Treatment of neuroinflammation

Abstract

Provided herein are compositions and methods for the treatment of neuroinflammatory diseases and conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (AES), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), Vascular dementia (VAD), Anti- myelin oligodendrocyte glycoprotein antibody disease (MOGAD), Transverse myelitis (TM), Autoimmune Encephalitis (AE), Acute disseminated encephalomyelitis (ADEM), Chronic meningitis (CM), Central nervous system (CNS) vasculitis, Hashimoto's encephalitis (HE), Neurosarcoidosis (NS), Multiple system atrophy (MSA), Migraine, Chemotherapy-induced pain or Dementia-related pain.

Description

TREATMENT OF NEUROINFEAMMATIONCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 454,011, filedMarch 22, 2023, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] A need exists in the medical art for compounds and methods for the treatment of neuroinflammatory diseases and conditions. Disclosed herein are solutions to this and other problems in the art.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are compositions and methods for the treatment of neuroinflammatory diseases and conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), Vascular dementia (VAD), Anti- myelin oligodendrocyte glycoprotein antibody disease (MOGAD), Transverse myelitis (TM), Autoimmune Encephalitis (AE), Acute disseminated encephalomyelitis (ADEM), Chronic meningitis (CM), Central nervous system (CNS) vasculitis, Hashimoto’s encephalitis (HE), Neurosarcoidosis (NS), Multiple system atrophy (MSA), Migraine, Chemotherapy-induced pain or Dementia-related pain. Said compositions useful for treating neuroinflammatory diseases comprise VAP-1 inhibitors.

[0004] One embodiment provides a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I) is: wherein the partial structure represented bythe symbol --- represents a point of attachment;X1is =N-, -NR8-, -O-, or -S-;X2is -N- or -CH-;X3is -O-, -S-, -NH-, -CH2-, or -C(O)-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, n7, n8, and nl2 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, m8, ml2, vl, v2, v5, v6, v7, v8, and vl2 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CXL13, -CHXL12, -CH2X1 1, -CN, -SOniR1A, - SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1\ -OCHX1\ R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2 13, -CHX2 12, -CH2X2 1, -CN, -SOn2R2A, -SOv2NR2BR2C, - NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2 J3, -OCHX2\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOn5R5A, - SOVSNR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5\ -OCHX5\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOneR6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6 I3. -OCHX6\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7 13, -CHX7 12, -CH2X7 1, -CN, -SOn7R7A, -SOv7NR7BR7C, - NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7\ -OCHX7\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is hydrogen, halogen, -CX8 13, -CHX8 12, -CH2X8 1, -CN, -SOn8R8A, -SOv8NR8BR8C, - NR8BR8C, -C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -OCX8 J3, -OCHX8\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, - SOvi2NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, -OCX12 J3, - OCHX12 12. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCI3, -CBr3, -Cl3,-COOH, -CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3,-COOH, -CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted orunsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;R1Cis hydrogen, halogen, -CF3, -CCI3, -CBr3, -Cl3,-COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCI3, -CBr3, -Cl3-COOH, -CONH2, R12D-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;R2AR2BR2CR2DR5AR5BR5CR5DR6AR6BR6CR6DR7AR7BR7CR7DR8AR8BR8C, R8D, R12A, R12B, R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCI3, -CBr3. - Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andX, X1 1, X2 1, X5 1, X6 1, X7 1, X8 1, and X12.1are independently -Cl, -Br, -I, or -F; and wherein, the structure of Formula (II) is:wherein:X1and X4are independently =N- or =CH-;X5is =N- or -CR5-;X6is =N- or -CR6-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, and n7 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, vl, v2, v5, v6, and v7 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CXL13, -CHXL12, -CH2X1 1, -CN, -SOniR1A, - SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -SOn2R2A, -SOv2NR2BR2C, - NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOnsR5A, - SOV5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOneR6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen ,-CX7.13, -CHX7.12, -CH2X7.1, -CN, -SOn7R7A, -SOv7NR7BR7C, - NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, - SOv12NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, -OCX12.13, - OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;R1Cis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12D-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl; R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, - CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andX, X1 1, X2 1, X5 1, X6 1, X7 1, and X12.1are independently -Cl, -Br, -I, or -F.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:Figure 1A illustrates the daily body weight of mice;Figure IB illustrates the percent change in body weight of mice from baseline;Figure 2 illustrates the TNF-a level in mice serum;Figure 3A illustrates Ibal IHC on hippocampus of mice;Figure 3B illustrates Ibal IHC on frontal cortex of mice;Figure 4A illustrates CD68 IHC on hippocampus of mice;Figure 4B illustrates CD68 IHC on frontal cortex of mice;Figure 5A illustrates Aβ1-42 IHC on hippocampus of mice; andFigure 5B illustrates Aβ1-42 IHC on frontal cortex of mice.Figure 6 illustrates Aβ1-42 IF on frontal cortex of mice.Figure 7 illustrates results of ELISA for brain TNF- α.Figure 8 illustrates results of ELISA for brain TREM2.Figure 9 illustrates results of western blot determination for brain TREM2 Syk activity.Figure 10 illustrates results of western blot determination for brain TREM2 p-Zap-70 activity. Figure 11 illustrates results of western blot determination for brain TREM2 DAP12 activity.INCORPORATION BY REFERENCE

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION

[0007] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such asmolecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.Definitions

[0008] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0009] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0010] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0011] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewercarbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0012] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2- CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)- CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH- N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0013] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(O)R', -C(O)NR, -NR'R", -OR, -SR', and / or -SO2R. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0014] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,”respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2, 5, 6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. “Cycloalkyl” is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0015] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0016] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0017] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5 -isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5 -thiazolyl, 2 -furyl, 3 -furyl, 2- thienyl, 3 -thienyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2-benzimidazolyl, 5 -indolyl, 1 -isoquinolyl, 5 -isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3 -quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0018] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0019] The symboldenotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0020] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0021] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In some embodiments, the alkylarylene group has the formula:

[0022] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCI3, -CBr3. -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, - OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl). In some embodiments, the alkylarylene is unsubstituted.

[0023] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Certain substituents for each type of radical are provided below.

[0024] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR, =N-0R', -NR'R", -SR', -halogen, -SiR'R'R'", -0C(O)R, - C(O)R', -CO2R, -CONR'R", -0C(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)2R', - NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR", -S(O)R, -S(O)2R, -S(O)2NR'R", -NRSO2R, - NR'NR'R", -ONR'R", -NR'C(O)NR"NR'"R"", -CN, -NO2, -NRSO2R", -NR'C(O)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0025] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR, -halogen, - SiR'R'R", -OC(O)R', -C(O)R, -CO2R, -CONR'R", -0C(O)NR'R", -NR"C(O)R, -NR'- C(O)NR"R", -NR"C(O)2R, -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR", -S(O)R, -S(O)2R', - S(O)2NR'R", -NRSO2R', -NR'NR'R", -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -R', -N3, - CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NRSO2R", -NR'C(O)R", -NR'C(O)- OR", -NROR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R1, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.

[0026] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0027] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring -forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.

[0028] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, - CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, - S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R, R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0029] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0030] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:(i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:(a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SOrH, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, - NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)- OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0031] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0032] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0033] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0034] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0035] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0036] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0037] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0038] The term “tautomer,” as used herein, refers to one of two or more structural isomers that exist in equilibrium and which are readily converted from one isomeric form to another.

[0039] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0040] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0041] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0042] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0043] The term “isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 ("C). carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be2H, for example, or any carbon can be13C, for example, or any nitrogen can be15N, for example, or any oxygen can be18O, for example, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of deuterium (D).

[0044] It should be noted that throughout the application alternatives are written in Markush groups, for example, each amino acid position contains more than one possible amino acid. It isspecifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0045] “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0046] The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0047] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13and optionally differently.

[0048] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0049] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with pharmaceutically acceptable acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methane sulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0050] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methane sulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0051] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In some embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted intoeither base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.

[0052] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration.

[0053] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms.

[0054] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as, Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0055] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0056] A “VAP-1 inhibitor” refers to a compound (e.g., compounds described herein) that reduces the activity of VAP-1 when compared to a control, such as absence of the compound or a compound with known inactivity.

[0057] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from areaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.

[0058] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme (e.g., VAP-1).

[0059] As defined herein, the terms “activation,” “activate,” and / or “activating” and the like in reference to a protein refer to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0060] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist. In some embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target. In some embodiments, activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up- regulate, e.g., a gene, protein, ligand, receptor, or cell.

[0061] As defined herein, the terms “inhibition,” “inhibit,” ’’inhibiting,” and the like, in reference to a protein-inhibitor interaction mean negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In some embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein). In some embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0062] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given geneor protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist. In some embodiments, inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An “antagonist” is a molecule that opposes the action(s) of an agonist.

[0063] The terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be an autoimmune disease. The disease may be an inflammatory disease.

[0064] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases and uveitis (e.g., anterior uveitis including iridocyclitis and iritis, intermediate uveitis or pars planitis, posterior uveitis or chorioretinitis, and pan- uveitis). Such conditions are frequently inextricably intertwined with other diseases, disorders, and conditions. A non-limiting list of inflammatory-related diseases, disorders, and conditions include, Behcet’s disease, Crohn’s disease, Fuchs heterochromic iridocyclitis, Granulomatosis with polyangiitis, HLA-B27 related uveitis, arthritis (e.g., Juvenile idiopathic arthritis), Sarcoidosis, Spondyloarthritis, Sympathetic ophthalmia, Tubulointerstitial nephritis, uveitis syndrome, ankylosing spondylitis, chronic granulomatous disease, enthesitis, inflammatory bowel disease, Kawasaki’s disease, multiple sclerosis, polyarteritis nodosa, psoriatic arthritis, reactive arthritis, sarcoidosis, systemic lupus erythematosus, Vogt-Koyanagi-Harada disease, Whipple’s disease, white dot syndromes, and Masquerade syndromes. Uveitis can also be associated with infectious disease such as brucellosis, herpes viruses (herpes simplex), varicella zoster, leptospirosis, Lyme disease, presumed ocular histoplasmosis syndrome, syphilis, toxocariasis, toxoplasmic chorioretinitis, tuberculosis, and Zika fever.

[0065] White dot syndromes include, but are not limited to, acute posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy, multifocal choroiditis and panuveitis, multiple evanescent white dot syndrome, punctate inner choroiditis, serpiginous choroiditis, and acute zonal occult outer retinopathy.

[0066] Masquerade syndromes are divided into non-neoplastic and neoplastic conditions. Non- limiting examples of non-neoplastic masquerade syndromes include retinitis pigmentosa, intraocular foreign body,juvenile xanthogranuloma, and retinal detachment. Non-limiting examples of neoplastic masquerade syndromes include retinoblastoma, lymphoma, malignant melanoma, leukemia, and reticulum cell sarcoma.

[0067] The terms “treating” or “treatment” refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term “treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In some embodiments, treating is preventing. In some embodiments, treating does not include preventing.

[0068] “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.

[0069] “Treating” and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes indosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0070] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In some embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0071] ‘ ‘Patient” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

[0072] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar,Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like. By way of example, measurement of the serum level of a VAP-1 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.

[0073] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0074] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0075] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

[0076] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts andintervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0077] As used herein, the term “administering” means oral administration or topical administration. The compositions of the present disclosure can be delivered by a topical route, formulated as solutions, suspensions, emulsions, gels, and ointments. Oral preparations include tablets, pills, and capsules, etc., suitable for ingestion by the patient.

[0078] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0079] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0080] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profde of the selected agent.

[0081] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include, but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0082] ‘ ‘Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimentaleffects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0083] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a VAP-1 associated disease (e.g., uveitis) means that the disease (e.g., uveitis) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. For example, a uveitis associated with VAP-1 activity or function may be a uveitis that results (entirely or partially) from aberrant VAP- 1 function (e.g. enzyme activity, protein-protein interaction, signaling pathway) or a uveitis wherein a particular symptom of the disease is caused (entirely or partially) by aberrant VAP-1 activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a uveitis associated with VAP-1 activity or function or a VAP-1 associated disease (e.g., uveitis), may be treated with a compound described herein (e.g., VAP-1 modulator or VAP-1 inhibitor), in the instance where increased VAP-1 activity or function (e.g. signaling pathway activity) causes the disease (e.g., uveitis). For example, an inflammatory disease associated with VAP-1 activity or function or a VAP-1 associated inflammatory disease, may be treated with a VAP-1 modulator or VAP-1 inhibitor, in the instance where increased VAP-1 activity or function (e.g., signaling pathway activity) causes the disease.

[0084] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0085] As used herein, the terms “VAP-1 inhibitor,” “VAP-1 antagonist,” “Vascular adhesion protein- 1 inhibitor,” “Vascular adhesion protein- 1 antagonist,” and all other related art-accepted terms, many of which are set forth below, refer to a compound capable of modulating, either directly or indirectly, the VAP-1 receptor in an in vitro assay, an in vivo model, and / or other means indicative of therapeutic efficacy. The terms also refer to a compound that exhibits at least some therapeutic benefit in a human subject.

[0086] The phrase “in a sufficient amount to effect a change” means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject’s feeling of well-being).

[0087] The “activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like.

[0088] “Substantially pure” indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total composition content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).VAP-1 inhibitors

[0089] Vascular adhesion protein- 1 (VAP-1) is a member of the family of copper-containing amine oxidases / semicarbazide-sensitive amine oxidase (AOC / SSAO), found in humans as a membrane -bound form and a soluble form. The membrane-bound form of VAP-1 is mainly expressed in endothelial cells, smooth muscle cells, and adipocytes, whereas the soluble VAP- 1 is released into plasma mainly from vascular endothelial cells. VAP-1 has a distal adhesion domain and an enzymatically active amine oxidase site outside of the membrane. As an adhesion molecule, VAP-1 is involved in leukocyte rolling, adhesion and transmigration, which are important in leukocyte extravasation to sites of inflammation. VAP-1 also acts as an amine oxidase. It possesses topaquinone (TPQ) in the active site as a cofactor, and catalyzes the conversion of primary amines, for example, methylamine and aminoacetone, into the corresponding aldehydes, for example, formaldehyde and methylglyoxal, while releasing ammonia and hydrogen peroxide.RCH2NH2+ O2+ H2O -+ RCHO + H2O2+NH3

[0090] Vascular adhesion protein-1 (VAP-1) inhibitors are being studied as potential therapeutics for inflammatory conditions, such as rheumatoid arthritis, asthma, and diabetic retinopathy. The mechanism of action of VAP-1 inhibitors involves blocking the enzymatic activity of VAP- 1. VAP- 1 has been shown to have amine oxidase activity, which is involved in the production of reactive oxygen species (ROS) and the adhesion and migration of leukocytes across the endothelium. By inhibiting the amine oxidase activity of VAP-1, VAP-1 inhibitors can reduce the production of ROS and inhibit the adhesion and migration of leukocytes, leading to a reduction in inflammation and tissue damage. VAP-1 inhibitors used herein have been previously described in WO 2020 / 069330 and WO 2020 / 069335, each of which is incorporated by reference in their entirety.Neuroinflammation

[0091] Neuroinflammation refers to the inflammation of the nervous tissue, which can be caused by various factors, including infection, injury, autoimmune disorders, and neurodegenerative diseases. Neuroinflammation involves the activation of glial cells, such as microglia and astrocytes, which release inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Neuroinflammation has been implicated in several neurological and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), Vascular dementia (VAD), Anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), Transverse myelitis (TM), Autoimmune Encephalitis (AE), Acute disseminated encephalomyelitis (ADEM), Chronic meningitis (CM), Central nervous system (CNS) vasculitis, Hashimoto’s encephalitis (HE), Neurosarcoidosis (NS), Multiple system atrophy (MSA), Migraine, Chemotherapy-induced pain or Dementia-related pain. The inflammatory response in these conditions can exacerbate neuronal damage and contribute to disease progression. Research is ongoing to better understand the mechanisms underlying neuroinflammation and to develop therapies to modulate the inflammatory response in order to reduce neuronal damage and improve outcomes for patients with neurological and psychiatric disorders.Alzheimer's disease (AD)

[0092] Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory and cognitive function. It is the most common cause of dementia in older adults, and its prevalence increases with age. The pathological hallmark of Alzheimer's disease is the accumulation of beta-amyloid plaques and tau protein tangles in the brain, which leads to the death of brain cells and the shrinking of brain tissue. These changes disrupt communication between brain cells and affect memory, thinking, and behavior. Symptoms of Alzheimer's disease usually begin with mild memory impairment, but progress to include difficulty with language, spatial orientation, and decision-making. As the disease advances, individuals may experience personality changes, mood swings, and loss of motor function.Parkinson 's disease (PD)

[0093] Parkinson's disease is a chronic and progressive neurological disorder that affects the movement and coordination of the body. The disease results from the degeneration of dopamine- producing neurons in the brain. Dopamine is a neurotransmitter that helps control movement and emotional responses. The symptoms of Parkinson's disease typically develop gradually and include tremors (usually beginning in one hand or arm), stiffness, slowed movement (bradykinesia), poor balance, and difficulty walking. Other symptoms can include depression,anxiety, sleep disturbances, and cognitive impairment. The cause of Parkinson's disease is not fully understood, but it is believed to be a combination of genetic and environmental factors. Age is also a major risk factor, with the disease primarily affecting people over the age of 60. Amyotrophic lateral sclerosis (ALS)

[0094] Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, is a neurodegenerative disease that affects the nerve cells responsible for controlling voluntary muscles. As the disease progresses, these nerve cells, called motor neurons, deteriorate, leading to weakness and eventual paralysis of the muscles they control. Symptoms of ALS include muscle weakness, stiffness, and twitching, difficulty speaking, swallowing and breathing, and eventually complete paralysis. There is currently no cure for ALS, and the disease is often fatal within a few years of diagnosis. Treatment options aim to alleviate symptoms, improve quality of life, and slow down the progression of the disease.Multiple Sclerosis (MS)

[0095] Multiple Sclerosis is a chronic and often disabling neurological disease that affects the central nervous system. In MS, the immune system mistakenly attacks the myelin sheath that surrounds and protects nerve fibers in the brain, spinal cord, and optic nerves. This damage disrupts the flow of electrical impulses between the brain and the body, leading to a range of symptoms. Symptoms of MS can vary widely and include fatigue, muscle weakness, spasticity, difficulty walking, numbness and tingling, vision problems, bladder and bowel dysfunction, and cognitive impairment. Symptoms may come and go (relapses) or worsen over time (progression).The cause of MS is not fully understood, but it is believed to be a combination of genetic and environmental factors. MS is more common in women than men, and typically begins between the ages of 20 and 40.Traumatic brain injury (TBI)

[0096] Traumatic brain injury is a type of brain damage that is caused by a sudden blow or jolt to the head or body. This can happen as a result of a car accident, a fall, a sports injury, or any other situation in which the head or body is hit with force. The severity of a TBI can vary from mild to severe, and the symptoms can also vary depending on the severity of the injury. Mild TBI, also known as a concussion, may result in brief loss of consciousness, confusion, headache, dizziness, or nausea. Severe TBI can result in long-term or permanent brain damage, including cognitive impairment, physical disability, or behavioral changes.Complex regional pain syndrome (CRTS)

[0097] Complex regional pain syndrome is a chronic pain condition that usually affects an arm, leg, hand, or foot. The exact cause of CRPS is not fully understood, but it is thought to involvean abnormal response by the immune system and nervous system to an injury or trauma. The symptoms of CRPS can vary, but typically include severe pain, swelling, stiffness, and changes in skin color and temperature in the affected area. Other symptoms may include muscle weakness, muscle spasms, and decreased mobility. The pain associated with CRPS can be constant and severe, and may spread to other parts of the body.Optic Neuritis (ON)

[0098] Optic neuritis is inflammation of the optic neruve. It is further classified into papillitis and retrobulbar neuritis. Papillitis is characterized by inflammation of the optic nerve head, and retrobulbar neuritis is characterized by inflammation of the posterior of the nerve. In some instances, multiple sclerosis is one of the most common etiology of optic neuritis. Additional causes include infection (e.g. syphilis, Lyme disease, herpes zoster), autoimmune disorders (e.g. lupus, neurosarcoidosis, neuromyelitis optica), inflammatory bowel disease, drug induced (e.g. chloramphenicol, ethambutol, isoniazid, streptomycin, quinine, penicillamine, aminosalicylic acid, phenothiazine, phenylbutazone), vasculitis, B12 deficiency and diabetes. The symptoms of optic neuritis include sudden blurred or foggy vision, pain associated with eye movement, impaired color vision, and impaired depth perception. In some instances, treatment includes corticosteroids.Neuromyelitis Optica (NMO)

[0099] Neuromyelitis optica (also known as Devic’s disease, Devic’s syndrome, or NMO) is a B-cell mediated disease associated with simultaneous inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). In some instances, the symptoms include vision loss, pain sensation within the eye, sensory disturbances, weakness, numbness and / or paralysis of the arms and legs, and loss of bladder and bowel control. In the disease process, autoantibodies NMO-IgG, derived from peripheral B cells, target CNS astrocytic Aquaporin 4 (AQP4), resulting in complement activation and inflammation. In some instances, the inflammatory lesions are similar to the lesions of multiple sclerosis (MS); however, they differ from MS in their perivascular distribution. There are two variants of neuromyelitis optica, AQP4+ NMO which leads to the attack of astrocytes of the optic nerves and spinal cords by a person’s own immune system, and AQP4- NMO, in which the etiology is unknown.

[0100] In some embodiments, neuromyelitis optica belongs to a collection of similar diseases termed neuromyelitis optica spectrum disorder (NMOSD). In some cases, the additional diseases belonging to NMOSD comprise Standard Devic’s disease, limited forms of Devic’s disease, Asian optic-spinal MS, longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease, optic neuritis, or NMO-IgG negative NMO.Chronic traumatic encephalopathy (CTE)

[0101] Chronic traumatic encephalopathy is a progressive neurological disorder that is caused by repetitive head injuries. CTE is commonly found in athletes who participate in contact sports, such as football, boxing, and hockey, as well as military personnel and individuals who have a history of head trauma. The hallmark feature of CTE is the buildup of an abnormal protein called tau in the brain, which leads to damage and death of brain cells. The symptoms of CTE can vary widely and may not appear until years after the initial head injury. Symptoms may include mood disorders, cognitive impairment, memory loss, and problems with impulse control and aggression.Ischemic stroke (IS)

[0102] An ischemic stroke is a type of stroke that occurs when a blood vessel in the brain becomes blocked, preventing blood flow to the affected area of the brain. This can result in brain damage and can cause a wide range of symptoms, depending on the severity of the stroke and the area of the brain that is affected. The most common cause of ischemic stroke is atherosclerosis, which is the buildup of plaque in the arteries that can narrow or block blood flow. Other causes of ischemic stroke include blood clots, heart conditions such as atrial fibrillation, and certain medical conditions such as sickle cell disease. Symptoms of ischemic stroke can include sudden onset of weakness or numbness on one side of the body, difficulty speaking or understanding speech, sudden vision changes, dizziness or loss of coordination, and severe headache.Vascular dementia (VAD)

[0103] Vascular dementia is a type of dementia that occurs when the blood supply to the brain is disrupted, leading to damage to brain cells. This can occur as a result of a stroke or a series of small, silent strokes that go unnoticed. Symptoms of vascular dementia can vary, but may include memory loss, difficulty with concentration, confusion, disorientation, problems with language and communication, and difficulty with decision making and problem solving. Other symptoms may include depression, anxiety, and changes in behavior and personality.Anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD)

[0104] Anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease is an autoimmune disorder that affects the central nervous system (CNS). MOG is a protein that is found on the surface of myelin, the protective coating around nerve fibers in the CNS. In this condition, the body's immune system mistakenly attacks MOG, leading to inflammation and damage to the myelin. Symptoms of anti-MOG antibody disease can vary widely and may include optic neuritis (inflammation of the optic nerve), transverse myelitis (inflammation of the spinal cord), encephalitis (inflammation of the brain), and acute disseminated encephalomyelitis (ADEM), which is a rare autoimmune disorder that affects the brain and spinal cord.Transverse myelitis (TM)

[0105] Transverse myelitis is a rare neurological disorder that involves inflammation of the spinal cord. The inflammation can damage or destroy myelin, the fatty substance that covers nerve fibers, and can cause scarring of the spinal cord. This can lead to a wide range of symptoms that can vary in severity and duration. Symptoms of transverse myelitis may include back pain, weakness or paralysis in the arms or legs, sensory disturbances such as numbness or tingling, bladder or bowel dysfunction, and difficulty with coordination and balance.Autoimmune Encephalitis (AE)

[0106] Autoimmune encephalitis is a rare neurological disorder that occurs when the immune system mistakenly attacks healthy cells in the brain, leading to inflammation and damage. The symptoms of autoimmune encephalitis can be broad and can vary widely between individuals, but may include: (a) Cognitive and behavioral changes, such as memory loss, confusion, personality changes, and mood swings (b) Movement disorders, such as tremors, ataxia (loss of coordination), and myoclonus (muscle spasms) (c) Seizures (d) Psychiatric symptoms, such as hallucinations, delusions, and paranoia (e) Autonomic dysfunction, such as changes in blood pressure, heart rate, and body temperature.Acute disseminated encephalomyelitis (ADEM)

[0107] Acute disseminated encephalomyelitis is a rare autoimmune neurological disorder that typically occurs after an infection or vaccination. The condition arises when the immune system attacks the myelin sheath that covers nerve fibers in the brain and spinal cord, leading to inflammation and damage. Symptoms of ADEM can include fever, headache, vomiting, seizures, and confusion. Patients may also experience weakness or paralysis in their limbs, visual disturbances, and difficulty with speech or swallowing. In severe cases, ADEM can lead to coma or even death.Chronic meningitis (CM)

[0108] Chronic meningitis is a persistent inflammation of the membranes that cover the brain and spinal cord. Unlike acute meningitis, which is a medical emergency, chronic meningitis develops slowly and can last for several weeks or months. The most common causes of chronic meningitis are bacterial or fungal infections, but the condition can also be caused by non- infectious factors such as certain medications, cancers, autoimmune disorders, and sarcoidosis. Symptoms of chronic meningitis can include headache, fever, neck stiffness, sensitivity to light, and confusion. Patients may also experience fatigue, weakness, and cognitive impairment. In some cases, chronic meningitis can cause seizures or strokes.Central nervous system vasculitis (CNS vasculitis)

[0109] Central nervous system vasculitis is a rare autoimmune disorder that affects the blood vessels in the brain and spinal cord. The condition arises when the immune system mistakenly attacks healthy blood vessels, causing inflammation and damage. The damage can lead to a range of neurological symptoms, including headache, confusion, seizures, and focal neurological deficits such as weakness, numbness, or loss of coordination.Hashimoto ’s encephalitis (HE)

[0110] Hashimoto's encephalitis (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare autoimmune disorder that affects the brain. It is caused by an autoimmune reaction against the thyroid gland, resulting in the production of antibodies that attack the brain's neurons. The symptoms of Hashimoto's encephalitis can vary greatly from person to person, but may include: Memory loss, Confusion, Personality changes, Seizures, Psychosis, Headaches, Tremors and Ataxia (loss of coordination). Neurosarcoidosis (NS)

[0111] Neurosarcoidosis is an uncommon manifestation of sarcoidosis, which is an inflammatory disorder that can affect multiple organs in the body. It specifically targets the nervous system, including the brain, spinal cord, and nerves. The signs and symptoms of neurosarcoidosis can vary greatly from person to person, depending on the affected area of the nervous system. Some common symptoms may include headaches, seizures, vision or hearing difficulties, numbness or weakness in the face, cognitive issues such as memory loss or confusion, balance problems, limb weakness or paralysis, and joint, muscle, or bone pain.

[0112] Multiple system atrophy (MSA)Multiple system atrophy is a rare and progressive neurodegenerative disorder that is characterized by the abnormal accumulation of the protein alpha-synuclein (a-syn) in oligodendrocytes, which are specialized cells that produce myelin, the insulating material that surrounds and protects nerve fibers. This accumulation of a-syn leads to inflammation, demyelination, and subsequent synapse and neuronal loss, which results in the characteristic symptoms of MSA, such as autonomic dysfunction and movement disorders.

[0113] MigraineMigraine a neurological condition characterized by recurrent episodes of moderate to severe headaches, which are usually accompanied by other symptoms such as sensitivity to light, sound, or smell, nausea, and vomiting. Migraines can last from a few hours to several days and can be very debilitating, interfering with daily activities and quality of life.

[0114] Chemotherapy-induced painChemotherapy-induced pain is a common side effect of cancer treatment that can be caused by the chemotherapy drugs themselves or by the cancer itself. The pain can be acute, meaning itcomes on suddenly and lasts for a short period of time, or it can be chronic, lasting for months or even years after treatment has ended. Chemotherapy-induced pain can manifest in different ways, including peripheral neuropathy which is damage to the nerves that control sensation and movement in the arms, legs, hands, and feet, causing pain, tingling, or numbness. Another manifestation of pain is mucositis, which is inflammation of the mucous membranes that line the digestive tract, causing pain and discomfort in the mouth, throat, and digestive system. Some patients may experience headaches, bone pain or joint pain which can be severe and debilitating.

[0115] Dementia-related pain Dementia-related pain is pain experienced by people with dementia, a progressive neurological condition that affects cognitive functioning, memory, and behavior. People with dementia may have difficulty expressing their pain, making it challenging for caregivers and healthcare professionals to identify and manage pain effectively. Dementia-related pain can manifest in different ways, including physical pain such as headaches, muscle or joint pain, and neuropathic pain. The pain may also be related to medical conditions commonly associated with dementia, such as arthritis, infections, or injuries resulting from falls. In addition to physical pain, people with dementia may also experience psychological or emotional pain, such as anxiety or depression, which can exacerbate physical pain symptoms.Pharmaceutical Compositions

[0116] In certain embodiments, the compound described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0117] Provided herein is a pharmaceutical composition comprising at least one compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0118] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt or solvate thereof.

[0119] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0120] In certain embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0. 1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0121] In certain embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0. 1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0122] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0123] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non- aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0124] The dose of the composition comprising at least one compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0125] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. In some embodiments thecompound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg to about 1000 mg, one to four times per day.Methods of Treatment

[0126] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I) is:the symbol — represents a point of attachment;X1is =N-, -NR8-, -O-, or -S-;X2is -N- or -CH-;X3is -O-, -S-, -NH-, -CH2-, or -C(O)-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, n7, n8, and n12 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 2re independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -SOniR1A, - SOviNR1BR1C, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -SOn2R2A, -SOv2NR2BR2C, - NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOn5R5A, - SOV5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5\ -OCHX5\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOneR6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6 I3. -OCHX6\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -SOn7R7A, -SOv7NR7BR7C, - NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is hydrogen, halogen ,-CX8A3, -CHX8 12, -CH2X8 1, -CN, -SOn8R8A, -SOv8NR8BR8C, - NR8BR8C, -C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -OCX8\ -OCHX8\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, - SOvi2NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, -OCX12A, - OCHX12.12. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;R1Cis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12D-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;R2AR2BR2CR2DR5AR5BR5CR5DR6AR6BR6CR6DR7AR7BR7CR7DR8AR8BR8C, R8D, R12A, R12B, R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCl3, -CBr3, - CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituentsbonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andX, X1 1, X2 1, X5 1, X6 1, X7 1, X8 1, and X12.1are independently -Cl, -Br, -I, or -F; and wherein, the structure of Formula (II) is:wherein:X1and X4are independently =N- or =CH-;X5is =N- or -CR5-;X6is =N- or -CR6-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, and n7 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, vl, v2, v5, v6, and v7 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -SOniR1A, - SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -SOn2R2A, -SOv2NR2BR2C, - NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, - SOvsNR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -SOn7R7A, -SOv7NR7BR7C, - NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOn12R12A, - SOv12NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, -OCX12\ - OCHX12.12. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;R1Cis hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3,-COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCI3, -CBr3, -Cl3-COOH, -CONH2, R12D-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl; R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3, -COOH, - CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andX, X1 1, X2 1, X5 1, X6 1, X7 1, and X12.1are independently -Cl, -Br, -I, or -F.

[0127] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I) is:

[0128] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I -A), or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-A) is:

[0129] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-B) is:

[0130] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-B 1) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-B 1) is:

[0131] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-B2) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-B2) is:

[0132] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical compositioncomprising a compound of Formula (I-C) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-C) is:

[0133] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-D) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-D) is:

[0134] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-E) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-E) is:

[0135] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-F) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I-F) is:

[0136] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II) is:

[0137] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-A) is:

[0138] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-B) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-B) is:

[0139] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-C) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-C) is:

[0140] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-D) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-D) is:

[0141] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-E) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-E) is:

[0142] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-F) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-F) is:

[0143] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-G) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-G) is:

[0144] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II-H) or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (II-H) is:

[0145] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound provided in Table 1.

[0146] The compounds of Tables 1, 2 or 3 have been characterized as VAP-1 inhibitors in the following publications WO 2020 / 069330 and WO 2020 / 069335.TABLE 1

[0147] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound provided in Table 2.TABLE 2

[0148] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound provided in Table 3.TABLE 3

[0149] In some embodiments is provided a method of treating neuroinflammatory disease in a patient in need thereof, wherein the neuroinflammatory disease is selected from Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), Vascular dementia (VAD), Anti-myelin oligodendrocyte glycoprotein antibody disease(MOGAD), Transverse myelitis (TM), Autoimmune Encephalitis (AE), Acute disseminated encephalomyelitis (ADEM), Chronic meningitis (CM), Central nervous system (CNS) vasculitis, Hashimoto’s encephalitis (HE), Neurosarcoidosis (NS), Multiple system atrophy (MSA), Migraine, Chemotherapy-induced pain or Dementia-related pain.

[0150] In some embodiments, the neuroinflammatory disease is Alzheimer's disease. In some embodiments, the neuroinflammatory disease is Parkinson's disease. In some embodiments, the neuroinflammatory disease is amyotrophic lateral sclerosis. In some embodiments, the neuroinflammatory disease is multiple sclerosis. In some embodiments, the neuroinflammatory disease is traumatic brain injury. In some embodiments, the neuroinflammatory disease is complex regional pain syndrome. In some embodiments, the neuroinflammatory disease is optic neuritis. In some embodiments, the neuroinflammatory disease is neuromye litis optica. In some embodiments, the neuroinflammatory disease is chronic traumatic encephalopathy. In some embodiments, the neuroinflammatory disease is ischemic stroke.

[0151] In some embodiments, the neuroinflammatory disease is Vascular dementia. In some embodiments, the neuroinflammatory disease is Anti-myelin oligodendrocyte glycoprotein antibody disease. In some embodiments, the neuroinflammatory disease is Transverse myelitis. In some embodiments, the neuroinflammatory disease is Autoimmune Encephalitis. In some embodiments, the neuroinflammatory disease is Acute disseminated encephalomyelitis. In some embodiments, the neuroinflammatory disease is Chronic meningitis. In some embodiments, the neuroinflammatory disease is Central nervous system (CNS) vasculitis. In some embodiments, the neuroinflammatory disease is Hashimoto’s encephalitis. In some embodiments, the neuroinflammatory disease is Neurosarcoidosis. In some embodiments, the neuroinflammatory disease is Multiple system atrophy. In some embodiments, the neuroinflammatory disease is Migraine. In some embodiments, the neuroinflammatory disease is Chemotherapy-induced pain. In some embodiments, the neuroinflammatory disease is Dementia-related pain.EXAMPLES

[0152] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:G GroupIACUC Institutional Animal Care and Use CommitteeQ .D Once a day i.p. Intraperitoneal injectionLPS Lipopolysaccharide°C Degree centigradeSEM Standard error of meanSPF Specific pathogen freeTNF-α Tumor necrosis factor alphaIba- 1 Ionized calcium binding adapter molecule 1Aβ1-42 Mouse Amyloid Beta Peptide 1-42DMSO Dimethyl sulfoxideVS. VersusI. Biological EvaluationLipopolysaccharide (LPS) is one of bacterial surface molecules glycolipid, which can induce inflammation and tissue injury. LPS-induced neuroinflammation manifested as microglia activation (labeled by Iba-1 and CD-68) and Api-42 expression in hippocampus and frontal cortex. Ap activates microglia and induces their release of proinflammatory cytokines, such as TNF-a.1. STUDY OBJECTIVEThe objective of this study is to evaluate the efficacy of compounds (A, B, C) on Lipopolysaccharide (LPS)-induced neuroinflammation in C57BL / 6J mice.2. STUDY MATERIALSREAGENTS• Lipopolysaccharide (LPS): Sigma-Aldrich, Catalog Number: L2880• Saline: Shijiazhuang Siyao CO., LTD., Catalog Number: 2107271904• DMSO: Sigma, Catalog Number: 472301-100ML• K2EDTA tube: BD, Catalog Number: 365974• Mouse TNF-alpha ELISA Kit: Invitrogen, Catalog Number: 88-7324• Ibal: Abeam, Catalog Number: abl78847• CD68: Cell Signaling, Catalog Number:97778• Api-42: Abeam, Catalog Number: ab201061• F(ab')2-Goat anti-Rabbit HRP antibody: Abeam, Catalog Number: Ab6013• Rabbit two-step test kit: ZSGB-Bio, Catalog Number: PV-9001• TSA570: Wi See Biotechnology, Cat No. DI 1011DAPI: Invitrogen, Catalog Number: D3571• DAPI: Invitrogen, Catalog Number:D3571• Antifade Mounting Medium: Absin, Catalog Number: abs9240EQUIPMENT• Electronic Balance: Sartorius, Catalog number: SECURA225D-1CN• Electronic scale: Shanghai Yueping Scientific instrument Co., Ltd., Cat: YP 10001 Ultrasonic• Ultrasonic cleaner: Kunshang, Catalog number: KQ3200E• Electronic oscillator: Scientific Industries, Catalog number: SI-0256• Centrifuge: Thermo Scientific, Catalog number: 75002440• Paraffin dehydrator: Leica, Catalog number: EG1150C• Paraffin microtome: Leica, Catalog number: RM2235• Paraffin embedding machine: Leica, Catalog number: EG115 OH• Forward fluorescent microscope: Olympus, Catalog number: BX53COMPOUNDSThe compounds are prepared according to reported procedure sstored at 4 °C.ANIMALSTable 4 Animal informationETHODSGROUPING AND REGIMEN40 female C57BL / 6 mice, 10 weeks old, from Shanghai Jihui Laboratory Animal Care Co., Ltd, were used in this experiment. All animals were labeled with ear tags. After 1- week-adaptation, all the mice were randomly divided into 5 groups based on body weight, as shown in Table 3.Table 5 Grouping and Dosing RegimenREAGENTS PREPARATION• LPS (0.75 mg / mL stock solution) preparation:Weigh 3.75 mg of LPS into an 8 mL polyethylene tube. Add 5 mL of PBS Stir or shake to mix. Divide into 1 ml stock solution aliquots , store at -20°C for use.• LPS (0.075 mg / mL) preparation:Add 9 mL PBS to the 1 mL LPS stock solution (0.75 mg / mL), shake to mix. Prepare right before dosing.• Compound A (0.6 mg / mL) preparation (in 2%DMSO and 98% saline):Weigh 30.0 mg of compound A into a brown bottle. Add 1 mb of DMSO, vortex to get a homogeneous solution (stock solution, concentration =30 mg / mL). Divide into 40 μl stock solution aliquots, store at -80°C, kept from light for use.Add 1.96 mL saline to the 1 mL compound A stock solution (30 mg / mL), shake to mix until completely dissolved (0.6 mg / mL) right before treatment.• Compound B (0.6 mg / mL) preparation (in 2%DMSO and 98% saline):Weigh 30. 1 mg of compound B into a brown bottle. Add 1 mL of DMSO, vortex to get a homogeneous solution (stock solution, concentration =30 mg / mL). Divide into 40 μl stock solution aliquots, store at -80°C, kept from light for use.Add 1.96 mL saline to the 1 mL compound B stock solution (30 mg / mL), shake to mix until completely dissolved (0.6 mg / mL) right before treatment.• Compound C (0.6 mg / mL) preparation (in 2%DMSO and 98% saline):Weigh 30.4mg of compound C into a brown bottle. Add 1.01 mL of DMSO, vortex to get a homogeneous solution (stock solution, concentration =30 mg / mL). Divide into 40 pl stock solution aliquots, store at -80°C, kept from light for use.Add 1.96 mL saline to the 1 mL compound C stock solution (30 mg / mL), shake to mix until completely dissolved (0.6 mg / mL) right before treatment.MODEL SET UP AND DOSINGMice were intraperitoneal injected with either LPS (750 pg / kg,10 mL / kg) or an equal volume of saline Ih after drug treatment from day 0 to day 4 (table 3). The day of the first LPS injection is recorded as day 0.ENDPOINTS• On day 4, Ih after LPS treatment, all animals were anaesthetized, the blood was into K2EDTA tube, and the plasma samples was separated at 3500 rpm, 10 min, and stored at -80 °C for analysis of TNF-a level.• The mice were perfused with lOmL ice-cold saline for three minutes via the left ventricle. The whole brains were stripped and soaked in formalin for immunohistochemistry analysis. (CD-68 (microphage), Iba-1 microglia and Aβ1-42 in hippocampus and frontal cortex).PARAMETERS• Body WeightDuring the experiment, daily body weight and clinical observation were recorded before dosing.• ELISA: TNF-a level1) Coated Coming™ Costar™ 9018 ELISA plate with 100 pL / well of capture antibody in Coating Buffer (dilute as noted in point 1 of Reagent preparation). Sealed the plate and incubate overnight at 4°C.2) Aspirated wells and wash 3 times with >250 pL / well Wash Buffer. Allowing time for soaking (~1 minute) during each wash step increases the effectiveness of the washes. Blot plate on absorbent paper to remove any residual buffer.3) Blocked wells with 200 pL of ELISA / ELISPOT Diluent (IX). Incubated at room temperature for 1 hour.4) Prepareed Standard. Reconstituted mouse TNF alpha standard by addition of distilled water. Reconstitution volume was stated on the label of the standard vial. Allowed the standard to reconstitute for 10-30 minutes. Swirlled or mixed gently to ensure complete and homogeneous solubilization (concentration of reconstituted standard = 1000 pg / mL).5) Aspirated and wash at least once with Wash Buffer.6) Performed 2-fold serial dilutions of the top standards to make the standard curve for a total of 8 points. For that add 100 pL of ELISA / ELISPOT Diluent (IX) to the wells leaving the first wells empty. Added 200 pL / well of top standard concentration to the first empty wells A1 / A2. Transfered 100 pL of top standard from wells A1 / A2 to wells B1 / B2. Mixed the contents of the wells B 1 and B2 by repeated aspiration and ejection and transfer 100 pL to wells C1 / C2. Took care not to scratch surface of the microwells. Continued this procedure 5 times.7) Added 100 pL / well of samples to the appropriate wells.8) Add edlOO pL of ELISA / ELISPOT Diluent (IX) to the blank well.9) Sealed the plate and incubate at room temperature for 2 hours (or overnight at 4°C for maximum sensitivity).10) Prepared the Detection Antibody (See Reagent preparation).11) Aspirated and wash as in Step 2. Repeated for a total of 3-5 washes. Allowing time for soaking (~1 minute) during each wash step increases the effectiveness of the washes. Blot plate on absorbent paper to remove any residual buffer.12) Added 100 pL / well diluted Detection Antibody to all wells.13) Sealed the plate and incubate at room temperature for 1 hour.14) Prepared the Streptavidin-HRP. Diluted HRP Concentrate (100X) 1: 100 in ELISA / ELISPOT Diluent(lX).15) Aspirated and wash as in Step 2. Repeated for a total of 3-5 washes. Allowing time for soaking (~1 minute) during each wash step increases the effectiveness ofthe washes. Blot plate on absorbent paper to remove any residual buffer.16) Added 100 pL / well of diluted Streptavidin-HRP.17) Sealed the plate and incubate at room temperature for 30 minutes.18) Aspirated and wash as in Step 2, making sure to allow time for soaking for 1 to 2 minutes prior to aspiration. Repeated for a total of 5-7 washes.19) Added 100 pL / well of IX TMB Solution.20) Incubated at room temperature for 15 minutes.21) Added 100 pL / well of Stop Solution.22) Read plate at 450 nm. If wavelength substraction was available, substracted the values of 570 nm from those of 450 nm and analyze data.• Immunohistochemistry1) Paraffin slides were placed in xylene for 30 min (10 min><3 times) and ethanol gradient for 5min (from high to low: 100%-100%-95-80%) to dewaxing and hydration; Then slides were placed into water for 10 min (in the water bottle).2) Washed slides with PBS for 3 times, each time for 3 min.3) Slides were immerged in Citrate retrieved buffer solution (pH 9.0) for 20 min when the temperature reach to 95 °C. Pick up slides holder and cooled to room temperature.4) Washed slides with PBS for 3 min, 3 min each time.5) Removed the fluid from the slides with tissue papers, drew a circle around the tissue with an immunohistochemical pen, and marked the edges with a pencil. Endogenous peroxidase blocker was added in moderation and incubated at room temperature for 10 min.6) Washed slides with PBS for 3 min, 3 min each time.7) The primary antibody Ibal,CD68, Aβ1-42 was diluted for 1:6000, 1: 150 and 1:500 with PBS (1.5% BSA + 0.5% Triton X-100) as required, and 200 μL of them were added into the circle (to avoid slides dry, one slide at a time). Then slides were incubated at 4 °C overnight.8) Took out the slide box and place it at room temperature for 20 min. Washed slides with PBS for 4 times, 3 min each time.9) Added the reaction enhancer and incubate at room temperature for 20 min.10) Washed slides with PBS for 4 times, 3 min each time.11) Enzyme -labeled goat anti-rabbit IgG polymer was added and incubated for 20 min at room temperature.12) Washed slides with PBS for 4 times, 3 min each time.13) 150 pL of DAB chromogenic reagent (250 μL of concentrated DAB solvent + 5 mL of DAB substrate solution were mixed in the dark and kept fresh) was added to the slide for color developing until brown was observed by naked eye.14) After the emergence of clear brown, slides were placed in water to terminate the reaction immediately, then washed with water for 10min.15) After drying the slides by throwing hands, redyed them in hematoxylin dye solution for 30 s and rinsed them with water for 5 min.16) After drying the slides by throwing hands, the slides were placed in alcohol hydrochloride and differentiated for Is. Then, the slides were taken out quickly and washed with water for 15 min.17) After washing, the slides were placed in gradient ethanol solutions (from low to high: 80%- 95%-95%-100%-100%-100% for 5 min each ether), and then dehydrated with xylene (5 min x 3 times).18) Sealed the slides with Neutral balsam.Immunofluorescent1) Paraffin slides were placed in xylene for 30min (10 minx 3 times) and ethanol gradient for 5min (from high to low: 100%-100%-95-80%) to dewaxing and hydration. Then slides were placed into water for 10 min (in the water bottle).2) Washed slides with PBS for 3 times, each time for 3 min.3) Slides were immerged in Citrate retrieved buffer solution (pH 9.0) for 20 min when the temperature reach to 95 °C. Pick up slides holder and cooled to room temperature.4) Washed slides with PBS for 3 min, 3 min each time.5) Removed the fluid from the slides with tissue papers, drew a circle around the tissue with an immunohistochemical pen, and marked the edges with a pencil. Endogenous peroxidase blocker was added in moderation and incubated at room temperature for 10 min.6) Washed slides with PBS for 3 min, 3 min each time.7) The primary antibody Aβ1-42 was diluted for 1:500 with PBS (1.5% BSA + 0.5% Triton X-100) as required, and 200 μL of them were added into the circle (to avoid slides dry, one slide at a time). Then slides were incubated at 4 °C overnight.8) Took out the slide box and place it at room temperature for 20 min. Washed slides with PBS for 4 times, 3 min each time.9) Incubated tissue with second antibody F(ab')2-Goat anti-Rabbit HRP 1: 1000 for 1 h at room temperature10) Washed slides with PBS for 3 min, 3 min each time.11) Incubated tissue with TSA570 1:400 for 1 h at room temperature from light.12) Washed slides with PBS for 4 times, 3 min each time.13) Incubated tissue with DAPI 1:5000 for 10 minutes at room temperature.14) Sealed the slides with Antifade Mounting Medium.4. RESULTSCLINICAL OBSERVATIONDuring the experiment, the control group were no abnormal clinical phenomena, while the model group exhibited classic signs of sickness behaviours, including decreased locomotion and body weight, a hunched posture and anorexia.1.1 BODY WEIGHT AND CHANGECompared with the control group, the model group has a significant decrease in body weight from day 1 to 4 (***P < 0.001). Compared with the model group, the treatment groups (A, B, C) had no obvious improvement in weight loss (Figure 1). The weight of D-3 was calculated as 100%; ###: compared to Gl, unpared T-test, p < 0.001, n=8.1.2 CYTOKINES ANALYSISCompared with control group, the TNF-a level in serum of model group showed a significant increase (***p < 0.001). Compared with model group, compound B and compound C treatment groups significantly inhibited TNF-a level in the serum of mice (* P < 0.05), while compound A treatment showed a slight inhibition tendency, indicating that compound B and compound C treatment have a better anti-inflammatory effect of TNF-α inhibition (figure 2). ###: compared to Gl, unpared T-test, p < 0.001, n=8. *: compared to G2, unpared T-test, p < 0.05, n=8.1.3 IMMUNOHISTOCHEMICAL ANALYSISIba-1 is a commonly used microglia membrane marker. The increasing of Iba-1 positive area in both hippocampus and cortex in model group compared with control showed the occurrence of neuroinflammation. Compared with the model group, compound A and compound B group showed a slight inhibition tendency of Iba-1 increasing in hippocampus, while compound C significantly inhibited Iba-1 increase in hippocampus (figure 3a). In cortex, all of the three treatment showed significantly Iba-1 inhibition effect compared with model group (figure 3b). It is suggested that these three compounds have a positive effect in improving neuroinflammation by inhibiting the increase of microglia, and compound C effects both in hippocamous and cortex.CD68 expresses at a higher level on the membrane of activated microglia, but at a lower level on the membrane of resting microglia. The increase of CD68 expression in both hippocampus and cortex of model group showed the activation of mocroglia in neuroinflammation, and all of the three treatment showed significant effect of inhibiting microglia activation in hippocampus (figure 4a). Compound A treatment showed this effect in cortex as well (figure 4b). Aβ1-42 is a marker to measure the microglia activation and neuronal cell loss in the mouse hippocampus and cortex. The increase of Api-42 expression in both hippocampus and cortex of model group compared with control showed the occurrence ofneuroinflammation. Compared with the model group, compound A group showed a slight inhibition tendency of Aβ1-42 increasing in hippocampus (figure 5 a). In cortex, all of the three treatment showed inhibition tendency of Aβ1-42 increasing compared with model group, while compound B significantly inhibited Aβ1-42 increase (figure 5b). #: compared to Gl, unpared T-test, p < 0.05, n=8. ###: compared to Gl, unpared T-test, p < 0.001. *: compared to G2, unpared T-test, p < 0.05. **: compared to G2, unpared T-test, p < 0.01. N=8. Figure 6 shows the effect of compounds A, B and C on Aβ1-42 in the frontal cortex as determined by immunofluoresce. Figure 7 shows the effect of compounds A, B and C on TNF-α levels in the brain. Figure 8 shows the effect of compounds A, B and C on TREM2 levels in the brain. Figure 9 shows the effect of compounds A, B and C on SYK levels in the brain as determined by western blot. Figure 10 shows the effect of compounds A, B and C on p-Zap-70 levels in the brain as determined by western blot. Figure 11 shows the effect of compounds A, B and C on DAP 12 levels in the brain as determined by western blot.

[0153] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein, the structure of Formula (I) is:wherein the partial structure represented by isthe symbol --- represents a point of attachment;X1is =N-, -NR8-, -O-, or -S-;X2is -N- or -CH-;X3is -O-, -S-, -NH-, -CH2-, or -C(O)-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, n7, n8, and nl2 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, m8, ml2, vl, v2, v5, v6, v7, v8, and vl2 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CXL13, -CHXL12, -CH2X1.1, -CN, -SOniR1A, -SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2 13, -CHX2 12, -CH2X2 1, -CN, -SOn2R2A, - SOV2NR2BR2C, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2 a3, - OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOn5R5A, - SOvsNR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5 a3, -OCHX5\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOneR6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6 a3, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7 1, -CN, -SOn?R7A, - SOV7NR7BR7C, -NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7.13, - OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is hydrogen, halogen, -CX8 13, -CHX8 12, -CH2X8 1, -CN, -SOn8R8A, - SOvsNR8BR8C, -NR8BR8C, -C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -OCX8A, - OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, - SOV12NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, - OCX12.13, -OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12A- substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A- substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12B- substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B- substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;Rlcis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12C- substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C- substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12D- substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D- substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;R2AR2BR2CR2DR5AR5BR5CR5DR6AR6BR6CR6DR7AR7BR7CR7DR8AR8BR8C, R8D, R12A, R12B, R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCl3, - CBr3, — CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; andX, X1 1, X2 1, X5 1, X6 1, X7 1, X8 1, and X12.1are independently -Cl, -Br, -I, or -F; and wherein, the structure of Formula (II) is:wherein:X1and X4are independently =N- or =CH-;X5is =N- or -CR5-;X6is =N- or -CR6-;Y is a bond, -O-, -S-, -NR7-, -OCX2-, -(CH2)z2W-, -C(O)O-, or -C(O)NH-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, and n7 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, vl, v2, v5, v6, and v7 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CXL13, -CHXL12, -CH2XL1, -CN, -SOniR1A, -SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1 a3, -OCHX1.12, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2 13, -CHX2 12, -CH2X2 1, -CN, -SOn2R2A, - SOV2NR2BR2C, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2 J3, - OCHX2 I2. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOn5R5A, - SOvsNR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, - N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5 a3, -OCHX5\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOneR6A, - SOV6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, - N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6 a3, -OCHX6\ substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7 13, -CHX7 12, -CH2X7 1, -CN, -SOn?R7A, - SOV7NR7BR7C, -NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7 A3, - OCHX7 I2. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, - SOvi2NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, - OCX12.13, -OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12A- substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A- substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A-substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12B- substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B- substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;Rlcis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12C- substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C- substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3,-COOH, -CONH2, R12D- substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D- substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D-substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;R2AR2BR2CR2DR5AR5BR5CR5DR6 AR6BR6CR6DR7AR7BR7CR7DR12AR12B, R12C, and R12Dare independently hydrogen, halogen, -CF3, -CC13, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X, X1 1, X2'1, X5'1, X6 1, X7'1, and X12'1are independently -Cl, -Br, -I, or -F.

2. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, has the structure:

3. The method of claim 1, wherein the compound of Formula (II), or a pharmaceutically acceptable salt thereof, has the structure:

4. The method of claim 1 or 2, wherein the compound of Formula (I-A), or a pharmaceutically acceptable salt thereof, has the structure:

5. The method of any one of claims 1, 2 or 4, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 1.

6. The method of claim 1 or 3, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 2.

7. The method of any one of claims 1, 2, 4 or 5, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 3.

8. The method of claim 1, wherein the neuroinflammatory disease is selected from Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), Vascular dementia (VAD), Anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), Transverse myelitis (TM), Autoimmune Encephalitis (AE), Acute disseminated encephalomyelitis (ADEM), Chronic meningitis (CM), Central nervous system (CNS) vasculitis, Hashimoto’s encephalitis (HE), Neurosarcoidosis (NS), Multiple system atrophy (MSA), Migraine, Chemotherapy-induced pain or Dementia-related pain.

9. The method of claim 1, wherein the neuroinflammatory disease is Alzheimer's disease.

10. The method of claim 1, wherein the neuroinflammatory disease is Parkinson's disease.

11. The method of claim 1, wherein the neuroinflammatory disease is amyotrophic lateral sclerosis (ALS).

12. The method of claim 1, wherein the neuroinflammatory disease is multiple sclerosis (MS).

13. The method of claim 1, wherein the neuroinflammatory disease is traumatic brain injury (TBI).

14. The method of claim 1, wherein the neuroinflammatory disease is complex regional pain syndrome (CRPS).

15. The method of claim 1, wherein the neuroinflammatory disease is optic neuritis.

16. The method of claim 1, wherein the neuroinflammatory disease is neuromye litis optica.

17. The method of claim 1, wherein the neuroinflammatory disease is chronic traumatic encephalopathy (CTE).

18. The method of claim 1, wherein the neuroinflammatory disease is ischemic stroke.

19. The method of claim 1, wherein the neuroinflammatory disease is Vascular dementia (VAD).

20. The method of claim 1, wherein the neuroinflammatory disease is Anti -myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

21. The method of claim 1, wherein the neuroinflammatory disease is Transverse myelitis (TM).

22. The method of claim 1, wherein the neuroinflammatory disease is Autoimmune Encephalitis (AE).

23. The method of claim 1, wherein the neuroinflammatory disease is Acute disseminated encephalomyelitis (ADEM).

24. The method of claim 1, wherein the neuroinflammatory disease is Chronic meningitis (CM).

25. The method of claim 1, wherein the neuroinflammatory disease is Central nervous system (CNS) vasculitis.

26. The method of claim 1, wherein the neuroinflammatory disease is Hashimoto’s encephalitis (HE).

27. The method of claim 1, wherein the neuroinflammatory disease is Neurosarcoidosis (NS).

28. The method of claim 1, wherein the neuroinflammatory disease is Multiple system atrophy (MSA).

29. The method of claim 1, wherein the neuroinflammatory disease is Migraine.

30. The method of claim 1, wherein the neuroinflammatory disease is Chemotherapy-induced pain.

31. The method of claim 1, wherein the neuroinflammatory disease is Dementia-related pain.

32. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 3.

33. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of (Z)-6-((2- (aminomethyl)-3-fluoroallyl)oxy)-N-((2-methoxypyridin-4-yl)methyl)benzo[d]oxazol-2 -amine.

34. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of (Z)-6-((2- (aminomethyl)-3-fluoroallyl)oxy)-N-((6-methoxypyridin-3-yl)methyl)benzo[d]oxazol-2 -amine.

35. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of (Z)-3-fluoro-2- (((2 -morpholinobenzo [d]oxazol-6-yl)oxy)methyl)prop-2-en- 1 -amine.

36. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 1.

37. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound provided in Table 2.

38. The method of any one of claims 8-31, wherein the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, having a structure of a compound selected from:and or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

39. The method of any one of claims 1, or 8-31, wherein the compound of Formula (I) has the structure of Formula (III -A):or an alkene isomer, tautomer, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:X1is -NR8-, -O-, or -S-;Y is -O-;W is a bond, -O-, -S-, or -NH-; zl and z2 are independently an integer from 0 to 3; nl, n2, n5, n6, n7, n8, and nl2 are independently an integer from 0 to 4; ml, m2, m5, m6, m7, m8, ml2, vl, v2, v5, v6, v7, v8, and vl2 are independently 1 or 2;L1is a bond, -O-, -S-, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;R1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is independently hydrogen, halogen, -CXL13, -CHXL12, -CH2X1 1, -CN, -SOniR1A, - SOviNR1BRlc, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, - N(O)mi, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BRlc, -OR1A, -NR1BSO2R1A, - NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1 J3, -OCHX1.12, R12-substituted orunsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl, or at least one amino acid;R2is hydrogen, halogen, -CX2 13, -CHX2 12, -CH2X2 1, -CN, -SOn2R2A, -SOv2NR2BR2C, - NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3and R4are independently hydrogen or -F;R5is hydrogen, halogen, -CX5 13, -CHX5 12, -CH2X5 1, -CN, -N3, -SOn5R5A, -SOvsNR5BR5C, - NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, - NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5 13, -OCHX5 12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6is hydrogen, halogen, -CX6 13, -CHX6 12, -CH2X6 1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, - NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, - NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6 13, -OCHX6 12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is hydrogen, halogen, -CX7 13, -CHX7 12, -CH2X7 1, -CN, -SOn7R7A, -SOv7NR7BR7C, - NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -OCX7 a3, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R8is hydrogen, halogen, -CX8 13, -CHX8 12, -CH2X8 1, -CN, -SOn8R8A, -SOv8NR8BR8C, - NR8BR8C, -C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -OCX8 a3, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R12is hydrogen, halogen, -CX12.13, -CHX12.12, -CH2X12.1, -CN, -SOni2R12A, -SOvi2NR12BR12C, -NR12BR12C, -C(O)R12D, -C(O)OR12D, -C(O)NR12BR12C, -OR12A, -OCX12 J3, -OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R1Ais hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3, -COOH, -CONH2, R12A-substituted or unsubstituted alkyl, R12A-substituted or unsubstituted heteroalkyl, R12A-substituted or unsubstituted cycloalkyl, R12A-substituted or unsubstituted heterocycloalkyl, R12A- substituted or unsubstituted aryl, or R12A-substituted or unsubstituted heteroaryl;R1Bis hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3, -COOH, -CONH2, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B- substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl;R1Cis hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3, -COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C- substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R1Dis hydrogen, halogen, -CF3, -CCI3, -CBr3. -Cl3, -COOH, -CONH2, R12C-substituted or unsubstituted alkyl, R12D-substituted or unsubstituted heteroalkyl, R12D-substituted or unsubstituted cycloalkyl, R12D-substituted or unsubstituted heterocycloalkyl, R12D- substituted or unsubstituted aryl, or R12D-substituted or unsubstituted heteroaryl;R2AR2BR2CR2DR5AR5BR5CR5DR6 AR6BR6CR6DR7AR7BR7CR7DR8AR8BR8CR8D, R12AR12B, R12C, and R12Dare independently hydrogen, halogen, -CF3, -CCI3, -CBr3.-Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2Band R2C; R5Band R5C; R6Band R6C; R7Band R7C; R8Band R8C; or R12Band R12Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X, X1 1, X2 1, X5 1, X6 1, X7 1, X8 1, and X12.1are independently -Cl, -Br, -I, or -F.

40. The compound of claim 39, wherein the compound has structural Formula (III-B):or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein X1is -NR8-, -O-, or -S-.

41. The compound of claim 39, wherein the compound has structural Formula (III-C):or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein X1is -NR8-, -O-, or -S-.

42. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X1is -O-.

43. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein z 1 is 1.

44. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R5and R6are independently hydrogen, -F, -Br, or -CH3.

45. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising a mixture of compounds having:R3is -F and R4is hydrogen; andR3is hydrogen and R4is -F.

46. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising a mixture of (E)- and (Z)-alkene isomers.

47. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R2is hydrogen.

48. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L1is a bond, -NR1L-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene .

49. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1is -NR1BR1C, - C(O)NR1BRlc, -OR1A, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl.

50. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1is R12-substituted or unsubstituted C1-C6alkyl.

51. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1is -(CH2)3CH3, - C(CH3)3,52. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1is -NR1BR1C.

53. The compound of claim 39, or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:R1Bis hydrogen, R12B-substituted or unsubstituted alkyl, R12B-substituted or unsubstituted heteroalkyl, R12B-substituted or unsubstituted cycloalkyl, R12B-substituted or unsubstituted heterocycloalkyl, R12B-substituted or unsubstituted aryl, or R12B-substituted or unsubstituted heteroaryl; andR1Cis hydrogen, R12C-substituted or unsubstituted alkyl, R12C-substituted or unsubstituted heteroalkyl, R12C-substituted or unsubstituted cycloalkyl, R12C-substituted or unsubstituted heterocycloalkyl, R12C-substituted or unsubstituted aryl, or R12C-substituted or unsubstituted heteroaryl; or R1Band R1Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

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