WO2024211432A1

WO2024211432A1 - N-(trans-4-hydroxycyclohexyl)-6-phenylhexanamide derivatives and related uses

Info

Publication number: WO2024211432A1
Application number: PCT/US2024/022862
Authority: WO
Inventors: Joseph P. Vacca
Original assignee: Mitochondria In Motion Inc
Current assignee: Mitochondria In Motion Inc
Priority date: 2023-04-03
Filing date: 2024-04-03
Publication date: 2024-10-10
Anticipated expiration: 2025-10-03

Abstract

Compounds having Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof may promote mitofusin activation and be useful, for example, in treating or preventing diseases, disorders, or conditions (e.g., associated with mitochondria). In example compounds, p is 0, Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, each R^b independently is H or C₁-C₆ alkyl, q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, and Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl.

Description

N-(TRANS-4-HYDROXYCYCLOHEXYL)-6-PHENYLHEXANAMIDE DERIVATIVES AND RELATED USES BACKGROUND [0001] Mitochondrial dysfunction may contribute to various types of neurodegenerative diseases. Defective mitochondrial fusion or fission may be especially problematic in this regard, especially when imbalanced fusion and fission lead to mitochondrial fragmentation. Among the many neurodegenerative diseases in which mitochondrial dysfunction has been implicated include, for example, Charcot-Marie- Tooth disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. [0002] Mitochondrial fusion is initiated by outer mitochondrial membrane-embedded mitofusin (MFN) proteins whose extra-organelle domains extend across cytosolic space to interact with counterparts on neighboring mitochondria. The physically linked organelles create oligomers of varying sizes. Mitofusins subsequently induce outer mitochondrial membrane fusion mediated by catalytic GTPase. Aberrant mitofusin activity is believed to be a primary contributor to mitochondrial-based neurodegenerative diseases. For these reasons, mitofusins are attractive targets for drug discovery. SUMMARY [0003] In some aspects, the present disclosure features compounds having a structure represented by Formula (I)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be joined to Z to form a heterocyclic ring; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. [0004] In some or other aspects, the present disclosure features compounds having a structure represented by Formula (I’)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be joined to Z to form a heterocyclic ring; Q is -(C=O)_m(CR^c ₂)_n-, wherein Q is bound to N via the (C=O), if the (C=O) is present; each R^c independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁵, NHR⁵, or N(R⁵)₂, wherein R⁵ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^c may be optionally joined to form a carbocyclic or heterocyclic ring; m is 0 or 1; n is 0, 1, or 2; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. [0005] In some aspects, the present disclosure features pharmaceutical compositions comprising any compound described herein or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient. [0006] In some aspects, the present disclosure features methods of treating diseases, disorders, or conditions, comprising administering any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof or a pharmaceutical composition described herein to a subject in need thereof. [0007] In some aspects, the present disclosure features any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof in a pharmaceutical composition for use for treating diseases, disorders, or conditions. The pharmaceutical compositions may be administered to a subject in need thereof. [0008] In some aspects, the present disclosure features use of any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof in a pharmaceutical composition in the manufacture of a medicament for treating diseases, disorders, or conditions. [0009] In some aspects, the present disclosure features any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof in a pharmaceutical composition for use in activating mitofusin in a subject. [0010] In some aspects, the present disclosure features methods for activating mitofusin in a subject, comprising administering any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof or a pharmaceutical composition described herein to a subject in need thereof. [0011] In some aspects, the present disclosure features use of any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof in a pharmaceutical composition in the manufacture of a medicament for activating mitofusin in a subject. [0012] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [0013] Without wishing to be bound by theory, it is understood that the compounds described herein may be effective in activating mitofusin. Thus, the compounds may be useful for treating various diseases and disorders, including mitochondria-associated diseases, disorders, or conditions. Compounds of the Present Disclosure [0014] Any structural feature described herein (e.g., for any exemplary formula described herein) can be used in combination with any other structural feature(s) described for any exemplary formula described herein. [0015] In various aspects, compounds of the present disclosure have a structure represented by Formula (I) or Formula (I’), as described in further detail below. The structures defined by Formulas (I) and (I’) are characterized by an amine moiety in a linker group between an amide carbonyl and an aryl group. Compared to similar compounds lacking the amine moiety, the compounds of the present disclosure may exhibit higher aqueous solubility, lower protein binding, increased in vivo stability to hepatocytes, and greater oral bioavailability. [0016] In some aspects, the present disclosure features compounds having a structure represented by Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be joined to Z to form a heterocyclic ring; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. [0017] In some aspects, the compounds may have a structure represented by Formula (Ia):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein the variables are defined as above for Formula (I). [0018] In some aspects, the compounds may have an additional spacer group Q interceding between NR^N and Z and have a structure represented by Formula (I’):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be joined to Z to form a heterocyclic ring; Q is -(C=O)(CR^c ₂)_n-, wherein Q is bound to N via the (C=O), if the (C=O) is present; each R^c independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁵, NHR⁵, or N(R⁵)₂, wherein R⁵ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^c may be optionally joined to form a carbocyclic or heterocyclic ring; m is 0 or 1; n is 0, 1 or 2; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. [0019] In some aspects, the compounds may have a structure represented by Formula (I’a):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein the variables are defined as above for Formula (I’). Variables Y and R^Y [0020] In some embodiments, Y is C₁-C₆ alkylene optionally substituted with one or more R^Y. Y may be methylene, ethylene, propylene, butylene, pentylene, or hexylene. [0021] In some embodiments, Y is C₃-C₈ cycloalkylene optionally substituted with one or more R^Y. Y may be cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, or cvclooctylene. In some embodiments, Y may be 1,2-cyclopropylene. [0022] When present, each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R² may be optionally joined to form a carbocyclic or heterocyclic ring. [0023] In some embodiments and when present, at least one R^Y is halogen (e.g., F, C1, Br, or I). [0024] In some embodiments and when present, at least one R^Y is cyano. [0025] In some embodiments and when present, at least one R^Y is OH. [0026] In some embodiments and when present, at least one R^Y is NH₂. [0027] In some embodiments and when present, at least one R^Y is C₁-C₆ alkyl, which may be straight-chain or branched, or two R^Y may be joined to form a carbocyclic ring. The C₁-C₆ alkyl may be further optionally substituted, such as with one or more halogen, cyano, OH, or NH₂. [0028] In some embodiments and when present, at least one R^Y is OR², wherein R² is C₁-C₆ alkyl which may be straight-chain or branched. The C₁-C₆ alkyl may be further optionally substituted, such as with one or more halogen, cyano, OH, or NH₂. [0029] In some embodiments and when present, R^Y is NHR², wherein R² is C₁-C₆ alkyl which may be straight- chain or branched. The C₁-C₆ alkyl may be further optionally substituted, such as with one or more halogen, cyano, OH, or NH₂. [0030] In some embodiments and when present, R^Y is N(R²)₂, wherein R² is C₁-C₆ alkyl which may be straight- chain or branched. The C₁-C₆ alkyl may be further optionally substituted, such as with one or more halogen, cyano, OH, or NH₂. Variables R^a, p, R^b. and q [0031] In some embodiments, each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. Two R^a may be optionally joined to form a carbocyclic or heterocyclic ring. [0032] In some embodiments, each R^a is H. [0033] In some embodiments, at least one R^a is halogen (e.g., F, Cl, Br, or I). [0034] In some embodiments, at least one R^a is cyano. [0035] In some embodiments, at least one R^a is OH. [0036] In some embodiments, at least one R^a is NH₂. [0037] In some embodiments, at least one R^a is C₁-C₆ alkyl, which may be straight-chain or branched. [0038] In some embodiments, at least one R^a is OR¹, wherein R¹ is C₁-C₆ alkyl, which may be straight- chain or branched. [0039] In some embodiments, at least one R^a is NHR¹, wherein R¹ is C₁-C₆ alkyl, which may be straight- chain or branched. [0040] In some embodiments, at least one R^a is N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, which may be straight-chain or branched. [0041] In some embodiments, p is 0, 1, 2, or 3. In specific examples herein, p is 0. [0042] In some embodiments, each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. Two R^b may be optionally joined to form a carbocyclic or heterocyclic ring. [0043] In some embodiments, each R^b is H. [0044] In some embodiments, at least one R^b is halogen (e.g., F, Cl, Br, or I). [0045] In some embodiments, at least one R^b is cyano. [0046] In some embodiments, at least one R^b is OH. [0047] In some embodiments, at least one R^b is NH₂. [0048] In some embodiments, at least one R^b is C₁-C₆ alkyl, which may be straight-chain or branched. [0049] In some embodiments, at least one R^b is OR³, wherein R³ is C₁-C₆ alkyl, which may be straight- chain or branched. [0050] In some embodiments, at least one R^b is NHR³, wherein R³ is C₁-C₆ alkyl, which may be straight- chain or branched. [0051] In some embodiments, at least one R^b is N(R³)₂, wherein R³ is C₁-C₆ alkyl, which may be straight-chain or branched. [0052] In some embodiments, q is 0, 1, 2, or 3. [0053] R^a and R^b may be the same or different and selected independently of one another. Variables p and q may be the same or different and selected independently of one another. Variable R^N [0054] R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. The C₁-C₆ alkyl may be straight-chain or branched. Optionally, R^N may be joined to Z to form a heterocyclic ring. [0055] In some embodiments, R^N is H. [0056] In some embodiments, R^N is methyl. [0057] In some embodiments, R^N is joined to Z to form a heterocyclic ring. Variables R^c, m and n [0058] Each R^c independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁵, NHR⁵, or N(R⁵)₂, wherein R⁵ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. Two R^c may be optionally joined to form a carbocyclic or heterocyclic ring. [0059] In some embodiments, each R^c is H. [0060] In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In some embodiments, m is 0 and n is 3. [0061] In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m is 1 and n is 2. Variables Z and R^Z [0062] In some embodiments, Z is C₆-C₁₀ aryl (e.g., phenyl, naphthyl, or tetrahydronaphthalenyl), which may be optionally substituted with one or more R^Z. Each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. The C₁-C₆ alkyl may be straight-chain or branched. [0063] In some embodiments, Z is phenyl, which may be optionally substituted with one or more R^Z. When present, there may be up to 5 occurrences of R^Z upon the phenyl. [0064] In some embodiments, Z is 1-naphthyl or 2-naphthyl, which may be optionally substituted with one or more R^Z. When present, there may be up to 7 occurrences of R^Z upon the 1-naphthyl or 2-naphthyl. [0065] In some embodiments, Z is 1-tetrahydronapthalenyl or 2-tetrahydronaphthalenyl, which may be optionally substituted with one or more R^Z. When present, there may be up to 3 occurrences of R^Z on the aromatic ring of the 1-tetrahydronapthalenyl or 2-tetrahydronaphthalenyl and/or up to 8 occurrences of R^Z on the non-aromatic ring of the 1-tetrahydronapthalenyl or 2-tetrahydronaphthalenyl. [0066] In some embodiments, Z is C₆-C₁₀ cycloalkyl, which may be optionally substituted with one or more R^Z. Each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. The C₁-C₆ alkyl may be straight-chain or branched. Optionally, two R^Z may be joined to form a carbocyclic ring or a heterocyclic ring. [0067] In some embodiments, Z is cyclohexyl, which may be optionally substituted with one or more R^Z. [0068] In some embodiments, Z is cyclooctyl, which may be optionally substituted with one or more R^Z. [0069] In some embodiments, Z is tetrahydronaphthalenyl, which may be optionally substituted with one or more R^Z. The tetrahydronaphthalenyl may have a structure represented by

[0070] In some embodiments, Z is 5- to 10-membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, or a fused variant thereof, such as benzimidazoyl or benzofuranyl). The 5- to 10-membered heteroaryl may be optionally substituted by one or more R^Z. Each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂. The C₁-C₆ alkyl may be straight-chain or branched. Optionally, two R^Z may be joined to form a carbocyclic ring or a heterocyclic ring. [0071] In some embodiments, Z is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, which may be optionally substituted by one or more R^Z. When present, there may be up to 4 occurrences of R^Z upon the 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl. [0072] In some embodiments, Z is pyrimidinyl, which may be optionally substituted by one or more R^Z. When present, there may be up to 3 occurrences of R^Z upon the pyrimidinyl. [0073] In some embodiments, at least one R^Z is present upon the 5- to 10-membered heteroaryl. [0074] In some embodiments, at least one R^Z independently is halogen (e.g., F, Cl, Br, or I). In some embodiments, at least one R^z is Cl. [0075] In some embodiments, at least one R^Z is cyano. [0076] In some embodiments, at least one R^Z is OH. [0077] In some embodiments, at least one R^Z is NH₂. [0078] In some embodiments, at least one R^Z is C₁-C₆ alkyl, which may be straight-chain or branched. In some embodiments, at least one R^Z is methyl or ethyl. [0079] In some embodiments, at least one R^Z is OR⁴. In some embodiments, at least one R^Z is OCH₃. [0080] In some embodiments, at least one R^Z is NHR⁴ or N(R⁴)₂. In some embodiments, at least one R^Z is NHCH₃, NHCH₂CH₃, N(CH₃)₂, or N(CH₂CH₃)₂. [0081] In some embodiments, at least one R^Z is CF₃. [0082] In some embodiments, at least one R^Z is OCF₃. Illustrative Embodiments of the Compounds [0083] In some embodiments, p may be 0, in which case, the compounds may have a structure represented by Formula (II), Formula (IIa), Formula (II’), or Formula (II’a) or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, wherein the variables are otherwise defined as above.

[0084] In some embodiments, the compounds have a structure represented by Formula (II), Formula (IIa), Formula (II’), or Formula (II’a), q is 0, and Y is C₁-C₆ alkylene optionally substituted with one or more R^Y. Preferably, Y is butylene. When p is 0 and q is 0, the compounds may have a structure represented by Formula (III), Formula (IIIa), Formula (III’) or Formula (III’a) or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

[0085] In specific examples, the compounds may have a structure represented by Formula (IV), Formula (IVa), Formula (IV’), or Formula (IV’a) or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

[0086] In some embodiments, the compounds have a structure represented by Formula (II), Formula (IIa), Formula (II’) or Formula (II’a), q is 2 or 3, and Y is C₃-C₈ cycloalkylene optionally substituted with one or more R^Y. Preferably, Y is cyclopropylene, and more preferably Y is 1,2-cyclopropylene. When p is 0, q is 2, and Y is 1,2-cyclopropylene, the compounds may have a structure represented by Formula (V), Formula (Va), Formula (V’) or Formula (V’a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. When p is 0, q is 3, and Y is 1,2-cyclopropylene, the compounds may have a structure represented by Formula (VI), Formula (VIa), Formula (VI’), or Formula (VI’a) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

In still more specific examples, the compounds may have a structure represented by Formula (VII), Formula (Vila), Formula (Vllb), or Formula (Vile) or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0087] In some embodiments, the compound may have a structure represented by Formulas 1-67 or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.



[0088] In some embodiments, the compound may have a structure represented by Formulas 68-82 or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

[0089] Advantageously, the trans-stereochemistry of the 4-hydroxycyclohexyl group and the stereochemistry of the cyclopropane ring may be established before assembling the compounds together. As such, the compounds may exhibit high stereoisomeric purity. In some embodiments, the compounds may have greater than a 1:1 molar ratio of the (R,R) configuration relative to the (S,S) configuration of the cyclopropane ring, or vice versa. In some embodiments, the compound is of about 60% or greater (R,R) configuration, or about 70% or greater (R,R) configuration, or about 80% or greater (R,R) configuration, or about 90% or greater (R,R) configuration, or about 95% or greater (R,R) configuration, or about 97% or greater (R,R) configuration, or about 99% or greater (R,R) configuration, or about 99.9% or greater (R,R) configuration. In some embodiments, the compound has an enantiomerically pure (R,R) configuration of the cyclopropane ring. [0090] In some embodiments, the compound may be of about 10% enantiomeric excess ("ee") or greater, or about 20% ee or greater, or about 30% ee or greater, or about 40% ee or greater, or about 50% ee or greater, or about 60% ee or greater, or about 70% ee or greater, or about 80% ee or greater, or about 90% ee or greater or about 95% ee or greater, or about 96% ee or greater, or about 97% ee or greater, or about 98% ee or greater, or about 99% ee or greater, or about 99.5% ee or greater, or about 99.9% ee or greater. [0091] In some aspects, the compounds may be an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds disclosed herein. It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the isotopic derivative is a deuterium labeled compound. The deuterium labeled compound may comprise an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%. [0092] A compound of the present disclosure or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof that contains one or more deuterium atoms is within the scope of the disclosure. Further, substitution with deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0093] A deuterium-labeled compound may have a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), or at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), or at least 5000 (75% deuterium incorporation), or at least 5500 (82.5% deuterium incorporation), or at least 6000 (90% deuterium incorporation), or at least 6333.3 (95% deuterium incorporation), or at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" means the ratio between the deuterium abundance and the natural abundance of a deuterium. [0094] A deuterium-labeled compound may be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent. [0095] It is to be understood that the compounds of the present disclosure may include pharmaceutically acceptable salts, solvates, hydrates, and/or tautomers of the compounds. As used herein, the term "pharmaceutically acceptable salt" refers to organic or inorganic salts of a compound of the present disclosure that have specified toxicity and/or biodistribution properties. Suitable salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and/or pamoate (i.e., 1,1`-methylene-bis-(2-hydroxy-3- naphthoate)) salts. The pharmaceutically acceptable salt may balance charge on the parent compound by being present as a counterion. More than one counterion may be present. When multiple counterions are present, the compounds may be present as a mixed pharmaceutically acceptable salt. [0096] A pharmaceutically acceptable salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound disclosed herein. Suitable anions may include, but are not limited to, chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, formate, and acetate. As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. [0097] Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. Suitable salts include those salts containing quaternary nitrogen atoms. As used herein, the term "pharmaceutically acceptable cation" refers to a cation suitable for forming a pharmaceutically acceptable salt. [0098] Suitable pharmaceutically acceptable salts may be, for example, an acid-addition salt of a compound of the present disclosure which is sufficiently basic. The acid-addition salt may be prepared with, for example, an inorganic or organic acid. Suitable acids may include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, methanesulfonic acid, maleic acid, or the like. In addition, a suitable pharmaceutically acceptable salt of a compound of the present disclosure may be an alkali metal salt (e.g., a sodium or potassium salt), an alkaline earth metal salt (e.g., a calcium or magnesium salt), an ammonium salt or a salt of an organic base which affords a pharmaceutically acceptable cation (e.g., a methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. [0099] It is to be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof may comprise stereoisomers, mixtures of stereoisomers, and/or polymorphs of all isomeric forms of said compounds. Any of the foregoing reside within the scope of the present disclosure. [0100] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non- superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture." [0101] As used herein, the term "chiral center" refers to a carbon atom that is a center of asymmetry and may be a carbon atom bonded to four nonidentical substituents. [0102] As used herein, the term "chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. A chiral molecule may also be characterized by the manner in which the molecule rotates the plane of polarized light and may be designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). The substituents attached to the chiral center under consideration are ranked in accordance with rules that will be familiar to one having ordinary skill in the art. [0103] As used herein, the term "geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., cyclopropyl or 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or E and Z, which indicate that the groups are on the same or opposite side of the double bond in accordance with rules that will be familiar to one having ordinary skill in the art. [0104] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [0105] It is to be understood that the compounds of the present disclosure or a pharmaceutically acceptable salt or tautomer thereof may exist in either a hydrated or non-hydrated (i.e., anhydrous) form or as a solvate with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, and higher hydrates. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, and the like. [0106] As used herein, the term "solvate" means solvent addition forms of the compounds or a pharmaceutically acceptable salt thereof that contain either stoichiometric or non-stoichiometric amounts of a solvent. A hydrate is a specific type of solvate in which the solvent is water. An alcoholate is a specific type of solvate in which the solvent is an alcohol. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O. [0107] As used herein, the term “pharmaceutically acceptable solvate" refers to an association between one or more solvent molecules and a compound of the present disclosure or a salt thereof_; wherein the solvate has specified toxicity and/or biodistribution properties. Examples of solvents that may form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and/or ethanolamine. As used herein, the term "pharmaceutically acceptable hydrate" refers to a compound of the present disclosure or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, wherein the hydrate has specified toxicity and/or biodistribution properties. [0108] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric equilibrium set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0109] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. Synthesis of the Compounds [0110] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0111] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0112] It will be understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. In view of the need for compatibility during synthesis, it will be appreciated that during the synthesis of the compounds of the disclosure, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0113] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art. Illustrative technique may include, but are not limited to, chromatography, recrystallization, sublimation, solvent washing, the like, and any combination thereof. Pharmaceutical Compositions [0114] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or any pharmaceutically acceptable form thereof. Pharmaceutically acceptable forms of a compound may include any pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. [0115] In some embodiments, suitable pharmaceutical composition may comprise any compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient. [0116] For the purposes of the present disclosure, the term "excipient" and "carrier" are used interchangeably herein and refer to ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition. Excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present disclosure have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability. [0117] Accordingly, in some embodiments, provided herein are pharmaceutical compositions comprising a compound of the present disclosure or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, isomer, prodrug, and/or isotopically labeled derivatives), and one or more pharmaceutically acceptable excipients. Excipients may include inert solid diluents and fillers, liquid diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In some embodiments, a pharmaceutical composition described herein may include a second active agent such as an additional therapeutic agent, (e.g., a chemotherapeutic agent). [0118] Compositions of the present disclosure may be stable to specified storage conditions. A "stable" composition refers to a composition having sufficient stability to allow storage at a convenient temperature, such as from about 0°C to about 60°C or about -20°C to about 50°C, for a commercially reasonable period of time, such as at least about one day, at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about two years. [0119] Controlled-release (or sustained-release) compositions may be formulated to extend the activity of the compounds and reduce dosing frequency. Controlled-release compositions may also be used to affect the time of onset of action or other characteristics, such as plasma levels of the compound, and consequently affect the occurrence of side effects. Controlled-release compositions may be designed to initially release an amount of one or more compounds that produces the desired therapeutic effect, and gradually and continually release other amounts of the compound to maintain the level of therapeutic effect over an extended period. In order to maintain a near-constant level of compound in the body, the compound may be released at a rate sufficient to replace the amount being metabolized or excreted from a subject. The controlled-release may be stimulated by various inducers (e.g., change in pH, change in temperature, enzymes, water, or other physiological conditions or molecules). [0120] More specific examples of suitable excipients are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington' s Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable excipients are those that are compatible with the other ingredients and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions. [0121] The chosen route of administration may determine the types of excipients that are chosen for formulating a pharmaceutical composition. Compounds of the present disclosure can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. Pharmaceutical compositions in the form of oral formulation containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99 % of the compound and/or up to 99% carrier. [0122] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like. [0123] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, and the like. [0124] Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. [0125] Oral formulations described herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). An oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed. [0126] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for oral or inhaled delivery. A compound of the present or a pharmaceutically acceptable form thereof can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or one or more pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers may include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized pharmaceutical compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. [0127] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form. [0128] In some embodiments, a pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, pocketed powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 50 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. [0129] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present disclosure can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically is subjectively determined by a physician. The variables involved include the specific condition and its state as well as the size, age, and response pattern of the patient. The compounds of the present disclosure may also be given to a patient at risk of developing a disease or condition, but who has not yet developed the disease or condition and/or is not exhibiting symptoms of the disease or condition, in which case the compound may prevent or inhibit development of the disease or condition and/or exhibiting symptoms of the disease or condition. [0130] In some cases, it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose thy- powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present disclosure can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present disclosure dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present disclosure intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present disclosure, propellants, surfactants, and co- solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable. [0131] Compounds of the present disclosure can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or pharmaceutically acceptable salts, hydrates, solvate, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms. [0132] Pharmaceutical compositions suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the compositions can be sterile and have a viscosity permitting flow through a syringe. The compositions preferably are stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. [0133] Compounds of the present disclosure can be administered transdermally, i .e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0134] Transdermal administration of the compounds disclosed herein can be accomplished through the use of a transdermal patch containing the compound and a carrier that is inert to the compound, is non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known to those having ordinary skill in the art.

[0135] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0136] Lipid formulations or nanocapsules can be used to introduce compounds of the present disclosure into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0137] To increase the effectiveness of compounds of the present disclosure, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present disclosure. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

Kits

[0138] In some embodiments, kits containing the compounds are provided herein. The kits can include a compound or pharmaceutically acceptable form thereof, or pharmaceutical composition as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Kits are well suited for the delivery of solid oral dosage forms such as tablets or capsules. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the pharmaceutical composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.

Methods of Use

[0139] Compounds and pharmaceutical compositions of the present disclosure can be useful for the treatment or prevention of a disease, disorder, or condition in a subject, for example, a human subject. The present disclosure accordingly provide methods of treating or preventing a disease, disorder, or condition in a subject by providing to a subject a compound of the present disclosure or a pharmaceutical composition thereof, as described above. Compounds of the present disclosure or a pharmaceutical composition thereof can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or prevention of a disease, disorder, or condition.

[0140] In some aspects, the present disclosure features methods for treating diseases, disorders, or conditions, comprising administering to a subject in need thereof any compound described herein in a pharmaceutical composition.

[0141] In some aspects, the present disclosure features any compound described herein in a pharmaceutical composition for use for treating diseases, disorders, or conditions.

[0142] In some aspects, the present disclosure features use of any compound described herein in a pharmaceutical composition in the manufacture of a medicament for treating diseases, disorders, or conditions.

[0143] In some aspects, the present disclosure features methods for activating mitofusin in a subject, comprising administering a compound of the present disclosure or a pharmaceutical composition thereof to a subject.

[0144] In some aspects, the present disclosure features any compound described herein in a pharmaceutical composition for use in activating mitofusin in a subject. [0145] In some aspects, the present disclosure features use of any compound described herein in a pharmaceutical composition in the manufacture of a medicament for activating mitofusin in a subject. [0146] In some embodiments, a compound described herein, or any pharmaceutically acceptable form thereof such as a pharmaceutically acceptable salt thereof, can be used to treat or prevent a disease, disorder, or condition in a subject. In some examples, the disease, disorder, or condition may be associated with mitochrondria. Upon administration of the compound or a pharmaceutically acceptable form thereof, mitochondria may be activated to address the disease, disorder, or condition. [0147] In some embodiments, a therapeutically effective amount of the compound or the pharmaceutical composition described herein is administered to the subject. The therapeutically effective amount may be sufficient for activating mitochondria in the subject. [0148] In some embodiments, the disease, disorder, or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, or chemical injury. [0149] In some embodiments, the PNS or CNS disorder is a chronic neurodegenerative condition in which mitochondrial fusion, fitness, and/or trafficking is/are impaired; a disease or disorder associated with mitofusin I (MFNI) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and/or dysmotility; a degenerative neuromuscular condition; Charcot- Marie-Tooth disease; Amyotrophic Lateral Sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathy; autism; autosomal dominant optic atrophy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetes mellitus and deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh syndrome; subacute sclerosing encephalopathy; neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); myoneurogenic gastrointestinal encephalopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS); mtDNA depletion; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); dysautonomic mitochondrial myopathy; mitochondrial channelopathy; pyruvate dehydrogenase complex deficiency (PDCD/PDH); diabetic neuropathy; chemotherapy-induced peripheral neuropathy; crush injury; spinal cord injury (SCI); traumatic brain injury; stroke; optic nerve injury; conditions that involve axonal disconnection; and any combination thereof. [0150] In some embodiments, the subject is human. [0151] In some embodiments, a compound described herein, or any pharmaceutically acceptable form thereof such as a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, can be used to active mitofusin in a subject (e.g., a human). [0152] Compounds or compositions described herein may also be used in combination with other therapeutic modalities, as described further below. Thus, in addition to the therapies described herein, one may also provide to the subject other therapies known to be efficacious for treatment of a disease, disorder, or condition being targeted by activation of mitosfusin or a related disease, disorder, or condition. [0153] Compounds of the present disclosure may stimulate mitochondrial fusion, increase mitochondrial fitness, and enhance mitochondrial subcellular transport. Accordingly, in another aspect of the present disclosure, any one or a combination of compounds of the present disclosure or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof may be administered in a therapeutically effective amount to a subject having or suspected of having a mitochondria-associated disease, disorder or condition. The subject may be a human or other mammal having or suspected of having a mitochondria- associated disease, disorder or condition. [0154] The mitochondria-associated disease, disorder or condition may be a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, and/or chemical injury. In some aspects, in the method of treating a disease, disorder or condition for which a mitofusin activator is indicated, the PNS or CNS disorder may be selected from any one or a combination of: a chronic neurodegenerative condition wherein mitochondrial fusion, fitness, or trafficking are impaired; a disease or disorder associated with mitofusin-1 (MFN1) or mitofusin-2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, or dysmotility; a degenerative neuromuscular condition such as Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, hereditary motor and sensory neuropathy, autism, autosomal dominant optic atrophy (ADOA), muscular dystrophy, Lou Gehrig's disease, cancer, mitochondrial myopathy, diabetes mellitus and deafness (DAD), Leber's hereditary optic neuropathy (LHON). Leigh syndrome, subacute sclerosing encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), mtDN A depletion, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), dysautonomic mitochondrial myopathy, mitochondrial channelopathy, or pyruvate dehydrogenase complex deficiency (PDCD/PDH), diabetic neuropathy, chemotherapy-induced peripheral neuropathy, crush injury, SC1, traumatic brain injury (TBI), stroke, optic nerve injury, and/or related conditions that involve axonal disconnection. [0155] Other mitochondria-associated diseases, disorders, or conditions that may be treated with the compounds and compositions disclosed herein, but are not limited to, Alzheimer's disease, ALS, Alexander disease, Alpers' disease, Alpers-Huttenlocher syndrome, alpha-methylacyl-CoA racemase deficiency, Andermann syndrome, Arts syndrome, ataxia neuropathy spectrum, ataxia (e.g., with oculomotor apraxia, autosomal dominant cerebellar ataxia, deafness, and narcolepsy), autosomal recessive spastic ataxia of Charlevoix-Saguenay, Batten disease, beta-propeller protein-associated neurodegeneration, cerebro-oculo-facio-skeletal syndrome (COFS), corticobasal degeneration, CLNI disease, CLN10 disease, CLN2 disease, CLN3 disease, CLN4 disease, CLN6 disease, CLN7 disease, CLN8 disease, cognitive dysfunction, congenital insensitivity to pain with anhidrosis, dementia, familial encephalopathy with neuroserpin inclusion bodies, familial British dementia, familial Danish dementia, fatty acid hydroxylase-associated neurodegeneration, Friedreich's Ataxia, Gerstmann-Straussler- Scheinker Disease, GM2-gangliosidosis (e.g., AB variant), HMSN type 7 (e.g., with retinitis pigmentosa), Huntington's disease, infantile neuroaxonal dystrophy, infantile-onset ascending hereditary spastic paralysis, infantile-onset spinocerebellar ataxia, juvenile primary lateral sclerosis, Kennedy's disease, Kuru, Leigh's Disease, Marinesco-SjOgren syndrome, mild cognitive impairment (MCI), mitochondrial membrane protein-associated neurodegeneration, motor neuron disease, monomelic amyotrophy, motor neuron diseases (MND), multiple system atrophy, multiple system atrophy with orthostatic hypotension (Shy-Drager Syndrome), multiple sclerosis, multiple system atrophy, neurodegeneration in down's syndrome (NDS), neurodegeneration of aging, neurodegeneration with brain iron accumulation, neuromyelitis optica, pantothenate kinase-associated neurodegeneration, opsoclonus myoclonus, prion disease, progressive multifocal leukoencephalopathy, Parkinson's disease, Parkinson's disease-related disorders, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, prion disease, progressive external ophthalmoplegia, riboflavin transporter deficiency neuronopathy, Sandhoff disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), striatonigral degeneration, transmissible spongiform encephalopathies (prion diseases), and/or Wallerian-like degeneration. [0156] Still other mitochondria-associated diseases, disorders, or conditions that may be treated with the compositions disclosed herein include abulia; agraphia; alcoholism; alexia; alien hand syndrome; Allen- Herndon-Dudley syndrome; alternating hemiplegia of childhood; Alzheimer's disease; amaurosis fugax; amnesia; ALS; aneurysm; angelman syndrome; anosognosia; aphasia; apraxia; arachnoiditis; Arnold- Chiari malformation; asomatognosia; Asperger syndrome; ataxia; attention deficit hyperactivity disorder; atr-16 syndrome; auditory processing disorder; autism spectrum; Behcets disease; bipolar disorder; Bell's palsy; brachial plexus injury; brain damage; brain injury; brain tumor; Brody myopathy; Canavan disease; capgras delusion; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; centronuclear myopathy; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); cerebral dysgenesis-neuropathy-ichthyosis-keratoderma syndrome (CEDNIK syndrome); cerebral gigantism; cerebral palsy; cerebral vasculitis; cervical spinal stenosis; Charcot-Marie-Tooth disease; chiari malformation; chorea; chronic fatigue syndrome; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; Cockayne syndrome; Coffin-Lowry syndrome; coma; complex regional pain syndrome; compression neuropathy; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cyclothymic disorder; cyclic vomiting syndrome (CVS); cytomegalic inclusion body disease (CH:3D); cytomegalovirus infection; Dandy-Walker syndrome; Dawson disease; de Morsier's syndrome; Dejerine- Klumpke palsy; Dejerine-Sottas disease; delayed sleep phase syndrome; dementia; dermatomyositis; developmental coordination disorder; diabetic neuropathy; diffuse sclerosis; diplopia; disorders of consciousness; down syndrome; Dravet syndrome; duchenne muscular dystrophy; dysarthria; dysautonomia; dyscalculia; dysgraphia; dyskinesia; dyslexia; dystonia; empty sella syndrome; encephalitis; encephalocele; encephalotrigeminal angiomatosis; encopresis; enuresis; epilepsy; epilepsy-intellectual disability in females; erb's palsy; erythromelalgia; essential tremor; exploding head syndrome; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fibromyalgia; Foville's syndrome; fetal alcohol syndrome; fragile x syndrome; fragile x-associated tremor/ataxia syndrome (FXTAS); Gaucher's disease; generalized epilepsy with febrile seizures plus; Cierstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; gray matter heterotopia; Guillain-Barre syndrome; generalized anxiety disorder; HTLV-1 associated myelopathy; Hallervorden-Spatz syndrome; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; Hirschsprung's disease; Holmes-Adie syndrome; holoprosencephaly; Huntington's disease; hydranencephaly ; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; isodicentric 15; Joubert syndrome; Karak syndrome; Keams-Sayre syndrome; Kinsboume syndrome; Kleine-Levin syndrome; Klippel-Feil syndrome; Krabbe disease; Kufor-Rakeb syndrome; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffrier syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; leukoencephalopathy with vanishing white matter; levy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (amyotrophic lateral sclerosis (ALS)); lumbar disc disease; lumbar spinal stenosis; lyme disease - neurological sequelae; Machado-Joseph disease (spinocerebellar ataxia type 3); macrencephaly; macropsia; mal de debarquement; megalencephalic leukoencephalopathy with subcortical cysts; megalencephaly; Melkersson—Rosenthal syndrome; menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; micropsia; migraine; Miller Fisher syndrome; mini-stroke (transient ischemic attack); misophonia; mitochondrial myopathy; moebius syndrome; monomelic amyotrophy; Morvan syndrome; motor neurone disease - see ALS; motor skills disorder; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis; multiple system atrophy; muscular dystrophy; myalgic encephalomyelitis; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotubular myopathy; myotonia congenita; narcolepsy; neuro-Behcet's disease; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of aids; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; neuropathy; neurosis; Niemann-Pick disease; non-24-hour sleep-wake disorder; nonverbal learning disorder; O'Sullivan- McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus syndrome; optic neuritis; orthostatic hypotension; otosclerosis; overuse syndrome; palinopsia; paresthesia; Parkinson's disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry-Romberg syndrome; pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS); Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; pervasive developmental disorders; phantom limb/phantom pain; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; PMG; polyneuropathy; polio; polymicrogyria; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia (phn); postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive supranuclear palsy; prosopagnosia; pseudotumor cerebri; quadrantanopia; quadriplegia; rabies; radiculopathy; Ramsay-Hunt syndrome type 1; Ramsay-Hunt syndrome type 2; Ramsay-Hunt syndrome type 3 - see Ramsay-Hunt syndrome; Rasmussen encephalitis; reflex neurovascular dystrophy; refsum disease; REM sleep behavior disorder; repetitive stress injury; restless legs syndrome; retrovirus- associated myelopathy; Rett syndrome; Reye's syndrome; rhythmic movement disorder; Romberg syndrome; Saint Vitus' dance; Sandhoff disease; Schilder's disease (two distinct conditions); schizencephaly; sensory processing disorder; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; sleeping sickness; snatiation; Sotos syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; spinal and bulbar muscular atrophy; spinocerebellar ataxia; split-brain; Steele-Richardson-Olszewski syndrome; stiff- person syndrome; stroke; Sturge-Weber syndrome; stuttering; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; superficial siderosis; Sydenham's chorea; syncope; synesthesia; syringomyelia; tarsal tunnel syndrome; tardive dyskinesia; tardive dysphrenia; Tarlov cyst; Tay-Sachs disease; temporal arteritis; temporal lobe epilepsy; tetanus; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd's Paralysis; Tourette syndrome; toxic encephalopathy; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trichotillomania; trigeminal neuralgia; tropical spastic paraparesis; trypanosomiasis; tuberous sclerosis; 22g13 deletion syndrome; Unverricht-Lundborg disease; vestibular schwannoma (acoustic neuroma); Von Hippel-Lindau disease (VHL); viliuisk encephalomyelitis (VE); Wallenberg's syndrome; west syndrome; whiplash; Williams syndrome; Wilson's disease; y-linked hearing impairment; and/or Zellweger syndrome. [0157] Each of the states, diseases, disorders, and conditions, described herein, as well as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes preventing or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition (e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof). Furthermore, treating can include relieving the disease (e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms). A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or to a physician. [0158] A mitochondria-associated disease, disorder, or condition may be a disease primarily caused by or secondarily associated with mitochondrial dysfunction, fragmentation, or loss-of-fusion, or associated with dysfunction in MFN1 or MFN2 catalytic activity or conformational unfolding. Mitochondrial dysfunction may be caused by genetic mutations of mitofusins or other (nuclear or mitochondrial encoded) genes, or may be caused by physical, chemical, or environmental injury to the CNS or PNS. [0159] In a particular example, cancer chemotherapy-induced sensory and motor neuropathies may be prevented or treated with the compositions of the present disclosure. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common complications of cancer chemotherapy, affecting 20% of all patients and almost 100% of patients receiving high doses of chemotherapeutic agents. Dose-dependent neurotoxicity of motor and sensory neurons can lead to chronic pain, hypersensitivity to hot, cold, and mechanical stimuli, and/or impaired neuromuscular control. The most common chemotherapeutic agents linked to CIPN are platinum, vinca alkaloids, taxanes, epothilones, and the targeted proteasome inhibitor, bortezomib. [0160] CIPN most commonly affects peripheral sensory neurons whose cell bodies are located in dorsal root ganglia lacking the blood-brain barrier that protects other components of the central and peripheral nervous system. Unprotected dorsal root ganglion neurons are more sensitive to neuronal hyperexcitability and innate immune system activation evoked by circulating cytotoxic chemotherapeutic agents. CIPN affects quality of life, and is potentially disabling, because it provokes chronic neuropathic pain that, like other causes of neuralgia (e.g., post herpetic neuralgia, diabetic mononeuropathy), is refractory to analgesic therapy. Motor nerve involvement commonly manifests as loss of fine motor function with deterioration in handwriting, difficulty in buttoning clothes or sewing, and sometimes upper and lower extremity weakness or loss of endurance. CIPN typically manifests within weeks of chemotherapy and in many cases improves after chemotherapy treatment ends, although residual pain, sensory, or motor defects are observed in one-third to one-half of affected patients. Unfortunately, CIPN-limited chemotherapy dosing can lead to delays, reduction, or interruption of cancer treatment, thus shortening survival. [0161] Mitochondrial dysfunction and oxidative stress are implicated in CIPN because of observed ultrastructural morphological abnormalities, impaired mitochondria DNA transcription and replication, induction of mitochondrial apoptosis pathways, and reduction of experimental CIPN signs by anticipatory mitochondrial protection. Mitofusin activators may enhance overall mitochondrial function in damaged neurons, increase mitochondrial transport to areas of neuronal damage, and accelerate in vitro neuron repair/regeneration after chemotherapy-induced damage. For this reason, it is believed that mitofusin activators may reduce neuronal injury conferred by chemotherapeutic agents in CIPN and accelerate regeneration/repair of nerves damaged by chemotherapeutic anticancer agents. As such, the present disclosure provides for compositions and methods to treat cancer chemotherapy induced nerve injury and neuropathy. [0162] In another example, injury in the CNS or PNS (e.g., trauma to the CNS or PNS, crush injury, SCI, TBI, stroke, optic nerve injury, or related conditions that involve axonal disconnection) may be treated with the compositions of the present disclosure. The CNS includes the brain and the spinal cord and the PNS is composed of cranial, spinal, and autonomic nerves that connect to the CNS. [0163] Damage to the nervous system caused by mechanical, thermal, chemical, or ischemic factors may impair various nervous system functions such as memory, cognition, language, and voluntary movement. Most often, this is through accidental crush or transection of nerve tracts, or as an unintended consequence of medical interventions, that interrupt normal communications between nerve cell bodies and their targets. Other types of injuries may include disruption of the interrelations between neurons and their supporting cells or the destruction of the blood-brain barrier. [0164] Mitofusin activation may rapidly reverse mitochondrial dysmotility in neurons from mice or patients with various genetic or chemotherapeutic neurodegenerative diseases, in axons injured by chemotherapeutic agents, and in axons severed by physical injury. For this reason, mitofusin activators may enhance regeneration/repair of physically damaged nerves, as in vehicular and sports injuries, penetration trauma from military or criminal actions, and iatrogenic injury during invasive medical procedures. As such, the present disclosure provides for compositions and methods to treat physical nerve injury. [0165] Mitochondrial motility is also implicated in neuropathy and traumatic crush or severance nerve injuries. After nerve laceration or crush injury, nerves will either regenerate and restore neuromuscular function or fail to regenerate such that neuromuscular function in permanently impaired. Mitofusin activation may increase mitochondrial trafficking, thereby enabling a nerve to regenerate after traumatic injuries. [0166] The amount of a mitofusin activator and excipient to produce a pharmaceutical composition in a given dosage form may vary depending upon the subject being treated, the condition being treated and the particular mode of administration. It will be appreciated that the unit content of mitofusin activator contained in an individual dose of a given dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses, or the therapeutic effect may be cumulative over time. [0167] Dosing of the compounds of the present disclosure may occur as a single event or over a time course of treatment. For example, a mitofusin activator may be administered daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment may be at least several days, with dosing taking place at least once a day or continuously. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For chronic conditions, treatment could extend from several weeks to several months or even years. Definitions [0168] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings. [0169] The terms "treat" or "treatment", unless otherwise indicated by context, refer to any administration of a therapeutic molecule (e.g., any compound described herein) that partially or completely alleviates, ameliorates, relieves, inhibits, reduces severity of and/or reduces incidence of one or more symptoms or features of a particular disease, disorder, and/or condition (e.g., cancer). [0170] As used herein, the term "preventing," "prevent," or "protecting against" describes delaying onset or slowing progression of a disease, condition or disorder. [0171] As used herein, the term "subject" includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human. [0172] As used herein, the term "subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received at least one prior therapy before being treated with the compounds described herein. [0173] The term "therapeutically effective amount" or "effective amount" refers to an amount of a conjugate effective to treat or prevent a disease or disorder in a subject. [0174] As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. [0175] As used herein, the term "administration" typically refers to the administration of a composition to a subject or system to achieve delivery of an agent that is, or is included in, the composition. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some embodiments, administration is parenteral (e.g., intravenous administration). In some embodiments, intravenous administration is intravenous infusion. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, and the like. [0176] Unless otherwise indicated, the term "alkyl" by itself or as part of another term refers to an optionally substituted, straight-chain or branched, saturated or unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., "C₁-C₈ alkyl" or "C₁-C₁₀" alkyl refer to an alkyl group having from 1 to 8 or 1 to 10 carbon atoms, respectively). An alkyl group is non-aromatic. When the number of carbon atoms in an alkyl group is not indicated, the alkyl group has from 1 to 8 carbon atoms. Illustrative straight-chain "C₁-C₈ alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl and n-octyl. Illustrative branched C₃-C₈ alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl. Unsaturated C₂-C₈ alkyls include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l- butenyl, 2-methyl-2-butenyl, 2,3 dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, acetylenyl, 1- propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentenyl, and 3-methyl-1-butynyl. [0177] The term “optionally substituted” means a group can be substituted or unsubstituted. For example, an optionally substituted alkyl group can be a substituted or unsubstituted alkyl group. [0178] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyithiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, allcylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0179] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety. For example, alkylene (e.g., methylene (-CH₂-) or ethylene (-CH₂CH₂-)) is the divalent moiety of an alkyl group. [0180] Unless otherwise indicated, "alkylene", by itself of as part of another term, refers to a substituted or unsubstituted, saturated or unsaturated, branched or straight-chain hydrocarbon radical of the stated number of carbon atoms, typically 1-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited t methylene (-CH₂-), 1,2-ethylene (-CH₂CH₂-), 1,3-propylene (-CH₂CH₂CH₂-), 1,4-butylene (-CH₂CH₂CH₂CH₂-) and the like. [0181] Unless otherwise indicated, "aryl", by itself or as part of another term, means an optionally substituted, monovalent aromatic hydrocarbon radical of the stated number of carbon atoms, typically 6- 20 carbon atoms, derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Common aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. An illustrative aryl group is a phenyl group. [0182]“Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocycloalkyl groups or another aromatic ring, wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on the aryl ring and/or the one or more cycloalkyl or heterocycloalkyl groups. Common aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octacene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthalenyl. Unless otherwise specified, such aryl groups may be optionally substituted as specified herein. [0183]As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated or unsaturated carbocyclic ring which may be optionally substituted. Illustrative saturated cycloalkyl groups include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. Cycloalkyl groups also include polycycloalkyl groups such as bicycloalkyl groups and tricycloalkyl groups are also included. Examples of bicycloalkyl groups include norbomyl groups such as exo-2-norbomyl groups, endo-2-norbomyl, 3-pinanyl, bicyclo [3.1.0] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] oct-2-yl, and the like. Other examples include an adamantyl group such as a 1-adamantyl group or a 2-adamantyl group. [0184] “Cycloalkyl" also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the radical or point of attachment is on the cycloalkyl ring, and in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the cycloalkyl ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on the cycloalkyl and/or the one or more aryl or heteroaryl groups. Unless otherwise specified, cycloalkyl group may be optionally substituted. [0185] As used herein, the term "cycloalkylene" refers a divalent moiety containing two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkane. Typical cycloalkylene radicals include, but are not limited to: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene and the like. Specific examples include 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2- cyclohexylene, and 1,4-cyclohexylene. [0186] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic or 6-10 membered bicyclic (fused, bridged, or spiro) ring system having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Heterocycloalkyl groups are non-aromatic. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, mozpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8- azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]]decanyl, 1- azaspiro [4.5]decanyl, 3'H-spiro[cyclohexane-1,1’ isobenzofuran]-3-yl, 7'H-spiro [cyclohexane-1,5'-furo[3,4- b]pyridin]-yl, 3'H-spiro [cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8- hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8- tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2- azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2- azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic. [0187] As used herein, the term "heteroaryl" refers to a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, or 10-membered bicyclic aromatic heterocyclic ring containing carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N-O and S(O)_p, where p = 1 or 2). Examples of monocycylic heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. [0188] Unless otherwise indicated, the term "heteroalkyl" refers to an optionally unsaturated, straight- or branched-chain hydrocarbon, containing at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The term “heteroalkylene” refers to an alkylene group derived from a heteroalkyl group. [0189] The terms "arylalkyl" or "heteroarylalkyl" refer to a substituent, moiety or group where an aryl moiety is bonded to an alkyl moiety, where bonding of the substituent, moiety or group to a larger molecule takes place through the alkyl moiety. Examples of arylalkyl groups include benzyl groups (C₆H5CH₂). [0190] A "metabolite" is a product produced through metabolism in the body of a specified compound, a derivative thereof, or a conjugate thereof, or salt thereof. Metabolites of a compound, a derivative thereof, or a conjugate thereof, may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present disclosure includes metabolites of compounds or a conjugate thereof, including compounds or conjugates produced by a process comprising contacting a compound, a derivative thereof, or a conjugate thereof, with a mammal for a period of time sufficient to yield a specified metabolite. [0191] Toxicity and therapeutic efficacy of the compounds and compositions described herein may be determined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that may be expressed as the ratio LD₅₀/ED₅₀, where larger therapeutic indices are generally understood in the art to be optimal. Activity Assays [0192] Compounds of the present disclosure may be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. [0193] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [0194] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. [0195] In some embodiments, the assay is an assay as described in U.S. Patent Application Publication Nos.2020/0345668 and 2020/0345669, each of which is incorporated herein by reference. [0196] In some embodiments, the biological assay involves evaluation of the dose-response of a compound described herein, e.g., in Mfn1- or Mfn2-deficient cells. [0197] In some embodiments, the biological assay involves evaluation of mitofusin-stimulating activities of a compound described herein, e.g., in Mfn1-null or Mfn2-null cells. [0198] In some embodiments, the biological assay is performed with wild-type MEFs (e.g., prepared from. E10.5 c57/b16 mouse embryos). [0199] In some embodiments, the biological assay was performed with SV-40 T antigen-immortalized MFN1-null (CRL-2992), MFN2-null (CRL-2993), and/or Mfn1/Mfn2-double null MEFs (CRL-2994). [0200] In some embodiments, the biological assay is performed in Mfn2-deficient MEFs (e.g., Mfn2-KO MEFs). [0201] The present disclosure is further directed to the following non-limiting embodiments. Embodiment 1. A compound having a structure represented by Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be optionally joined to Z to form a heterocyclic ring; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. Embodiment 2. The compound of Embodiment 1, wherein the compound has a structure represented by Formula (Ia)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof. Embodiment 3. The compound of Embodiment 1 or Embodiment 2, wherein the compound has a structure represented by Formula (II) or Formula (IIa)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

Embodiment 4. The compound of Embodiment 3, wherein the compound has a structure represented by Formula (III) or Formula (Illa)

Embodiment 5. The compound of Embodiment 3, wherein the compound has a structure represented by Formula (IV) or Formula (IV a)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

Embodiment 6.The compound of Embodiment 3, wherein the compound has a structure represented by Formula (V), Formula (Va), Formula (VI), or Formula (Via)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

Embodiment 7. The compound of Embodiment 6, wherein the compound has a structure represented by Formula (VII), Formula (Vila), Formula (Vllb), or Formula (Vile)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof. Embodiment 8. A compound having a structure represented by Formula (I’)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be optionally joined to Z to form a heterocyclic ring; Q is -(C=O)_m(CR^c ₂)_n-, wherein Q is bound to N via the (C=O), if the (C=O) is present; each R^c independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁵, NHR⁵, or N(R⁵)₂, wherein R⁵ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^c may be optionally joined to form a carbocyclic or heterocyclic ring; m is 0 or 1; n is 0, 1, or 2; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring. Embodiment 9. The compound of Embodiment 8, wherein the compound has a structure represented by Formula (I’a)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof. Embodiment 10. The compound of Embodiment 8 or Embodiment 9, wherein R^c is H. Embodiment 11. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Y is C₁-C₆ alkylene optionally substituted by one or more R^Y. Embodiment 12. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Y is C₃-C₈ cycloalkylene optionally substituted with one or more R^Y. Embodiment 13. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Y is cyclopropylene. Embodiment 14. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Z is C₆- C₁₀ aryl optionally substituted with one or more R^Z. Embodiment 15. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Z is phenyl, naphthyl, or tetrahydronaphthalenyl, optionally substituted with one or more R^Z. Embodiment 16. The compound of any one of Embodiments 1, 2, 8, or 9, wherein Z is C₆- C₁₀ cycloalkyl or 5- to 10-membered heteroaryl, optionally substituted with one or more R^Z. Embodiment 17. A pharmaceutical composition, comprising the compound of any one of the preceding Embodiments or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient. Embodiment 18. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising administering the compound of any one of Embodiments 1-16 or the pharmaceutical composition of Embodiment 17 to the subject. Embodiment 19. The method of Embodiment 18, wherein a therapeutically effective amount of the compound or the pharmaceutical composition is administered to the subject. Embodiment 20. The method of Embodiment 18 or Embodiment 19, wherein the disease, disorder, or condition is associated with mitochondria. Embodiment 21. The method of any one of Embodiments 18-20, wherein the disease, disorder, or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, or chemical injury. Embodiment 22. The method of Embodiment 21, wherein the PNS or CNS genetic or non- genetic disorder is one or more conditions selected from the group consisting of a chronic neurodegenerative condition in which mitochondrial fusion, fitness, and/or trafficking is/are impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and/or dysmotility; a degenerative neuromuscular condition; Charcot-Marie-Tooth disease; Amyotrophic Lateral Sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathy; autism; autosomal dominant optic atrophy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetes mellitus and deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh syndrome; subacute sclerosing encephalopathy; neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); myoneurogenic gastrointestinal encephalopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS); mtDNA depletion; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); dysautonomic mitochondrial myopathy; mitochondrial channelopathy; pyruvate dehydrogenase complex deficiency (PDCD/PDH); diabetic neuropathy; chemotherapy-induced peripheral neuropathy; crush injury; spinal cord injury (SCI); traumatic brain injury; stroke; optic nerve injury; conditions that involve axonal disconnection; and any combination thereof. Embodiment 23. A method of activating mitofusin in a subject, comprising administering the compound of any one of Embodiments 1-16 or the pharmaceutical composition of Embodiment 17 to the subject. Embodiment 24. The compound of any one of Embodiments 1-16 or the pharmaceutical composition of Embodiment 17 for use in treating or preventing a disease, disorder, or condition to a subject in need thereof. Embodiment 25. The compound of any one of Embodiments 1-16 or the pharmaceutical composition of Embodiment 17 for use in activating mitofusin in a subject. Embodiment 26. Use of the compound of any one of Embodiments 1-16 or the pharmaceutical composition of Embodiment 17 in the manufacture of a medicament for treating or preventing a disease, disorder, or condition to a subject in need thereof. [0202] To facilitate a better understanding of the present disclosure, the following examples of preferred or representative embodiments are given. In no way should the following examples be read to limit, or to define, the scope of the invention. EXAMPLES [0203] Example 1: Synthesis of Compounds Having Formulas 1-21 and 23. The general synthetic route for synthesizing the compound having a structure represented by Formula 1 is outlined in Scheme 1 below. Detailed synthetic procedures follow. Compounds 2-23 were synthesized in a similar manner. ¹H NMR and ESI MS characterization data for Compounds 1-21 and 23 is provided in Table 1 below.

Scheme 1 [0204] Step 1: Preparation of Compound C1-2.

To a solution of Compound C1-1 (15.00 g, 130.24 mmol, 1 eq.) in DCM (200 mL) was added imidazole (26.60 g, 390.72 mmol, 3 eq.) and TBSCl (29.44 g, 195.36 mmol, 23.94 mL, 1.5 eq.) at 0°C. The mixture was stirred at 25°C for 12 hrs. The reaction mixture was quenched with water 100 (mL), and then extracted with DCM 240 mL (80 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% MeOH in DCM). Then the product was re-purified by trituration with petroleum ether (200 mL) to give Compound C1-2 (23 g, 100.25 mmol, 76.97% yield) as a white solid. ESI [M+H] = 230.2. [0205] Step 2: Preparation of compound C1-3.

To a solution of A1C13 (5.81 g, 43.59 mmol, 2.38 mL, 2 eq.) in DCM (20 mL) was added TEA (6.62 g, 65.38 mmol, 9.10 mL, 3 eq.) at 0°C. The mixture was stirred at 25°C for 0.5 hr. Then, Compound C1-2 (5 g, 21.79 mmol, 1 eq.) and tetrahydropyran-2-one (2.18 g, 21.79 mmol, 1.97 mL, 1 eq.) were added to the mixture at 0°C. The mixture was stirred at 25°C for 1.5 hrs. The reaction mixture was quenched with saturated Na₂CO₃ (100 mL) at 0°C and extracted with DCM 120 mL (40 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% MeOH in DCM) to give Compound C1-3 (5 g, 15.17 mmol, 69.62% yield) as a yellow oil. ESI [M+H] = 330.2. [0206] Step 3: Preparation of compound C1-4.

To a solution of (COC1)₂ (1.16 g, 9.10 mmol, 796.86 μL, 2 eq.) in DCM (50 mL) was added DMSO (1.42 g, 18.21 mmol, 1.42 mL, 4 eq.) at -78°C under N₂. The mixture was stirred at -78°C for 0.5 h. Thereafter, a solution of Compound C1-3 (1.5 g, 4.55 mmol, 1 eq.) in DCM (5 mL) was added to the mixture at - 78°C. The mixture was stirred at -78°C for 1 h. After 1 h, TEA (3.68 g, 36.41 mmol, 5.07 mL, 8 eq.) was added to the mixture at -78°C and stirred at -78°C for 30 min under N2. Then, the mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched with H₂O (50 mL) at 0°C and extracted with DCM 150 mL (50 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give Compound C1-4 (1.5 g, crude) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 328.2. [0207] Step 4: Preparation of compound C1-5.

[0208] To a solution of aniline (639.73 mg, 6.87 mmol, 625.964, 1.5 eq.) in CHCl₃ (10 mL) was added Compound C1-4 (1.5 g, 4.58 mmol, 1 eq.) at 0°C. The mixture was stirred at 25°C for 0.5 h. Thereafter, NaBH(OAc)₃ (1.46 g, 6.87 mmol, 1.5 eq.) was added at 0°C, and the mixture was stirred at 25°C for 1.5 h. The reaction mixture was quenched with saturated NaHCO₃10 mL at 0°C and extracted with DCM 60 mL (20 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give Compound C1-5 (1.5 g, 3.71 mmol, 80.94% yield) as a yellow oil. ESI = 405.3. [0209] Step 5: Synthesis of the Compound Having Formula 1.

A mixture of Compounds C1-5 (1.4 g, 3.46 mmol, 1 eq.) in HCl/MeOH (15 mL 1M) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*40mm*3 μm; mobile phase: [H₂O(0.1%TFA)-ACN]; gradient: 1%-30% B over 8.0 min) to give N-((1r,4r)-4- hydroxycyclohexyl-5-(phenylamino)pentanamide, Formula 1 (695.9 mg, 2.40 mmol, 69.26% yield, 100% purity) as a colorless oil. Table 1

[0210] Example 2: Synthesis of Compounds Having Structures Represented by Formulas 24, 27 and 28. The general synthetic route for synthesizing the compound having a structure represented by Formula 24 is outlined in Scheme 2 below, followed by chiral separation to afford compounds having structures represented by Formulas 27 and 28. Detailed synthetic procedures follow. ¹H NMR and ESI MS characterization data for Compounds 24-28 is provided in Table 2 below.

Scheme 2 [0211] Step 1: Preparation of Compound C24-2.

To a solution of tert-butylphenylcarbamate (10 g, 51.75 mmol, 1 eq.) in THF (300 mL) was added NaH (7.24 g, 181.12 mmol, 60% purity, 3.5 eq.) at 0°C, and the mixture was stirred at 25°C for 1 hr. Thereafter, 4-bromobut-1-ene (20.96 g, 155.25 mmol, 15.76 mL, 3 eq.) was added at 0°C, and the mixture was then stirred at 70°C for 11 hrs. The reaction mixture was quenched with saturated NH4Cl 50 mL at 0°C and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C¹⁸250*100 mm#10 μm; mobile phase: [H₂0 (0.1% TFA)- ACN]; gradient: 55%-85% B over 25.0 min) to give Compound C24-2 (3 g, 12.13 mmol, 46.15% yield) as a yellow oil. ESI [M+H] 248.2. [0212] Step 2: Preparation of Compounds C24-3, C24-3-trans, and C24-3-cis

To a solution of Compound 24-2 (3 g, 12.13 mmol, 1 eq.) and Rh₂(OAc)₄ (536.11 mg, 1.21 mmol, 0.1 eq.) in CHCl₃ (50 mL) was added ethyl 2-diazoacetate (5.54 g, 48.52 mmol, 5.10 mL, 4 eq.). The mixture was degassed and purged 3 times with N2, and then the mixture was stirred at 50°C for 72 hrs under N2. The reaction mixture was combined with H₂O (50 mL) at 0°C, and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). The residue was re-purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 μm; mobile phase: [water(TFA)-ACN]; gradient: 45%-75% B over 8 min) to give Compound 24-3-trans (1.2 g, 3.60 mmol, 29.67% yield) as a yellow oil. ES1 [M+H] = 334.2; and Compound 24-3-cis (1.5 g, 4.50 mmol, 37.09% yield) as a yellow oil. ESI [M+H] = 334.2. [0213] Step 3: Preparation of Compound C24-4.

A mixture of Compound C24-3 (cis/trans mixture) (1.2 g, 3.60 mmol, 1 eq.) and LiOH•H20 (453.09 mg, 10.80 mmol, 3 eq.) in EtOH (6 mL) and H₂O (6 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The mixture was combined with H₂O (20 mL) and extracted with MTBE 30 mL (10 mL x 3). The aqueous layer was adjusted to pH = 6 with 1M HCI 10 mL at 0°C and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give Compound 24-4 (1 g, crude) as a yellow oil. ESI [M+H] = 306.2. [0214] Step 4: Preparation of Compound C24-5

To a solution of Compound C24-4 (1 g, 3.27 mmol, 1 eq.), 4-aminocyclohexanol (565.74 mg, 4.91 mmol, 1.5 eq.) and DIEA (1.27 g, 9.82 mmol, 1.71 mL, 3 eq.) in DCM (20 mL) was added PyAOP (2.22 g, 4.26 mmol, 1.3 eq.). The mixture was stirred at 25°C for 1 hr. The reaction mixture was combined with H₂O (15 mL), and extracted with DCM 60 mL (20 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100- 200 mesh, 0-100% ethyl acetate in petroleum ether) to give tert-butyl (2-(2-(((1r,4r)-4- hydroxycyclohexyl)carbamoyl)cyclopropyl)ethyl)(phenyl)carbamate, Compound C24-5 (1 g, 2.48 mmol, 75.86% yield) as a yellow oil. ESI [M+H] = 403.3. [0215] Step 5: Preparation of the Compound Having Formula 24

A mixture of Compound C24-5 (1 g, 2.48 mmol, 1 eq.) in HCl/EtOAc (15 mL, 4 M) was stirred at 25°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated NaHCO₃ (15 mL) at 0°C and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*50 mm*10 μm;mobile phase: [H₂O(10 mM NH₄HCO₃)-ACN]; gradient: 10%-50% B over 10.0 min) to give N-(1r,4r)-4-hydroxycyclohexyl)-2-(2-(phenylamino)ethyl)cyclopropane-1- carboxamide, Formula 24 (500 mg, 1.59 mmol, 63.94% yield, 96.07% purity) as a white solid. [0216] The racemic mixture was then separated by SFC (column: DAICEL CHIRALPAKAD (250mm*30mm,10 μm); mobile phase: [CO₂-EtOH(0.1% NH₄OH)]; B%:35%, isocratic elution mode) to give: (1R,2S)-N-(1r,4r)-4-hydroxycyclohexyl)-2-(2-(phenylamino)ethyl)cyclopropane-1- carboxamide, Formula 26 (Peak 1, retention time = 1.265) (36.6 mg, 121.03 μmol, 24.40% yield, 100% purity, ee%=100%) as a white solid; and (1S,2R)-N-(1r,4r)-4-hydroxycyclohexyl)-2-(2- (phenylamino)ethyl)cyclopropane-1-carboxamide, Formula 27 (Peak 2, retention time = 1.349) (34.7 mg, 114.74 μmol, 23.13% yield, 100% purity, ee%=99.66%) as a white solid. [0217] Example 3: Synthesis of Compounds Having a Structure Represented by Formula 26. The general synthetic route for synthesizing the compound having a structure represented by Formula 26 is outlined in Scheme 3 below. Detailed synthetic procedures follow. ¹H NMR and ESI MS characterization data for Formula 26 is provided in Table 2 below.

Scheme 3 [0218] Step 1: Preparation of compound C26-2

To a solution of N-methylaniline (10 g, 93.32 mmol, 10.13 mL, 1 eq.) and 4-bromobut-1-ene (44.10 g, 326.64 mmol, 33.16 mL, 3.5 eq.) in EtOH (200 mL) was added Na₂CO3 (14.84 g.139.99 mmol, 1.5 eq.). The mixture was stirred at 80°C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was combined with H₂O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to obtain Compound C26-2 (13 g, 80.62 mmol, 70.88% yield) as a yellow oil. ESI [ M+H] = 162.1. [0219] Step 2: Preparation of compound C26-3

To a solution of Compound C26-2 (4 g, 24.81 mmol, 1 eq.) and cuprous acetonitrile tetrafluoroborate (1.17 g, 3.72 mmol, 0.15 eq.) in DCM (30 mL) was added ethyl 2-diazoacetate (8.49 g, 74.42 mmol, 3 eq.) under N2 atmosphere. The mixture was stirred at 25°C for 12 hrs. The reaction mixture was combined with H₂O (200 mL), and extracted with DCM 600 mL (200 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Welch Xtimate C18180*70mm*10 μm;mobile phase: [H₂O(0.01%TFA)-ACN:THF=1:1];gradient:5%-35% B over 20.0 min) to give Compound C26-3 (400 mg, 1.62 mmol, 6.52% yield) as a yellow oil. ESI [M+H] = 248.16. [0220] Step 3: Preparation of Compound C26-4

The hydrolysis reaction was conducted in a similar manner to that used to prepare compound 24- 4. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was combined with H₂O (5 mL) and extracted with MTBE (10 mL). The aqueous layer was adjusted to pH=2 with 6 M HCl (2mL) at 0°C and extracted with EtOAc 15 mL (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give Compound C26-4 (250 mg, crude) as a yellow oil. ESI [M+H] = 220.13. [0221] Step 4: Preparation of Compound Having Formula 26

The amide coupling reaction was conducted in similar manner to that used to prepare Compound C24-5. The reaction mixture was concentrated and the residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 μm;mobile phase: [H₂O (0.1%TFA)-ACN] gradient 1%-30% B over 8.0 min) to give N-((1r,4r)-4-hydroxycyclohexyl)-2-(2- methyl(phenyl)amino)ethyl)cyclopropane-1-carboxamide, Formula 26 (119.6 mg, 377.96 μmol, 33.15% yield, 100% purity) as a white solid. [0222] Example 4: Synthesis of the Compound Having Formula 25

[0223] Step 1: Preparation of Compound C25-2

To a solution of 3-(trifluoromethoxy)aniline (10 g, 56.46 mmol, 7.55 mL, 1 eq.) in MeOH (100 mL) was added Boc₂O (19.71 g, 90.33 mmol, 20.75 mL, 1.6 eq.) at 0°C. The mixture was stirred at 45°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give Compound C25-2 (14 g, 50.50 mmol, 89.44% yield) as a white solid. ¹H NMR. (400 MHz, MeOD-d₄) δ 7.41 (s, 1H), 7.22 - 7.16 (m, 2H), 6.78 - 6.73 (m, 1H), 1.42 - 1.41 (m, 9H). ESI [M+H]= 278.1. [0224]Step 2: Preparation of Compound C25-3.

The alkylation reaction was conducted in similar manner to that used to prepare Compound 24-2, except using NaH as the base and THF as the solvent. The crude product was purified by prep- HPLC (column: Phenomenex luna C18 (250*70 mm,15 μm);mobile phase: [H₂O(0.1% TFA)-ACN;gradient:68%-88% B over 20.0 min) to give Compound C25-3 (2 g, 6.04 mmol, 33.47% yield) as a yellow oil. ¹H NMR (400 MHz, MeOD-d4) δ 7.39 - 7.32 (m, 1H), 7.14 (br d, J = 8.1 Hz, 1H), 7.09 - 7.03 (m, 2H), 5.67 (tdd, J = 6.9, 10.3, 17.1 Hz, 1H), 4.98 - 4.90 (m, 2H), 3.64 (t, J = 7.1 Hz, 2H), 2.17 (q, J = 7.0 Hz, 2H), 1.36 - 1.30 (m, 9H). ESI [M+H]= 332.1. [0225] Step 3: Preparation of Compound C25-4.

Cyclopropanation was conducted in a similar manner to that described for Compound 26-3. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 μm;mobile phase: [H₂O(0.1%TFA)-ACN];gradient:55%-85% B over 8.0 min) to give Compound C25-4 (90 mg, 215.61 μmol, 7.14% yield) as a yellow oil.¹H NMR (400 MHz, MeOD-d₄) δ 7.51 - 7.44 (m, 1H), 7.30 - 7.15 (m, 3H), 4.09 (ttd, J = 3.6, 7.0, 10.6 Hz, 2H), 3.81 (t, J = 6.9 Hz, 2H), 1.72 - 1.60 (m, 1H), 1.52 - 1.47 (m, 1H), 1.45 (s, 9H), 1.43 - 1.39 (m, 1H), 1.37 - 1.29 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (td, J = 4.3, 8.7 Hz, 1H), 0.76 (ddd, J = 4.2, 6.3, 8.0 Hz, 1H). ESI [M+H] = 418.2. [0226] Step 4: Preparation of compound C25-5.

Hydrolysis was conducted in a similar fashion to Compound 26-4. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was combined with H₂O (10 mL) and extracted with MTBE 30 mL (10 mL x 3). The aqueous layer was adjusted to pH=2 with 6 M HC12 mL at 0°C, and extracted with EtOAc 15 mL (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give Compound C25-5 (90 mg, crude) as a colorless oil. ESI [M+H] = 390.2. [0227] Step 5: Preparation of compound C25-6.

The amide coupling reaction was conducted in a similar manner to that used to prepare the compound having Formula 26. The crude product was purified by prep-TLC (SiO₂, Petroleum ether:Ethyl acetate = 0:1) to give Compound C25-6 (80 mg, 164.43 mmol, 71.14% yield) as a colorless oil. ESI [M+H] = 487.2. [0228] Step 6: Preparation of the Compound Having Formula 25.

Deprotection was conducted in a similar manner to Compound 24. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 μm;mobile phase: [H₂O(0.1%TFA)- ACN1;gradient:25%-55% B over 8.0 min.) to give tert-butyl (2-(2-(((1r,4r)-4-hydroxycyclohexyl)- 2-(2-((3-(trifluoromethoxy)phenyl)amino)ethyl)cyclopropane-1-carboxamide, Formula 25 (34.7 mg, 88.93 mmol, 61.81% yield, 99.031% purity) as a white solid.

Table 2

[0229] Example 5: Biological Activity of Selected Compounds. Dose-response of mitofusin agonist fusogenicity was performed in Mfn2-deficient MEFs (e.g., Mfn2-KO MEFs) cultured at 37°C and 5% CO₂-95% air. Cells were seeded on day 1 in 12-well plates at a density of 0.5x10⁴ cells/ml. Compounds were added at either one single concentration (1.04 M dissolved in DMSO) to estimate % fusogenicity or in a dose-response manner to determine EC₅₀ for 48 hours. Mitochondria were then stained with MitoTracker Orange (200 nM; M7510; Invitrogen, Carlsbad, CA, USA). Nuclei were stained with Hoescht (10 µg/ml; Invitrogen, Thermo Fisher Scientific Cat: # H3570). Images were acquired in the cell incubator (5% CO₂-95% air) of a Keyence BL-X800 All in-One Fluorescence Microscope using the 40X high-dry objective with image size set to 1920*1440 pixels and 8 images per well. Laser excitation was 549 nm with emission at 590 nm for MitoTracker Orange and excitation at 306 nm with emission at 405 nm for Hoescht. Merged images were manually reviewed. For each usable visual field, the number of cells having filamentous (elongated) mitochondria was determined, and expressed as a percent of the total number of cells in that field (i.e. nuclei). Data were indexed to the maximal response elicited by Reference Compound C1 (shown below). Response curves were interpolated using the sigmoidal model using Prism 8 software.

Reference Compound C1 [0230] Tables 3 and 4 show the fusogenic response in Mfn2-KO MEFs % and EC₅₀ values of selected compounds. In Table 3, + indicates an EC₅₀ of > 50 nM; ++ indicates an EC₅₀ of 30 nM up to 50 nM; +++ indicates an EC₅₀ of 15 nM up to 30 nM; ++++ indicates an EC₅₀ of < 15 nM; A indicates a fusogenicity % of > 70%; B indicates a fusogenicity % of 50% up to 70%; and C indicates a fusogenicity % < 50%. ND is not determined. Table 3

Table 4

[0231] Unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the embodiments of the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claim, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. [0232] One or more illustrative embodiments incorporating various features are presented herein. Not all features of a physical implementation are described or shown in this application for the sake of clarity. It is understood that in the development of a physical embodiment incorporating the embodiments of the present invention, numerous implementation-specific decisions must be made to achieve the developer's goals, such as compliance with system-related, business-related, government-related and other constraints, which vary by implementation and from time to time. While a developer's efforts might be time-consuming, such efforts would be, nevertheless, a routine undertaking for those of ordinary skill in the art and having benefit of this disclosure. [0233] While various systems, tools and methods are described herein in terms of “comprising” various components or steps, the systems, tools and methods can also “consist essentially of” or “consist of” the various components and steps. [0234] As used herein, the phrase “at least one of” preceding a series of items, with the terms “and” or “or” to separate any of the items, modifies the list as a whole, rather than each member of the list (i.e., each item). The phrase “at least one of” allows a meaning that includes at least one of any one of the items, and/or at least one of any combination of the items, and/or at least one of each of the items. By way of example, the phrases “at least one of A, B, and C” or “at least one of A, B, or C” each refer to only A, only B, or only C; any combination of A, B, and C; and/or at least one of each of A, B, and C. [0235] Therefore, the disclosed systems, tools and methods are well adapted to attain the ends and advantages mentioned as well as those that are inherent therein. The particular embodiments disclosed above are illustrative only, as the teachings of the present disclosure may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular illustrative embodiments disclosed above may be altered, combined, or modified and all such variations are considered within the scope of the present disclosure. The systems, tools and methods illustratively disclosed herein may suitably be practiced in the absence of any element that is not specifically disclosed herein and/or any optional element disclosed herein. While systems, tools and methods are described in terms of “comprising,” “containing,” or “including” various components or steps, the systems, tools and methods can also “consist essentially of” or “consist of” the various components and steps. All numbers and ranges disclosed above may vary by some amount. Whenever a numerical range with a lower limit and an upper limit is disclosed, any number and any included range falling within the range is specifically disclosed. In particular, every range of values (of the form, “from about a to about b,” or, equivalently, “from approximately a to b,” or, equivalently, “from approximately a-b”) disclosed herein is to be understood to set forth every number and range encompassed within the broader range of values. Also, the terms in the claims have their plain, ordinary meaning unless otherwise explicitly and clearly defined by the patentee. Moreover, the indefinite articles “a” or “an,” as used in the claims, are defined herein to mean one or more than one of the elements that it introduces. If there is any conflict in the usages of a word or term in this specification and one or more patent or other documents that may be incorporated herein by reference, the definitions that are consistent with this specification should be adopted.

Claims

CLAIMS What is claimed is the following: 1. A compound having a structure represented by Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be optionally joined to Z to form a heterocyclic ring; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring.

2. The compound of claim 1, wherein the compound has a structure represented by Formula (Ia)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

3. The compound of claim 1 or claim 2, wherein the compound has a structure represented by Formula (II) or Formula (IIa)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

4. The compound of claim 3, wherein the compound has a structure represented by Formula (III) or Formula (IIIa)

5. The compound of claim 3, wherein the compound has a structure represented by Formula (IV) or Formula (IVa)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

6. The compound of claim 3, wherein the compound has a structure represented by Formula (V), Formula (Va), Formula (VI), or Formula (Via)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

7. The compound of claim 6, wherein the compound has a structure represented by Formula (VII), Formula (VIIa), Formula (VIIb), or Formula (VIIc)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

8. A compound having a structure represented by Formula (I’)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof; wherein: each R^a independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR¹, NHR¹, or N(R¹)₂, wherein R¹ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^a may be optionally joined to form a carbocyclic or heterocyclic ring; p is 0, 1, 2, or 3; Y is C₁-C₆ alkylene or C₃-C₈ cycloalkylene, wherein the C₁-C₆ alkylene or C₃-C₈ cycloalkylene is optionally substituted with one or more R^Y; each R^Y independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR², NHR², or N(R²)₂, wherein R² is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Y may be optionally joined to form a carbocyclic or heterocyclic ring; each R^b independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR³, NHR³, or N(R³)₂, wherein R³ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^b may be optionally joined to form a carbocyclic or heterocyclic ring; q is 0, 1, 2, or 3; R^N is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, and R^N may be optionally joined to Z to form a heterocyclic ring; Q is -(C=O)m(CR^c2)n-, wherein Q is bound to N via the (C=O), if the (C=O) is present; each R^c independently is H, halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁵, NHR⁵, or N(R⁵)₂, wherein R⁵ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two R^c may be optionally joined to form a carbocyclic or heterocyclic ring; m is 0 or 1; n is 0, 1, or 2; Z is C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl, C₆-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Z; and each R^Z independently is halogen, cyano, OH, NH₂, C₁-C₆ alkyl, optionally substituted phenyl, OR⁴, NHR⁴, or N(R⁴)₂, wherein R⁴ is C₁-C₆ alkyl, and each occurrence of C₁-C₆ alkyl is optionally substituted with one or more halogen, cyano, OH, or NH₂, or two or more R^Z may be optionally joined to form a carbocyclic or heterocyclic ring.

9. The compound of claim 8, wherein the compound has a structure represented by Formula (I’a)

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof.

10. The compound of claim 8 or claim 9, wherein R^c is H.

11. The compound of any one of claims 1, 2, 8, or 9, wherein Y is C₁-C₆ alkylene optionally substituted by one or more R^Y.

12. The compound of any one of claims 1, 2, 8, or 9, wherein Y is C₃-C₈ cycloalkylene optionally substituted with one or more R^Y.

13. The compound of any one of claims 1, 2, 8, or 9, wherein Y is cyclopropylene.

14. The compound of any one of claims 1, 2, 8, or 9, wherein Z is C₆-C₁₀ aryl optionally substituted with one or more R^Z.

15. The compound of any one of claims 1, 2, 8, or 9, wherein Z is phenyl, naphthyl, or tetrahydronaphthalenyl, optionally substituted with one or more R^Z.

16. The compound of any one of claims 1, 2, 8, or 9, wherein Z is C₆-C₁₀ cycloalkyl or 5- to 10-membered heteroaryl, optionally substituted with one or more R^Z.

17. A pharmaceutical composition, comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient.

18. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising administering the compound of any one of claims 1-16 or the pharmaceutical composition of claim 17 to the subject.

19. The method of claim 18, wherein a therapeutically effective amount of the compound or the pharmaceutical composition is administered to the subject.

20. The method of claim 18 or claim 19, wherein the disease, disorder, or condition is associated with mitochondria.

21. The method of any one of claims 18-20, wherein the disease, disorder, or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, or chemical injury.

22. The method of claim 21, wherein the PNS or CNS genetic or non-genetic disorder is one or more conditions selected from the group consisting of a chronic neurodegenerative condition in which mitochondrial fusion, fitness, and/or trafficking is/are impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and/or dysmotility; a degenerative neuromuscular condition; Charcot-Marie-Tooth disease; Amyotrophic Lateral Sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathy; autism; autosomal dominant optic atrophy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetes mellitus and deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh syndrome; subacute sclerosing encephalopathy; neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); myoneurogenic gastrointestinal encephalopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS); mtDNA depletion; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); dysautonomic mitochondrial myopathy; mitochondrial channelopathy; pyruvate dehydrogenase complex deficiency (PDCD/PDH); diabetic neuropathy; chemotherapy-induced peripheral neuropathy; crush injury; spinal cord injury (SCI); traumatic brain injury; stroke; optic nerve injury; conditions that involve axonal disconnection; and any combination thereof.

23. A method of activating mitofusin in a subject, comprising administering the compound of any one of claims 1-16 or the pharmaceutical composition of claim 17 to the subject.

24. The compound of any one of claims 1-16 or the pharmaceutical composition of claim 17 for use in treating or preventing a disease, disorder, or condition to a subject in need thereof.

25. The compound of any one of claims 1-16 or the pharmaceutical composition of claim 17 for use in activating mitofusin in a subject.

26. Use of the compound of any one of claims 1-16 or the pharmaceutical composition of claim 17 in the manufacture of a medicament for treating or preventing a disease, disorder, or condition to a subject in need thereof.