I or Ia: 【Chemistry 31】 [In the formula, subscripts n and p are independently selected from 0, 1, or 2; Each R １ is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro; A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is -O-, -S-, -SO-, -S(O) ２ - and -NR ２ -, wherein R ２ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; X is -O-, -S-, -SO-, -S(O) ２ - and -NR ２ -, where A is arylene and Y is -S- or -NR ２ -, with the proviso that X is not -S-; Y is -O-, -S-, -SO-, S(O) ２ - and -NR ２ - selected from the group consisting of Z is -N(CH ３ ) ２ CH ２ CH ２ OC(O)CH ３ and -(CH ２ CH(R ３ ) O) ｑ -T, where the subscript q is an integer selected from 1 to 100, R ３ is selected from the group consisting of hydrogen and methyl; T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharides and -L-oligosaccharides; and L is selected from the group consisting of a bond, phosphate, and sulfate. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

2. The composition of claim 1 , wherein in the compound of formula I or Ia, A is phenylene or pyridylene.

3. The composition of claim 1 , wherein in the compound of formula I, X is S.

4. The composition of claim 1, wherein in the compound of formula I or Ia, Y is -O-.

5. The composition of claim 1, wherein in the compound of formula I, X is S, Y is --O--, and A is phenylene.

6. The compound of formula I is a compound of formula Ik: 【Chemistry 32】 or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof; During the ceremony, The subscripts n and p are each independently 0, 1, or 2; The subscript q is an integer from 2 to 8; Each R ４１ and each R ４２ is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro; The composition of claim 1.

7. The composition of claim 5 , wherein each of the subscripts n and p is 0.

8. The compound of formula I is 【Chemical 33】 or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

9. 1. A composition for treating spinal cord injury or damage or complications thereof in a patient, comprising a compound of formula II: 【Chemical 34】 [In the formula, Y is -NR ３３ - or -S-, Each R ３１ are independently halogen, -CX ３１ , -CHX ３１ , -CH ２ X ３１ , -OCX ３１ ３ , -OCHX ３１ ２ , -OCH ２ X ３１ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -C(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each R ３２ are independently halogen, -CX ３２ ３ , -CHX ３２ ２ , -CH ２ X ３２ , -OCX ３２ ３ , -OCHX ３２ ２ , -OCH ２ X ３２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R ３３ is H, alkyl, or substituted alkyl; X ３１ and X ３２ each is independently a halogen; Each of z1 and z2 is independently an integer from 0 to 4; z3 is an integer from 1 to 12. or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

10. The composition of claim 9 wherein Y is S.

11. The composition of claim 9, wherein each of z1 and z2 is 0.

12. The compound of formula II is 【Chemistry 35】 or a pharma- ceutically acceptable salt or solvate thereof.

13. The composition of claim 9 wherein Y is NH.

14. z1 is 1, z2 is 0, R ３１ The composition of claim 9 , wherein is alkyl.

15. The compound of formula II is 【Chemical 36】 or a pharma- ceutically acceptable salt, solvate, and / or N-oxide thereof.

16. 20. The composition of any one of the preceding claims, wherein the complication of spinal cord injury or damage is respiratory complications, cardiovascular complications, hypotension, bradycardia, neurogenic shock, autonomic dysreflexia, secondary immunodeficiency, syringomyelia, neuropathic arthropathy, Charcot arthropathy, loss of motor control, loss of sensory function, quadriplegia, paraplegia, loss of bladder control, spasms, loss of sexual function, anesthesia, loss of balance, autonomic dysreflexia, deep vein thrombosis, spasticity, pain, neuropathic pain, syringomyelia, nerve heterotopic ossification, shock, bradycardial arrhythmia, hypotension, ectopic beats, abnormal thermoregulation, changes in sweat secretion, vasodilation, autonomic dysreflexia, thromboembolism, pressure ulcers, or heterotopic ossification, or a combination thereof.

17. 20. The composition of any one of the preceding claims, wherein the patient has a neurological disorder due to Chiari malformation, radiculopathy, hydrocephalus, or infection.

18. 18. The composition of claim 17, wherein the neuropathy resulting from an infectious disease is due to Lyme disease.

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