Mitofusin activators having an endocyclic carbonyl group and methods of using same

Abstract

Compositions capable of promoting mitofusin activation include [C115] The present invention includes a mitofusin activator having a structure represented by the formula (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (41), (42), (43), (44), (45), (46), (47), (5), (5), (6), (7), (8), (11), (12), (13), (14), (15), (16), (17), (18), (25), (26), (27), (34), ( 1 (CH2)3, NR 1 OCH2CH2, NR 1 CH2OCH2, NR 1 CH2CH2O or NR 1 Y and R 1 is H or C1-C6 alkyl, and Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl. Z is (CH2) n or (CH2) n1 O(CH2) n2 R 2 is an optionally substituted aryl or heteroaryl group. The variable n is an integer from 1 to 5, the variable n1 is an integer from 0 to 4, the variable n2 is an integer from 0 to 4, and n1+n2=n-1.

Description

[Technical field]

[0001] (STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT)

[0001] This invention was made with Government support under Grant R42NS115184 awarded by the National Institutes of Health. The Government has certain rights in the invention. [Background technology]

[0002]

[0002] Mitochondrial dysfunction may be involved in various neurodegenerative diseases, and defective mitochondrial fusion and fission may be particularly problematic in this regard, especially when unbalanced fusion and fission lead to mitochondrial fragmentation. There are many neurodegenerative diseases in which mitochondrial dysfunction is involved, such as Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease.

[0003]

[0003] Mitochondrial fusion is initiated by mitofusin (MFN) proteins embedded in the outer mitochondrial membrane. The extraorganelle domain of this protein spans the cytoplasmic space and interacts with proteins on neighboring mitochondria. The physically associated organelles form oligomers of various sizes. Mitofusins ​​then induce fusion of the outer mitochondrial membrane via GTPase catalysis. Aberrant mitofusin activity is thought to be a major factor in mitochondrial-based neurodegenerative diseases. For these reasons, mitofusins ​​are interesting targets for drug development.

[0004]

[0004] Although several chemicals that target mitofusins ​​have been discovered, most of them do not exhibit suitable pharmacokinetic properties for in vivo use. US Patent Application Publication Nos. 2020 / 0345668 and 2020 / 0345669 describe various 6-phenylhexanamide compounds and their structural variants. These can activate mitofusins, have acceptable pharmacokinetic profiles, and show blood-brain barrier fractionation tendencies as evidenced by PAMPA (Passive Artificial Blood-Brain Barrier Membrane Permeability Assay) values.

[0005] BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Not applicable. Summary of the Invention

[0006]

[0006] The present disclosure relates generally to mitofusin activation, and more specifically to compositions comprising mitofusin activators having a terminal cycloalkyl or heterocycloalkyl group in which an atom in the ring is bonded to a carbonyl group.

[0007]

[0007] As mentioned above, various 6-phenylhexanamide compounds are potent mitofusin activators that may have good pharmacokinetic properties. N-(4-hydroxycyclohexyl)-6-phenylhexanamide (Formula 1) is a representative example of a mitofusin activator in this class of compounds.

[0008] [ka]

[0009]

[0008] As described herein, the manner in which the cyclic moiety is attached to the carbonyl group of the mitofusin activator is surprisingly permissive. That is, instead of attaching the cyclic moiety to the carbonyl group via an exocyclic nitrogen atom as in formula 1, the cyclic moiety may be attached directly to the carbonyl group by an endocyclic atom (e.g., an endocyclic nitrogen atom or an endocyclic carbon atom) while still retaining its strong mitofusin activating properties. Even more surprisingly, attaching the cyclic moiety to the carbonyl group in this manner allows for considerable structural diversity in the linker added to the carbonyl group, e.g., the linker length can vary more than is feasible for analogs of formula 1. Attaching the carbonyl group to an endocyclic atom can improve pharmacokinetic properties in some cases.

[0010]

[0009] Accordingly, the present disclosure provides a composition comprising a mitofusin activator having a structure represented by Formula 2, a stereoisomer thereof, or a pharma ceutically acceptable salt thereof.

[0011] [ka]

[0012] In formula 2, G is N or CH, and A is an optionally substituted 5- or 6-membered cycloalkyl or heterocycloalkyl ring. X is (CH 2 ) 3 , O.C.H. 2 CH 2 , C.H. 2 OCH 2 , C.H. 2 CH 2 O, Cyc, C.H. 2 Cyc, N.R. 1 (CH 2 ) 3 , N.R. 1 OCH 2 CH 2 , N.R. 1 CH 2 OCH 2 , N.R. 1 CH 2 CH 2 O or NR 1 Cyc. R1 is H or C 1 ~C 6 Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl. Z is (CH 2 ) n or (CH 2 ) n1 O(CH 2 ) n2 where n is an integer from 1 to 5, 1 is an integer from 0 to 4, and n 2 is an integer from 0 to 4, and n 1 +n 2 = n-1. 2 is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl group in any embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In any embodiment herein, X is CH 2 , Cyc, or CH 2 The variable substituents may be selected such that when G is Cyc, then G is not CH.

[0014] The 5- or 6-membered cycloalkyl or heterocycloalkyl ring or the optionally substituted aryl or heteroaryl group in formula 2 may optionally contain one or more of the following groups at any position: amine, alkylamine, amide, alkylamide, alkoxy, aryloxy, hydroxyalkyl, azo, halogen (F, Cl, Br, I), C 1~8 Alkyl, C 1 ~C 8 Carbonyl (acyl), carboxylic acid or carboxylic acid ester, cyano, C 3~8 Cycloalkyl, C 3~8 Heteroaryl, C 3~8 Heterocyclyl, C 6 ~C 10Optionally substituted with aryl, hydroxy, thiol, thioether, sulfoxide, sulfone, and sulfonamide, some of which are optionally substituted with acetamide, alkoxy, amino, azo, Br, C 1~8 Alkyl, carbonyl, carboxyl, cyano, C 3~8 Cycloalkyl, C 3~8 Heteroaryl, C 3~8 Heterocyclyl may be further substituted with hydroxy, halogen (F, Cl, Br, I), indole, nitrile, phenyl, sulfoxide, sulfone, sulfonamide, and / or thiophene. Heterocyclyl groups may contain one or more N, O, or S atoms within their ring structure. Any alkyl or cycloalkyl group may be optionally substituted in its carbon chain or ring with one or more heteroatoms or groups containing heteroatoms as side groups.

[0015]

[0012] R 2 Suitable aryl or heteroaryl groups that may be include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, tetrahydronaphthyl, benzofuranyl, benzothienyl, indolyl, benzopyrazolyl, coumarinyl, isocoumarinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, or isomers thereof. These aryl or heteroaryl groups may be optionally substituted as further specified above.

[0016] In the mitofusin activator described herein, R 2 can be an optionally substituted phenyl group. The phenyl group can be substituted with one or more of the following groups: amine, alkylamine, amide, alkylamide, alkoxy, aryloxy, hydroxyalkyl, azo, halogen (F, Cl, Br, I), C 1~8 Alkyl, C 1~C 8 Carbonyl (acyl), carboxylic acid or carboxylic acid ester, cyano, C 3~8 Cycloalkyl, C 3~8 Heteroaryl, C 3~8 Heterocyclyl, C 6 ~C 10 It may be optionally substituted with aryl, hydroxy, thiol, thioether, sulfoxide, sulfone, and sulfonamide. The alkyl or cycloalkyl group may be optionally substituted in its carbon chain or ring with one or more heteroatoms or groups containing heteroatoms as side groups. The optional substitutions on the phenyl group may be at any vacant position of the phenyl ring. There may be 0, 1, 2, 3, 4, or 5 optional substitutions.

[0017] In some examples, the 5- or 6-membered cycloalkyl or heterocycloalkyl ring may be selected from the group below, which rings may further bear optional substitutions at vacant positions:

[0018] [ka]

[0019] [ka]

[0020]

[0015] In more specific examples, the 5- or 6-membered cycloalkyl or heterocycloalkyl may be an optionally substituted piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, cyclopentyl, or cyclohexyl group. In some or other examples, the 5- or 6-membered cycloalkyl or heterocycloalkyl may be an optionally substituted piperidinyl, piperazinyl, morpholinyl, or cyclohexyl group.

[0021]

[0016] In some or alternative even more specific examples, G may be N and A may represent an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group. Such mitofusin activators may have a structure represented by formula 5.

[0022] [ka]

[0023] In formula 5, J is a bond, CH(hal), C(hal) 2 , CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 and Q is an optional substitution as specified above. For the variable substituents of formula 3, hal is halogen (F, Cl, Br, I), R 3 is H or C 1 ~C 6 is alkyl, R 4 and R 5 are independently H, C 1 ~C 6 Alkyl or C 1 ~C 6 In yet more specific examples, G may be N and A may represent an optionally substituted piperidinyl, piperazinyl, or morpholinyl group, where J is CH(hal), C(hal), 2 , CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 and Q is optionally substituted, the variable substituents being as defined above.

[0024] In some instances, A may represent an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group, as defined in 53, and X is (CH 2 ) 3, 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl, where Z and R 2 In some examples, A may represent an optionally substituted piperidinyl, piperazinyl, or morpholinyl group, and X is (CH 2 ) 3 , 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl, where Z and R 2 may be as defined above. In more specific examples of mitofusin activators, Z is (CH 2 ) n or O(CH 2 ) n-1 In the mitofusin activator, R 2 may represent an optionally substituted phenyl group.

[0025] In some examples of mitofusin activators defined by formula 5, A may represent an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0026] In some examples, A may represent an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group as defined in formula 5, and X is OCH 2 CH 2 , C.H. 2 OCH 2 , C.H. 2 CH 2 O or CH 2 Cyc, where Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl; Z and R 2 may be as defined above. In more detailed examples of such mitofusin activators, Z is (CH 2 ) n or O(CH2 ) n-1 where X and Z are simultaneously each CH 2 CH 2 O and O(CH 2 ) n-1 When not, n is an integer from 2 to 5. In still more detailed examples of such mitofusin activators, A may be an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0027] In some examples, A may be an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl, as defined in formula 5; X may be 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl; Z and R may be optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl, as defined in formula 5; 2 may be as defined above. In more detailed examples of such mitofusin activators, Z is (CH 2 ) n or O(CH 2 ) n-1 where n is an integer from 2 to 5. In still more detailed examples of such mitofusin activators, A may represent an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0028]

[0021] In a more specific example, the mitofusin activator disclosed in the present specification may have a structure represented by the following formulas 6 to 8.

[0029] [ka] [ka] [ka]

[0030] In formula 6, o is an integer from 4 to 8, or preferably an integer from 5 to 7; in formulas 7 and 8, p is an integer from 3 to 8, or an integer from 4 to 6, or preferably an integer from 4 to 5. Q represents one or more optional substitutions on the phenyl group or on the 5- or 6-membered heterocycle, and each Q, if present, may be independently selected. In some examples, the 5- or 6-membered heterocycle may be an optionally substituted piperidinyl, piperazinyl, or morpholinyl group. The other variable substituents are as defined above.

[0031]

[0022] In even more specific examples, the mitofusin activator may have a structure represented by the following formulas 9 to 16 or stereoisomers thereof:

[0032] [ka] [ka] [ka]

[0033] [ka] [ka] [ka]

[0034] [ka] [ka]

[0035] In some examples, A may be an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl, as defined in formula 5, and X is NR 1 (CH 2 ) 3 or X may be NR 1 (CH 2 ) 3 , N.R. 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 (1,3-cyclobutyl), and Z and R 2 may be as defined above. In a more specific example, R 1 In any of the foregoing, Z can be H. In more specific examples of such mitofusin activators, Z is (CH 2 ) n or O(CH 2 ) n-1 where n is an integer from 1 to 4. In a more specific example, X is NR 1 (CH 2 ) 3 Z may be (CH 2 ) n where n is an integer from 1 to 4, and preferably R 1 can be H.

[0036] In still more detailed examples, A may represent an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0037] In some examples, A may represent an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group, as defined in formula 5, and X is NR 1 OCH 2 CH 2 , N.R. 1 CH 2 OCH2 , N.R. 1 CH 2 CH 2 O or NR 1 Cyc, where Cyc can be 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl; Z and R 2 may be as defined above. In some embodiments, R 1 In any of the foregoing, Z can be H. In more specific examples of such mitofusin activators, Z is (CH 2 ) n or O(CH 2 ) n-1 where X and Z are simultaneously each NR 1 CH 2 CH 2 O and O(CH 2 ) n-1 When not, n is an integer from 1 to 4. In more detailed examples, A may represent an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0038] In some embodiments, A may represent an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group, as defined in formula 5, and X is NR 1 (1,2-cyclopentyl), NR 1 (1,3-cyclopentyl), NR 1 (1,2-cyclohexyl), NR 1 (1,3-cyclohexyl), or NR 1 (1,4-cyclohexyl), and Z and R 2 may be as defined above. In some embodiments, R 1 In any of the foregoing, Z can be H. In more specific examples of such mitofusin activators, Z is (CH 2 ) n or O(CH 2 )n-1 where n is an integer from 1 to 4. In a more detailed example, A may represent an optionally substituted piperidinyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxypiperidinyl.

[0039]

[0027] In a more specific example, the mitofusin activator disclosed in the present specification may have a structure represented by the following formulas 17 to 19.

[0040] [ka] [ka]

[0041] [ka]

[0042] In formula 17, o is an integer from 5 to 7 or 4 to 6, and in formulas 18 and 19, p is an integer from 4 to 6 or 3 to 5. Q represents one or more optional substitutions on the phenyl group or on the 5- or 6-membered heterocycle, and each Q, if present, can be independently selected. In some examples, the 5- or 6-membered heterocycle can be an optionally substituted piperidinyl, piperazinyl, or morpholinyl group. The other variable substituents are as defined above.

[0043] In an even more specific example, the mitofusin activator may have a structure represented by formula 20 or a stereoisomer thereof:

[0044] [ka]

[0045]

[0029] In another example of the mitofusin activator disclosed herein, the 5- or 6-membered cycloalkyl or heterocycloalkyl may be an optionally substituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopentyl, or cyclohexyl group when G is CH. Preferably, A may represent an optionally substituted cyclopentyl or cyclohexyl group. Such a mitofusin activator may have a structure represented by formula 21 or a stereoisomer thereof.

[0046] [ka]

[0047] In formula 21, J is a bond, CH(hal), C(hal) 2 , CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 and Q is any substitution as specified above. In formula 21, hal is halogen (F, Cl, Br, I), R 3 is H or C 1 ~C 6 is alkyl, R 4 and R 5 are independently H, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments, J is a bond, O, or NR 4 and thus A represents an optionally substituted cyclohexyl group. 3 or CHR 4 In certain instances, A may represent a 4-hydroxycyclohexyl group, and the other variable substituents may be as described above.

[0048] In some examples, A may represent an optionally substituted cyclohexyl group, as defined in formula 21, and X is NR1 (CH 2 ) 3 , N.R. 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 (1,3-cyclobutyl). 1 In the above, H or C 1 ~C 6 Z and R may be alkyl. 2 may be as defined above. In more detailed examples of such mitofusin activators, Z is (CH 2 ) n or O(CH 2 ) n-1 where n is an integer from 2 to 4. 1 In various examples of such mitofusin activators, X can be H. In some examples, X is NR 1 (CH 2 ) 3 Z may be (CH 2 ) n where n is an integer from 2 to 4. In some examples, X is NR 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 (1,3-cyclobutyl), and Z may be (CH 2 ) n and O(CH 2 ) n-1 and n is an integer from 2 to 4. In a more detailed example, A may be an optionally substituted cyclohexyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxycyclohexyl.

[0049] In some examples, A may represent an optionally substituted cyclohexyl group as defined and designated in formula 21, and X is NR 1 OCH 2 CH 2 , N.R. 1 CH2 OCH 2 , or NR 1 CH 2 CH 2 It may be O. 1 is H or C 1 ~C 6 Z and R may be alkyl. 2 may be as defined above. 1 In an example of such a mitofusin activator, Z can be H. In a more detailed example of such a mitofusin activator, Z can be (CH 2 ) n or O(CH 2 ) n-1 where X and Z are simultaneously each NR 1 CH 2 CH 2 O and O(CH 2 ) n-1 When not, n is an integer from 2 to 4. In more detailed examples, A may represent an optionally substituted cyclohexyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxycyclohexyl.

[0050] In some embodiments, A may represent an optionally substituted cyclohexyl group as defined in formula 21 and designated above, and X is NR 1 (1,2-cyclopentyl), NR 1 (1,3-cyclopentyl), NR 1 (1,2-cyclohexyl), NR 1 (1,3-cyclohexyl), or NR 1 (1,4-cyclohexyl). 1 is H or C 1 ~C 6 Z and R may be alkyl. 2 may be as defined above. 1 In examples of such mitofusin activators, Z can be H. In more detailed examples of such mitofusin activators, Z can be (CH2 ) n or O(CH 2 ) n-1 where n is an integer from 2 to 4. In a more detailed example, A may represent an optionally substituted cyclohexyl group, where J is CHOR 3 or CHR 4 In an even more detailed example, A can be 4-hydroxycyclohexyl.

[0051]

[0033] In a more specific example, the mitofusin activator disclosed in the present specification may have a structure represented by the following formulas 22 to 27.

[0052] [ka] [ka]

[0053] [ka] [ka] [ka] [ka]

[0054] In formulae 22 and 23, o is an integer of 4 to 6, and in formulae 24 to 27, p is an integer of 2 to 4.

[0055]

[0034] In even more specific examples, the mitofusin activator may have a structure represented by the following formulas 28-36 or stereoisomers thereof:

[0056] [ka] [ka] [ka]

[0057] [ka] [ka] [ka]

[0058] [ka] [ka] [ka]

[0059]

[0035] Mitofusin activators may exist as a mixture of stereoisomers (enantiomers or diastereomers depending on the structure) or may exist as a single enantiomer or diastereomer. Suitable techniques for resolving stereoisomers of mitofusin activators or synthetic techniques for producing a particular stereoisomer of a mitofusin activator will be known to those skilled in the art. In a non-limiting example, a mitofusin activator in which A is a 4-hydroxypiperidine group may include the R-enantiomer of the 4-hydroxypiperidine group.

[0060]

[0036] As used herein, the term "pharmaceutical acceptable salt" refers to an organic or inorganic salt of the disclosed compound that has a particular toxicity and / or biodistribution property. 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, acid tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and / or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt). A pharma- ceutically acceptable salt can have a counterion present to balance the charge of the parent compound. More than one counterion can be present. When multiple counterions are present, the compound can be present as a mixture of pharma- ceutically acceptable salts.

[0061]

[0037] Pharmaceutically acceptable salts and / or hydrates of mitofusin activators may be present in the compositions of the present disclosure. As used herein, the term "pharmaceutical acceptable solvates" refers to associations between one or more solvent molecules and the mitofusin activators of the present disclosure or salts thereof, which have specific toxicity and / or biodistribution properties. Examples of solvents that can form pharmaceutical 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 "pharmaceutical acceptable hydrates" refers to the mitofusin activators of the present disclosure or salts thereof, which further include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, which have specific toxicity and / or biodistribution properties.

[0062]

[0038] The mitofusin activators described herein may be formulated with one or more pharma- ceutically acceptable additives (carriers) known to those skilled in the art. As used herein, the term "pharma- ceutically acceptable additive" refers to a substance or component that, when administered to a subject, does not cause unacceptable loss of pharmacological activity or unacceptable adverse side effects. Examples of "pharma- ceutically acceptable additives" include, but are not limited to, solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, and absorption delaying agents, provided that these substances do not cause significant side effects and are not incompatible with the mitofusin activators in the composition. Examples of additives are described, for example, in Remington's Pharmaceutical Sciences (AR Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005), the United States Pharmacopeia (USP29), the National Formulary (NF24), the USP Convention, Rockville, Maryland, 2005 ("USP / NF") or newer editions, and in the ingredients listed in the FDA's continuously updated "Inactive Ingredient Search" online database. Additional useful ingredients not listed in the USP / NF can also be used. Such formulations may include a therapeutically effective amount of one or more mitofusin activators, optionally as salts, hydrates, and / or solvates, together with an appropriate amount of additives to provide a suitable dosage form for administration to a subject.

[0063]

[0039] The composition of the present disclosure may be stable under certain storage conditions. A "stable" composition refers to a composition that has sufficient stability to be stored at a convenient temperature, such as 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 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years.

[0064]

[0040] The composition of the present disclosure may be prepared for a desired administration method, which may include, but is not limited to, parenteral, pulmonary, oral, topical, transdermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal, epidural, ophthalmic, pulmonary, epidural, buccal, vaginal, and rectal administration. The composition may be administered in combination with one or more other agents, or with other biologically active or biologically inactive agents.

[0065]

[0041] Controlled release (or sustained release) compositions may be formulated to extend the activity of mitofusin activators and reduce the frequency of administration. Controlled release compositions may be used to affect the onset of action or other characteristics, such as the plasma concentration of mitofusin activators, and thus the occurrence of side effects. Controlled release compositions may be designed to initially release one or more mitofusin activators in an amount sufficient to produce a desired therapeutic effect, and gradually and continuously release another amount of mitofusin activators to maintain a level of therapeutic effect over an extended period of time. To maintain a nearly constant concentration of mitofusin activators in the body, mitofusin activators may be released at a rate sufficient to compensate for the amount metabolized or excreted from the subject. Controlled release may be stimulated by a variety of factors, such as changes in pH, changes in temperature, enzymes, water, or other physiological conditions or molecules.

[0066]

[0042] The agents or compositions described herein may be used in combination with another treatment, such as those described below. Thus, in addition to the treatments described herein, the subject may be provided with another treatment known to be effective in treating the disease, disorder or condition targeted by the mitofusin activator, or a related disease, disorder or condition.

[0067]

[0043] The mitofusin activators of the present disclosure can stimulate mitochondrial fusion, enhance mitochondrial fitness, and enhance mitochondrial intracellular trafficking. Thus, in another aspect of the present disclosure, a therapeutically effective amount of one, combination, or pharma- ceutically acceptable salt of the mitofusin activators of the present disclosure can be administered to a subject suffering from or suspected of suffering from a mitochondrial-related disease, illness, or condition. The subject can be a human or another mammal suffering from or suspected of suffering from a mitochondrial-related disease, illness, or condition.

[0068]

[0044] The mitochondrial-related disease, disorder or condition may be a genetic or non-genetic disease, physical injury, and / or chemical injury of the peripheral nervous system (PNS) or central nervous system (CNS). In some embodiments, in the method of treating a disease, disorder or condition for which a mitofusin activator is required, the PNS disease or CNS disease may be selected from one or a combination of the following: a chronic neurodegenerative condition in which mitochondrial fusion, adaptation, or transport is impaired; a disease or condition associated with mitofusin-1 (MFN1) or mitofusin-2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, or movement disorder; Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, hereditary motor and sensory neuropathies, autism, autosomal dominant optic atrophy (ADOA), muscular dystrophy, Lou Gehrig's disease, cancer, mitochondrial myopathy, diabetic deafness (DAD), Degenerative neuromuscular conditions such as Leber's Hereditary Optic Neuropathy (LHON), Leigh's syndrome, subacute sclerosing encephalopathy, neuropathy, ataxia, retinitis pigmentosa and ptosis (NARP), myoneuropathic gastrointestinal encephalopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy, encephalomyopathy with hyperlactatemia and stroke-like symptoms (MELAS), mtDNA depletion, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), autonomic neuropathy mitochondrial myopathy, mitochondrial channelopathy, or pyruvate dehydrogenase complex deficiency (PDCD / PDH), diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and related disorders involving crush injury, SCI, traumatic brain injury (TBI), stroke, optic nerve injury, and / or axonal transection.

[0069] Other mitochondrial-related diseases, disorders, or conditions that may be treated with the compositions disclosed herein include Alzheimer's disease, ALS, Alexander disease, Alpers syndrome, Alpers-Huttenlocher syndrome, α-methylacyl-CoA racemase deficiency, Andermann syndrome, Artz syndrome, ataxic neuropathy spectrum, ataxia (e.g., with oculomotor apraxia, autosomal dominant cerebellar ataxia, hearing loss, and narcolepsy), autosomal recessive spastic ataxia of Charlevoix-Saguenay type, and others. Charlevoix-Saguenay, Batten disease, beta-propeller protein-associated neurodegeneration, cerebro-oculofacial syndrome (COFS), corticobasal degeneration, CLN1 disease, CLN10 disease, CLN2 disease, CLN3 disease, CLN4 disease, CLN6 disease, CLN7 disease, CLN8 disease, cognitive impairment, congenital analgesia with anhidrosis, dementia, familial encephalopathy with neuroserpin inclusion bodies, familial British dementia, familial Danish dementia, fatty acid hydroxylase-associated neurodegeneration, Friedreich's ataxia, Gerstmann-Sträussler-Scheinker syndrome, 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 paraplegia spastic paralysis, infantile-onset spinocerebellar ataxia, early-onset primary lateral sclerosis, Kennedy disease, kuru disease, Leigh disease, Marinesco-Sjogren syndrome, mild cognitive impairment (MCI), mitochondrial membrane protein-associated neurodegeneration, motor neuron disease, monomeric muscular atrophyamyotrophy), motor neuron disease (MND), multiple system atrophy, multiple system atrophy with orthostatic hypotension (Shy-Drager syndrome), multiple sclerosis, multiple system atrophy, neurodegeneration in Down's syndrome (NDS), age-related neurodegeneration, neurodegeneration with cerebral iron accumulation, neuromyelitis optica, pantothenate kinase-associated neurodegeneration, opsoclonus-myoclonus, prion diseases, progressive multifocal leukoencephalopathy, Parkinson's disease, Parkinson's disease-related disorders, polycystic lipomembranous dysplasia with sclerosing leukoencephalopathy, prion diseases, progressive external ophthalmoplegia, riboflavin transporter deficiency neuropathies, Sandhoff disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), striatonigral degeneration, transmissible spongiform encephalopathies (prion diseases), and / or Wallerian-like degeneration.

[0070]

[0046] Further mitochondrial-related diseases, disorders, or conditions that may be treated with the compositions disclosed herein include abulia; agraphia; alcoholism; dyslexia; alien hand syndrome; Allan Herndon Dudley syndrome; alternating hemiplegia of childhood; Alzheimer's disease; amaurosis fugax; amnesia; ALS; aneurysm; Angelman syndrome; anosognosia; aphasia; apraxia; arachnoiditis; Arnold-Chiari malformation; somatosensory cognition; Asperger syndrome; ataxia; attention deficit hyperactivity disorder; ATR-16 syndrome; auditory processing disorder; autism spectrum; Behcet's disease; bipolar disorder; Bell's palsy; brachial plexus injury; brain injury; brain injury; brain tumor; Brody myopathy; Canavan disease; Capgras syndrome; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; centronuclear myopathy; head injury (cephalic disorder);cerebral aneurysm;cerebral arteriosclerosis;cerebral atrophy;cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL);cerebral dysplasia-neuropathy-ichthyosis-keratoderma syndrome (CEDNIK syndrome);cerebral gigantism;cerebral palsy;cerebral vasculitis;cerebral 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;compressive neuropathy;congenital bilateral facial palsy;corticobasal degeneration;cranial arteritis;craniosynostosis;Creutzfeldt-Jakob disease;accumulated trauma disorder;Cushing's syndrome;cyclothymic disorder;cyclic vomiting syndrome (CVS); Cytomegalic inclusion body disease (CIBD);Cytomegalovirus infection;Dandy-Walker syndrome;Dawson's disease;Domorsia syndrome;Dejerine-Klumpke palsy;Dejerine-Sottas disease;Delayed sleep phase syndrome;Dementia;Dermatomyositis;Developmental coordination disorder;Diabetic neuropathy;Diffuse sclerosis;Diplopia;Disturbance of consciousness;Down syndrome;Dravet syndrome;Duchenne muscular dystrophy;Dysarthria;Autonomic neuropathy;Dyscalculia;Dysgraphia;Movement disorder;Dyslexia;Dystonia;Empty Sella syndrome;Encephalitis;Encephalocele;Hemangiomatosis of the trigeminal region of the brain;Encopresis;Enuresis;Epilepsy;Epilepsy and intellectual disability in women;Erb's palsy;Erythromelalgia;Essential tremor;Exploding head syndrome;Fabry disease;Fahr's syndrome;Syncope;Family spastic paraplegia;Febrile convulsions;Fisher syndrome;Friedreich's ataxia;Fibromyalgia;Faubille syndrome;Fetal alcohol syndrome;Fragile X syndrome;Fragile X-associated tremor / ataxia syndrome (FXTAS);Gaucher disease;Generalized epilepsy febrile convulsions plus;Gerstmann's syndrome;Giant cell arteritis;Giant cell inclusion disease;Globoid cell leukodystrophy;Ectopic gray matter;Guillain-Barré syndrome;Generalized anxiety disorder;HTLV-1-associated myelopathy;Hallervorden-Spatz syndrome;Head injury;Hemifacial spasm;Hereditary spastic paraplegia;Hereditary polyneuropathic ataxia;Herpes zoster oticus;Hirayama syndrome;Hirschsprung's disease;Holmes-Ardie syndrome;Holoprosencephaly;Huntington's disease;Hydroanencephaly;Hydrocephalus;Hypercortisolism;Hypoxia;Immune-mediated encephalomyelitis encephalomyelitis);inclusion body myositis;incontinentia pigmenti;Refsum disease, infantile;infantile spasms;inflammatory myopathy;intracranial cyst;intracranial hypertension;isodicentric duplication of chromosome 15;Joubert syndrome;Karak syndrome;Kerns-Sayre syndrome;Kinsbourne syndrome;Klein-Levin syndrome;Klippel-Feil syndrome;Krabbe disease;Kuffour-Rakeb syndrome;Lafora disease;Lambert-Eaton myasthenic syndrome;Landau-Kleffner syndrome;lateral medullary (Wallenberg) syndrome;learning disability;Leigh disease;Lennox-Gastaut syndrome;Lesch-Nyhan syndrome;leukodystrophy;leukoencephalopathy with vanishing white matter matter);Lewy body dementia;lissencephaly;locked-in syndrome;Lou Gehrig's disease (amyotrophic lateral sclerosis (ALS));lumbar discopathy;lumbar spinal stenosis;Lyme disease - neurological sequelae;Machado-Joseph disease (spinocerebellar ataxia type 3);megaloencephalopathy;megalopsia;post-landing syndrome (mal de debarquement);macocephalous leukoencephalopathy with subcortical cysts;megaloencephaly;Melkersson-Rosenthal syndrome;Ménière's disease;meningitis;Menkes disease;metachromatic leukodystrophy;microcephaly;micropsia;migraine;Miller-Fisher syndrome;mild stroke (transient ischemic attack);misophonia;mitochondrial myopathy;Moebius syndrome; monomelic amyotrophy; Morvan syndrome; motor neuron disease (see ALS); motor disability; Moyamoya disease; mucopolysaccharidosis; multiinfarct dementia; multifocal motor neuropathy; multiple sclerosis; multiple system atrophy; muscular dystrophy; myosyelitis; myasthenia gravis; generalized myelinoclastic diffuse sclerosis sclerosis);infantile myoclonic encephalopathy;myoclonus;myopathy;myotonia congenita;narcolepsy;neuro-Behçet's disease;neurofibromatosis;neuroleptic malignant syndrome;AIDS neurological symptoms;neurological sequelae of lupus;neuromyotonia;neuronal ceroid-lipofuscinosis;neuronal migration disorder;neuropathy;neuropathy;Niemann-Pick disease;non-24-hour sleep-wake disorder;nonverbal learning disorder;O'Sullivan-McLeod syndrome;occult neuralgia;occult spinal dysraphism sequence); Ohtahara syndrome; Olivopontocerebellar atrophy; Opsoclonus-myoclonus syndrome; Optic neuritis; Orthostatic hypotension; Otosclerosis; Overuse syndrome; Recurrent vision; Paresthesia; Parkinson's disease; Paramyotonia congenita; Paraneoplastic disorder; Seizures; Parry-Romberg syndrome; Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS); Pelizaeus-Merzbacher disease; Periodic paralysis; Peripheral neuropathy; Pervasive developmental disorder; Phantom limb / phantom pain; Photosensitive sneeze reflex; Phytanic acid storage disease; Pick's disease; Nerve compression nerve);pituitary tumor;pmg;polyneuropathy;polio;polymicrogyria;polymyositis;porencephaly;post-polio syndrome;postherpetic neuralgia (PHN);orthostatic hypotension;Prader-Willi syndrome;primary lateral sclerosis;prion disease;progressive facial hemifacial atrophy;progressive multifocal leukoencephalopathy;progressive supranuclear palsy;prosopagnosia;pseudotumor cerebri;quaternal blindness;tetraplegia;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's disease;REM sleep behavior disorder;repetitive stress injury;restless legs syndrome;retrovirus-associated myelopathy;Rett syndrome;Reye's syndrome;Rhythmic movement disorder;Romberg syndrome;Choreas;Sandhoff disease;Schilder's disease (two different conditions);Schisencephaly;Sensory processing disorder;Septo-optic dysplasia;Shaken baby syndrome;Herpes zoster;Shy-Drager syndrome;Sjogren's syndrome;Sleep apnea;Sleeping sickness;Snatiation;Sotos syndrome;Spasticity;Spina bifida;Spinal cord injury;Spinal tumor;Spinal muscular atrophy;Spinobulbar muscular atrophy;Spinocerebellar ataxia;Split encephaly;Steele-Richardson-Olszewski syndrome;Stiff person syndrome;Stroke;Sturge-Weber syndrome;Stuttering syndrome;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's disease;thoracic outlet syndrome;painful tics;Todd's palsy;Tourette's syndrome;toxic encephalopathy;transient ischemic attack;transmitting spongiform encephalopathy;transverse myelitis;traumatic brain injury;tremor;trichotillomania;trigeminal neuralgia;tropical spastic paraparesis;trypanosomiasis;tuberous sclerosis;22q13 deletion syndrome; Unverricht-Lundborg disease; vestibular schwannoma (acoustic neuroma); von Hippel-Lindau disease (VHL); viliuisk encephalomyelitis (VE); Wallenberg syndrome; West syndrome; whiplash injury; Williams syndrome; Wilson's disease; y-linked hearing impairment; and / or Zellweger syndrome.

[0071] Each of the conditions, disorders, diseases, and conditions described herein may benefit from the compositions and methods described herein. Typically, treating a condition, disorder, disease, or condition includes preventing or delaying the onset of clinical symptoms in a mammal that may be affected or susceptible to the condition, disorder, disease, or condition, but has not yet manifested clinical or subclinical symptoms. Treating also includes inhibiting the condition, disorder, disease, or condition (e.g., arresting or attenuating the progression of the disease or at least one of the clinical or subclinical symptoms). Treating also includes alleviating the disease (e.g., reducing the condition, disorder, disease, or condition, or at least one of the clinical or subclinical symptoms). The benefit to a subject receiving treatment may be statistically significant or at least discernible by the subject or physician.

[0072] A mitochondrial-related disease, disorder, or condition may be a disease that is primarily caused by or secondarily associated with mitochondrial dysfunction, fragmentation, or loss of fusion, or that is associated with impaired function or structural unfolding of MFN1 or MFN2 catalytic activity. Mitochondrial dysfunction may occur due to genetic mutations in mitofusins ​​or other (nuclear or mitochondrial-encoding) genes, or due to physical, chemical, or environmental insults to the CNS or PNS.

[0073] In a detailed example, cancer chemotherapy-induced sensory and motor neuropathy can be prevented or treated by the composition of the present disclosure. Chemotherapy-induced peripheral neuropathy is one of the most common cancer chemotherapy complications, affecting 20% ​​of all patients and nearly 100% of patients receiving high-dose chemotherapy. Dose-dependent neurotoxicity of motor and sensory neurons can lead to chronic pain, hypersensitivity to heat, cold, mechanical stimuli, and / or impaired neuromuscular control. The most common chemotherapeutic agents involved in CIPN are platinum, vinca alkaloids, taxanes, epothilones, and the targeted proteasome inhibitor bortezomib.

[0074] CIPN most commonly affects peripheral sensory neurons, whose cell bodies are located in the dorsal root ganglion, which lacks the blood-brain barrier that protects other components of the central and peripheral nervous systems. Unprotected dorsal root ganglion neurons are more sensitive to neuronal hyperexcitation and innate immune system activation induced by circulating cytotoxic chemotherapeutic agents. CIPN can affect quality of life and cause disability, because, like other causes of neuralgia (e.g., postherpetic neuralgia and diabetic mononeuropathy), CIPN causes chronic neuropathic pain that is resistant to analgesic therapy. Motor nerve involvement typically manifests as loss of fine motor function, making handwriting difficult, buttoning clothes, or sewing difficult, and sometimes causing weakness and stamina in the upper and lower limbs. CIPN usually develops within a few weeks of chemotherapy and often improves after chemotherapy treatment is completed, but one-third to one-half of patients are left with pain, paresthesia, or movement abnormalities. Unfortunately, limiting chemotherapy administration due to CIPN can lead to delays, reductions, or interruptions in cancer treatment, potentially shortening survival.

[0075]

[0051] Mitochondrial dysfunction and oxidative stress are involved in CIPN. This is because abnormalities in ultrastructural morphology are observed, mitochondrial DNA transcription and replication are impaired, mitochondrial apoptotic pathways are induced, and pre-protection of mitochondria reduces experimental CIPN symptoms. Mitofusin activators can globally enhance mitochondrial function in injured neurons, increase mitochondrial transport to sites of neuronal injury, and promote in vitro neuronal repair / regeneration after chemotherapy injury. Thus, it is believed that mitofusin activators can reduce neuronal injury caused by chemotherapeutic agents in CIPN and promote regeneration / repair of damaged nerves caused by chemotherapeutic anticancer agents. Therefore, the present disclosure provides compositions and methods for treating cancer chemotherapy-induced nerve injury and neuropathy.

[0076] In another example, injuries in the CNS or PNS (e.g., CNS or PNS trauma, crush injury, SCI, TBI, stroke, optic nerve injury, or related diseases involving axotomy) may be treated with the compositions of the present disclosure. The CNS includes the brain and spinal cord, and the PNS is composed of the cranial nerves, spinal nerves, and autonomic nerves that connect to the CNS.

[0077]

[0053] Nervous system damage caused by mechanical, thermal, chemical, or ischemic factors can impair various nervous system functions, such as memory, cognition, language, and voluntary movement. In most cases, this is due to accidental crushing or severing of neural tracts, or is an unintended consequence of medical intervention that interrupts normal communication between neuronal cell bodies and their targets. Other types of damage can include disruption of the interrelationship between neurons and their supporting cells, or disruption of the blood-brain barrier.

[0078]

[0054] Mitofusin activators can rapidly reverse mitochondrial motility disorders in neurons from mice or patients with various genetic or chemotherapy-induced neurodegenerative diseases, axons damaged by chemotherapeutic agents, and axons severed by physical injury. Thus, mitofusin activators can promote regeneration / repair of physically damaged nerves, such as injuries from vehicles or sports, penetrating trauma from military or criminal acts, and iatrogenic injury during invasive medical procedures. Thus, the present disclosure provides compositions and methods for treating physical nerve injury.

[0079]

[0055] Mitochondrial motility is also involved in neuropathy, traumatic crush, and nerve injury due to amputation.After nerve laceration or crush injury, nerve regenerates and recovers neuromuscular function, or fails to regenerate and loses neuromuscular function permanently.Mitofusin activator can enhance mitochondrial transport and enable nerve regeneration after traumatic injury.

[0080]

[0056] The amount of mitofusin activator and additives to prepare a composition of a given dosage form may vary depending on the subject to be treated, the condition to be treated, and the form of administration. Of course, the unit content of mitofusin activator contained in each dose of a given dosage form does not need to be a therapeutically effective amount, and the required therapeutically effective amount may be achieved by administering each dose multiple times, and the therapeutic effect may be cumulative over time.

[0081]

[0057] The administration of the mitofusin activator of the present disclosure may be once or over a treatment period. For example, the mitofusin activator may be administered daily, weekly, biweekly, or monthly. For the treatment of acute conditions, the treatment period may be at least several days, and the administration may be at least once a day or continuously. In certain conditions, the treatment may be administered for several days to several weeks. For example, the treatment may last for one week, two weeks, or three weeks. For chronic conditions, the treatment may last for several weeks to several months, or even more than a year.

[0082] Toxicity and therapeutic efficacy of the compositions described herein are determined by standard pharmaceutical procedures in cell cultures or experimental animals, with LD 50 (a dose lethal to 50% of the population) and ED 50 The toxic to therapeutic dose ratio can be measured by determining the LD (the amount that is therapeutically effective in 50% of the population). 50 / ED 50 It is the therapeutic index that can be expressed as a ratio, and it is commonly understood in the art that a larger therapeutic index is most optimal.

[0083]

[0059] Embodiments disclosed in this specification include the following.

[0084] A. Compositions Comprising Mitofusin Activators. Mitofusin activators include

[0085] [ka]

[0086] or a pharma- ceutically acceptable salt thereof, wherein G is N or CH, A is an optionally substituted 5- or 6-membered cycloalkyl or heterocycloalkyl ring; 2 ) 3 , O.C.H. 2 CH 2 , C.H. 2 OCH 2 , C.H. 2 CH 2 O, Cyc, C.H. 2 Cyc, N.R. 1 (CH 2 ) 3 , N.R. 1 OCH 2 CH 2 , N.R. 1 CH 2 OCH 2 , N.R. 1 CH 2 CH 2 O or NR 1 Cyc;R 1 is H or C 1 ~C 6 alkyl, Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl; Z is (CH 2 ) n or (CH 2 ) n1 O(CH 2 ) n2 n is an integer from 1 to 5, 1 is an integer from 0 to 4, and n 2 is an integer from 0 to 4, and n 1 +n 2 = n-1; R 2 is an optionally substituted aryl or heteroaryl group.

[0087] B. A method of administering a mitofusin activator to a subject having or suspected of having a mitochondrial-associated disease, the method comprising administering to a subject having or suspected of having a mitochondrial-associated disease, disorder, or condition a therapeutically effective amount of a composition of A, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0088]

[0062] Embodiments A and B may have one or more of the following additional elements in combination.

[0089] Element 1: R 2 is an optionally substituted phenyl group.

[0090] Element 2: G is N and A represents an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group.

[0091] Element 3: Mitofusin activator

[0092] [ka]

[0093] or a stereoisomer thereof, wherein J is a bond, CH(hal), CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 where Q is an optional substitution; hal is a halogen; and R 3 is H or C 1 ~C 6 is alkyl, R 4 and R 5 are independent of each other, H, C 1 ~C 6 Alkyl or C 1 ~C 6 It is acyl.

[0094]

[0066] Element 4: J is CHOR 3or CHR 4 It is.

[0095] Element 5: X is (CH 2 ) 3 , 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl.

[0096] Element 6: Z is (CH 2 ) n or O(CH 2 ) n-1 and n is an integer from 2 to 5.

[0097] Element 7: A is 4-hydroxypiperidinyl.

[0098] Element 8: Mitofusin activator

[0099] [ka] [ka] [ka] [ka]

[0100] [ka] [ka] [ka] [ka]

[0101] or a stereoisomer thereof.

[0102] Element 9: X is NR 1 (CH 2 ) 3 , N.R. 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 (1,3-cyclobutyl).

[0103] Element 10: Z is (CH 2 ) n or O(CH 2 ) n-1 and n is an integer from 1 to 4.

[0104] Element 11: Mitofusin activator

[0105] [ka]

[0106] and its stereoisomers.

[0107] Element 12: G is CH and A represents an optionally substituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopentyl, or cyclohexyl group.

[0108] Element 13: Mitofusin activator

[0109] [ka]

[0110] or a stereoisomer thereof, wherein J is a bond, CH(hal), CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 where Q is an optional substitution; hal is a halogen; and R3 is H or C 1 ~C 6 is alkyl, R 4 and R 5 are independent of each other, H, C 1 ~C 6 Alkyl or C 1 ~C 6 It is acyl.

[0111] Element 14: Z is (CH 2 ) n or O(CH 2 ) n-1 and n is an integer from 2 to 4.

[0112] Element 15: A is 4-hydroxycyclohexyl.

[0113] Element 16: A mitofusin activator comprising:

[0114] [ka] [ka] [ka] [ka]

[0115] [ka] [ka] [ka] [ka]

[0116] [ka]

[0117] or a stereoisomer thereof.

[0118]

[0079] Element 17: The composition further comprises a pharma- ceutically acceptable excipient.

[0119] Element 18: The mitochondrial-related disease, disorder or condition is a genetic or non-genetic disease, physical injury, and / or chemical injury of the peripheral nervous system (PNS) or central nervous system (CNS).

[0120]

[0081] Element 19: The PNS or CNS disease is a chronic neurodegenerative condition in which mitochondrial fusion, adaptation, or transport is impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and / or movement disorders; a degenerative neuromuscular condition; Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathies; autism; autosomal dominant optic neuropathy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetic deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh's syndrome; subacute sclerosing encephalopathy; neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); myoneurogenic gastrointestinal encephalopathy (myoneurogenic gastrointestinal encephalopathy); The condition is one or more conditions selected from the group consisting of myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, hyperlactatemia and encephalomyopathy with stroke-like symptoms (MELAS); mtDNA depletion; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); autonomic neuropathy 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 involving axotomy; and combinations thereof.

[0121]

[0082] As a non-limiting example, examples of combinations applicable to A and B include, but are not limited to, 1 and 2 or 3; 1, 3 and 4; 1 and 3-5; 1 and 8; 1, 2 and 9; 1-3 and 9; 1-3, 9 and 10; 1 and 11; 1 and 12; 1, 12 and 13; 1, 9, 12 and 13; 1, 9, and 12-14; 1 and 16; 3 and 4; 3-5; 3 and 5; 3 and 6; 3 and 7; 3 and 9; 3, 4 and 9; 3, 4, 9 and 10; 3 and 7; 12 and 13; 12 and 14; 12-14; 4, 12 and 13; 4 and 12-14; 4, 12 and 15; 12 and 15; 12, 14 and 15; 4, 12, 14 and 15. Any of the above may be further combined with 17. Further examples of combinations applicable to B include any of the foregoing further combined with one or more of 17, 18, and 19.

[0122]

[0083] The present disclosure is further directed to the following non-limiting terms.

[0123] Article 1.

[0124] [ka]

[0125] A composition comprising a mitofusin activator having a structure represented by the following formula: wherein G is N or CH; A is an optionally substituted 5- or 6-membered cycloalkyl or heterocycloalkyl ring; X is (CH 2 ) 3 , O.C.H. 2 CH 2 , C.H. 2 OCH 2 , C.H. 2 CH 2 O, Cyc, C.H. 2 Cyc, N.R. 1 (CH 2 ) 3 , N.R. 1 OCH 2 CH 2 , N.R.1 CH 2 OCH 2 , N.R. 1 CH 2 CH 2 O or NR 1 Cyc, R 1 is H or C 1 ~C 6 alkyl, and Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl; Z is (CH 2 ) n or (CH 2 ) n1 O(CH 2 ) n2 And, n is an integer from 1 to 5, 1 is an integer from 0 to 4, and n 2 is an integer from 0 to 4, and n 1 +n 2 = n-1, R 2 is an optionally substituted aryl or heteroaryl group.

[0126] Article 2.R 2 The composition of clause 1, wherein is an optionally substituted phenyl group.

[0127] Clause 3. The composition of clause 1 or clause 2 (or the composition of clause 1) wherein G is N and A represents an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group.

[0128] Clause 4. The mitofusin activator

[0129] [ka]

[0130] or a stereoisomer thereof, In the formula, J is a bond, CH(hal), CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 and Q is any substitution, hal is a halogen and R 3 is H or C 1 ~C 6 is alkyl, R 4 and R 5 are independent of each other, H, C 1 ~C 6 Alkyl or C 1 ~C 6 The composition of claim 3, which is acyl.

[0131] Article 5.J CHOR 3 or CHR 4 The composition of claim 4,

[0132] Article 6.X. 2 ) 3 6. The composition of any one of clauses 3 to 5 (or the composition of clause 3), wherein R is 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl.

[0133] Article 7.Z (CH 2 ) n or O(CH 2 ) n-1 and n is an integer from 2 to 5.

[0134] Clause 8. The composition of any one of clauses 3 to 7 (or the composition of clause 6), wherein A is 4-hydroxypiperidinyl.

[0135] Article 9.R 2 The composition of any one of clauses 3 to 8 (or the composition of clause 6), wherein is optionally substituted phenyl.

[0136] Article 10. Mitofusin activators

[0137] [ka] [ka] [ka]

[0138] [ka] [ka] [ka] [ka]

[0139] [ka]

[0140] or a stereoisomer thereof.

[0141] Clause 11.X applies to the NR 1 (CH 2 ) 3 , N.R. 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 (1,3-cyclobutyl).

[0142] Article 12.Z (CH 2 ) n or O(CH 2 ) n-1 and n is an integer from 1 to 4.

[0143] Clause 13. The composition of any one of clauses 3 to 5, 11 or 12 (or the composition of clause 6 or clause 11) wherein A is 4-hydroxypiperidinyl.

[0144] Article 14.R 2 The composition of any one of clauses 3 to 5 or 11 to 13 (or the composition of clause 6 or clause 11), wherein

[0145] Article 15. Mitofusin activators

[0146] [ka]

[0147] 15. The composition of any one of clauses 3 to 5 or 11 to 14 (or the composition of clause 3), having the structure represented by

[0148] Clause 16. The composition of clause 1 or clause 2 (or the composition of clause 1) wherein G is CH and A represents an optionally substituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopentyl, or cyclohexyl group.

[0149] Article 17. Mitofusin activators

[0150] [ka]

[0151] or a stereoisomer thereof, In the formula, J is a bond, CH(hal), CHOR 3 , C.H.R. 4 , C.H.N.R. 4 R 5 , O, or NR 4 and Q is any substitution, hal is a halogen and R 3 is H or C 1 ~C6 is alkyl, R 4 and R 5 are independent of each other, H, C 1 ~C 6 Alkyl or C 1 ~C 6 The composition of any one of clauses 1, 2 or 16 (or the composition of clause 16), which is acyl.

[0152] Article 18.J CHOR 3 or CHR 4 The composition of clause 17.

[0153] Clause 19.X applies to the NR 1 (CH 2 ) 3 , N.R. 1 (1,2-cyclopropyl), NR 1 (1,2-cyclobutyl), or NR 1 19. The composition of any one of clauses 16 to 18 (or the composition of clause 17), wherein the moiety is (1,3-cyclobutyl).

[0154] Article 20.Z (CH 2 ) n or O(CH 2 ) n-1 20. The composition of any one of clauses 16 to 19 (or the composition of clause 19), wherein n is an integer from 2 to 4.

[0155] Clause 21. The composition of any one of clauses 16 to 20 (or the composition of clause 19), wherein A is 4-hydroxycyclohexyl.

[0156] Article 22.R 2 The composition of any one of clauses 16 to 21 (or the composition of clause 19), wherein is optionally substituted phenyl.

[0157] Article 23. Mitofusin activators

[0158] [ka] [ka]

[0159] [ka] [ka] [ka] [ka]

[0160] [ka] [ka] [ka]

[0161] 23. The composition of any one of clauses 16 to 22 (or the composition of clause 19), having the structure represented by

[0162] Clause 24. The composition of any one of clauses 1 to 23 (or the composition of clause 1), further comprising a pharma- ceutically acceptable excipient.

[0163] Clause 25. A method comprising administering a therapeutically effective amount of a composition of any one of clauses 1 to 24 (or a composition of any one of clauses 1 to 5 or 16 to 18), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof to a subject suffering from or suspected of suffering from a mitochondrial-related disease, disorder, or condition.

[0164] Clause 26. The method of clause 25, wherein the mitochondrial associated disease, disorder or condition is a genetic or non-genetic disease, physical injury, and / or chemical injury of the peripheral nervous system (PNS) or central nervous system (CNS).

[0165] Article 27. The PNS or CNS disease is a chronic neurodegenerative condition in which mitochondrial fusion, adaptation, and / or trafficking is impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and / or movement disorders; a degenerative neuromuscular condition; Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathies; autism; autosomal dominant optic neuropathy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetic deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh's syndrome; subacute sclerosing encephalopathy; neuropathy and movement disorders The method of clause 26, wherein the condition is one or more conditions selected from the group consisting of ataxia-retinitis pigmentosa-ptosis (NARP); myoclonus gastrointestinal encephalopathy (MNGIE); myoclonus epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, hyperlactatemia and encephalomyopathy with stroke-like symptoms (MELAS); mtDNA depletion; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); autonomic neuropathy 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 involving axotomy; and combinations thereof.

[0166]

[0084] In order to facilitate a better understanding of the present disclosure, examples of preferred or typical embodiments are given below. The following examples are not to be construed as limiting or defining the scope of the present invention.

[0167] (Example)

[0085] HPLC analysis was performed using a Kinetex C18 column (4.6 x 50 mm, 5 μm; mobile phase A: 0.0375% TFA (v / v) in water, mobile phase B: 0.01875% TFA (v / v) in acetonitrile) at 50°C with an absorption wavelength of 200 nm.

[0168]

[0086] LC-MS / MS (ESI) was performed using two systems. 1) A SHIMADZU LC-MS-2020 equipped with LABSOLUTION V5.72 analysis software and a CHROMALITH@FLASH RP-18E 25*2.0 mm column was operated at 50°C with a PDA (220 and 254 nm) detector. Data were obtained in the measurement MS mode (positive mode) with a measurement range of m / z = 100 to 1000. Drying gas (N 2 1) Flow rate: 15 L / min, DL voltage: 120 V and Quarry DC voltage: 20 V, or 2) Agilent 1200 / G6110A instrument equipped with Agilent ChemStation Rev.B.04.03 software and XBRIDGE C18 2.1*50 mm column was operated at 40 °C with DAD (220 nm) / ELSD detector. Data was obtained in the measurement MS mode (positive mode) with a measurement range of m / z = 100 to 1000. Drying gas (N 2 ) Flow rate: 10 L / min, 350° C., nebulizer pressure: 35 psi, capillary voltage: 2500 V. NMR spectroscopy was performed on a Brucker AVANCE NEO 400 MHz equipped with a 5 mm PABBO BB / 19F-1H / D Z-GRD probe.

[0169] Dose-response studies of mitofusin agonist fusion activity were performed at 37° C., 5% CO 2 Mfn1-KO MEFs or Mfn2-KO MEFs were cultured in -95% air. Cells were plated at 2x10 per well in a 6-well plate. 4Cells were seeded at a density of 100x on day 1 and compounds were added overnight at nine concentrations (0.5 nM-10 μM dissolved in DMSO). 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 captured using a Nikon Ti confocal microscope equipped with a 60× 1.3NA oil immersion objective in Krebs-Henseleit buffer (138 NaCl, 3.7 nM KCl, 1.2 nM KH 2 PO 4 , 15 nM glucose, 20 nM HEPES pH: 7.2-7.5, and 1 mM CaCl 2 ) at room temperature. Laser excitation was 549 nm with an emission wavelength of 590 nm for MitoTracker Orange and 306 nm with an emission wavelength of 405 nm for Hoescht. Images were analyzed using ImageJ and fusion activity was quantified as mitochondrial aspect ratio (length / width) as a percentage of the maximal response induced by compound 35, a known mitofusin activator. Response curves were interpolated using a sigmoidal model in Prism8 software. EC 50 Values ​​are reported as the mean with 95% confidence limits of at least three independent experiments.

[0170] [ka]

[0171] In vitro pharmacokinetic analysis was performed in duplicate using standard methods by WuXi AppTec Co.Ltd. (Shanghai, China). Plasma protein binding was measured by equilibrium dialysis as % binding = (1-[free compound in dialysate] / [total compound in retentate]) x 100. Plasma stability of 2 uM compound in clarified frozen-thawed plasma was evaluated by LC-MS / MS of the supernatant after protein precipitation. Data for 120 min are reported for studies including 0, 10, 30, 60, and 120 min. Liver microsomal stability of 1 uM compound in liver microsomes (0.5 mg / ml) was evaluated by LC / MS / MS of reaction extracts after 0, 5, 10, 20, 30, 60 min incubation.

[0172] Passive artificial blood-brain barrier membrane permeability assay (PAMPA-BBB) was performed by adding 150 μL of 10 μM compound (5% DMSO) to a PVDF membrane pre-coated with 5 μL of 1% brain polar lipid extract (porcine) / dodecane mixture and incubating at room temperature for 4 hours with shaking at 300 rpm. Donor and acceptor samples were analyzed by LC-MS / MS.

[0173]

[0090] Further details of MFN activity and PAMPA testing are described in U.S. Patent Application Nos. 2020 / 0345668 and 2020 / 0345669, which are incorporated herein by reference.

[0174] Synthesis of N-(trans-4-hydroxycyclohexyl)-5-phenylpentanamide (Formula 1) This mitofusin activator was prepared as described in U.S. Patent Application Publication No. 2020 / 0345668, which is incorporated by reference, and was used as a standard in the following activity studies.

[0175] Synthesis of 1-(4-hydroxypiperidin-1-yl)-7-phenylheptan-1-one (Formula 80)

[0176] [ka]

[0177]

[0093] To a solution of 7-phenylheptanoic acid (100 mg, 484 μmol) in DMF (1.00 mL), HOBt (78.6 mg, 581 μmol), EDCI (139 mg, 727 μmol) and DIEA (125 mg, 969 μmol, 168 μL) were added. Piperidin-4-ol (53.9 mg, 533 mol) was added and stirred at 25 °C for 16 hours. The mixture was purified by HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 45%-55%, 7 min). After HPLC purification, the residue was adjusted to pH = 7 with saturated sodium bicarbonate solution and extracted with EtOAc (20.0 mL x 2). The combined organic layers were washed with Na 2 SO 4 The residue was dried over H 2 0 (20.0 mL) and ACN (2.50 mL). The mixture was lyophilized to give the title compound as a yellow oil (31.1 mg, 106 umol, 22.1% yield, 99.5% purity). LC-MS: Rt=0.868 min, m / z=290.1 ​​(M+H). HPLC: Rt=1.983 min, 99.5% purity at 220 nm. 1 H NMR: 400MHz CDCl 3 δ:7.26-7.30(m,2H),7.16-7.19(m,3H),4.08-4.14(m,1H),3.92-3.94(m,1H),3.70-3.76(m,1H),3.14-3.23(m,2H) ,2.59-2.63(m,2H),2.30-2.34(m,2H),1.86-1.89(m,2H),1.55-1.62(m,4H),1.46-1.53(m,2H),1.35-1.39(m,4H). 13 C NMR: 400MHz CDCl 3 δ:(171,142,128,125,77.3,77.2,76.7,67.3,42.8,38.8,35.8,34.6,34.0,33.3,31.3,29.3,29.0,25.3)ppm.

[0178] Synthesis of 1-(3-hydroxypiperidin-1-yl)-7-phenylheptan-1-one (Formula 81)

[0179] [ka]

[0180] To a solution of 7-phenylheptanoic acid (100 mg, 484 μmol) in DMF (1.00 mL), HOBt (78.6 mg, 581 μmol), EDCI (139 mg, 727 μmol) and DIEA (125 mg, 969 μmol, 168 μL) were added. Piperidin-3-ol (53.9 mg, 533 μmol) was added to the mixture and stirred at 25° C. for 16 h. The mixture was then purified by HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 48%-58%, 7 min). The residue was adjusted to pH=7 with saturated sodium bicarbonate solution and extracted with EtOAc (20.0 mLx3). The combined organic layers were washed with Na 2 SO 4 Dry at 45°C under reduced pressure and hydrate. 2 2H 2 O (20.0 mL) and ACN (2.50 mL). The mixture was lyophilized to give the title compound as a pale yellow oil (35.5 mg, 121 μmol, 25.2% yield, 99.4% purity). LC-MS: Rt=0.876 min, m / z=290.2 (M+H)-. HPLC: Rt=2.018 min, 99.4% purity at 220 nm. 1 H NMR:400MHz MeOD-d4 δ:7.20-7.28(m,2H),7.10-7.18(m,3H),3.62-3.70(m,2H),3.23-3.29(m,1H),3.15-3.21(m,1H),2 .60(t,J=7.6Hz,2H),2.35-2.40(m,2H),1.90-1.95(m,1H),1.75-1.83(m,1H),1.36-1.64(m,11H). 13C NMR:400MHz MeOD-d4 δ:(174,144,129,126,67.3,53.7,47.3,43.3,36.9,34.3,33.8,33.5,32.7,30.4,30.2,26.6,24.7,23.3)ppm.

[0181] Synthesis of 1-(4-hydroxypiperidin-1-yl)-6-phenylhexan-1-one (Formula 82)

[0182] [ka]

[0183]

[0097] To a solution of 6-phenylhexanoic acid (100mg, 520μmol, 98.0μL) in DMF (1.00mL), HOBt (84.3mg, 624μmol), DIEA (134mg, 1.04mmol, 181μL), EDCI (150mg, 780μmol) and piperidin-4-ol (57.9mg, 572μmol) were added. The mixture was stirred at 30℃ for 16h and purified by HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (0.1%TFA)-ACN]; B%: 38%~48%, 7min). The residue was adjusted to pH=7 with saturated sodium bicarbonate solution and extracted with EtOAc (20.0mLx3). The combined organic layer was washed with Na 2 SO 4 The residue was dried over H and concentrated under reduced pressure to give a residue. 2 2H (15 mL) and ACN (5.0 mL). The mixture was lyophilized to give the title compound as a white solid (49.2 mg, 178 μmol, 34.3% yield, 99.8% purity). LC-MS: Rt=0.836 min, m / z=276.1 (M+H). HPLC: Rt=1.854 min, 99.8% purity at 220 nm. 1 H NMR: 400MHz CDCl 3δ:7.27-7.31(m,2H),7.18-7.20(m,3H),4.09-4.13(m,1H),3.92-3.95(m,1H),3.71-3.91(m,1H),3.17-3.21(m,2H) ,2.61-2.65(m,2H),2.31-2.35(m,2H),1.87-1.89(m,3H),1.67-1.69(m,4H),1.64-1.65(m,2H),1.40-1.42(m,2H). 13 C NMR: 400MHz CDCl 3 δ:(171,143,128,126,67.2,42.8,38.9,35.7,34.6,33.9,33.2,31.2,29.1,25.2)ppm.

[0184] Synthesis of 1-(4-hydroxypiperidin-1-yl)-8-phenyloctan-1-one (Formula 83)

[0185] [ka]

[0186] To a solution of 8-phenyloctanoic acid (100 mg, 453 μmol) in DMF (1.00 mL), HOBt (73.6 mg, 544.6 μmol), EDCI (130 mg, 680 μmol), DIEA (117 mg, 907 μmol, 158 μL) and piperidin-4-ol (53.9 mg, 533 μmol) were added. The mixture was stirred at 30° C. for 3.5 h and purified by HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 52%-62%, 7 min). The residue was adjusted to pH=7 with saturated sodium bicarbonate solution and extracted with EtOAc (20 mLx3). The combined organic layers were washed with Na 2 SO 4 The residue was dried over H and concentrated under reduced pressure. 22H 2 O (10 mL) and ACN (1.00 mL). The mixture was then lyophilized to give the title compound as an off-white solid (45.2 mg, 146 μmol, 32.3% yield, 98.4% purity). LC-MS: Rt=0.885 min, m / z=304.2 (M+H)+. HPLC: Rt=2.111 min, 98.4% purity at 220 nm. 1 H NMR:400MHz MeOD δ:7.2-7.25(m,2H),7.11-7.17(m,3H),4.05-4.08(m,1H),3.78-3.86(m,2H),3.26-3.29(m,1H),3.11-3. 12(m,1H),2.58-2.62(m,2H),2.36-2.40(m,2H),1.56-1.63(m,2H),1.38-1.39(m,4H),1.33-1.36(m,8H). 13 C NMR:400MHz MeOD δ:174,144,130,127,67.9,44.6,40.5,37.0,35.8,35.0,34.2,32.8,30.5,30.3,26.8)ppm.

[0187] Synthesis of 4-hydroxy-N-(5-phenylpentyl)piperidine-1-carboxamide (Formula 84) [ka]

[0188] To a solution of 5-phenylpentan-1-amine (100 mg, 500 μmol, HCl) in DMF (1.0 mL) was added CDI (97.4 mg, 600 μmol) and TEA (152 mg, 1.50 mmol, 209 μL). The mixture was degassed and purified with N 2 Purge three times with N 2 The mixture was stirred at 30° C. for 0.5 hours under atmospheric conditions. Piperidin-4-ol (60.7 mg, 600 μmol) was added, and N 2 The mixture was stirred at 30° C. for 16 hours under atmospheric pressure. 2 The mixture was diluted with 200 mL of 2H2O (15 mL) and extracted with EtOAc (15 mLx3). The combined organic layer was washed with brine (10 mLx3) and then with Na 2 SO 4The residue was purified by HPLC (column: Waters Xbridge C18 150x50mmx10μm; mobile phase: [water (10mm NH 4 HCO 3 )-ACN]; B%: 20%-50%, 10 min) to give the title compound as an off-white solid (44.8 mg, 151 μmol, 30.2% yield, 98.0% purity). LCMS: Rt=0.860 min, m / z=291.3 (M+H)+. HPLC: Rt=2.165 min, 98.1% purity at 220 nm. 1 H NMR:400MHz MeOD-d4 δ:7.25-7.13(m,5H),3.79-3.75(m,3H),3.14-3.11(m,2H),3.03-2.99(m,2H),2.63-2. 59(m,2H),1.80-1.66(m,2H),1.64-1.62(m,2H),1.52-1.41(m,2H),1.38-1.34(m,4H). 13 C NMR:400MHz MeOD-d4 δ:160,143,130,129,127,68.4,42.8,41.9,36.9,35.1,32.6,31.3,27.6)ppm.

[0189] Synthesis of 4-hydroxy-N-(5-phenylpentyl)cyclohexane-1-carboxamide (Formula 85)

[0190] [ka]

[0191] To a solution of 4-hydroxycyclohexane-1-carboxylic acid (32.8 mg, 227 μmol) in DMF (1.0 mL), HOBt (36.9 mg, 273 μmol), EDCI (65.4 mg, 341 μmol), DIEA (88.2 mg, 682 μmol, 118 μL) and 5-phenylpentan-1-amine (50.0 mg, 250 μmol, HCl) were added. The mixture was stirred at 30° C. for 16 h and purified by HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%-50%, 7 min). The title compound was obtained as an off-white solid (44.0 mg, 150 μmol, yield 66.0%, purity 98.7%). LC-MS: Rt=0.847 min, m / z=290.1(M+H)-.HPLC: Rt=1.881 min, Rt=1.922 min, purity 98.7% at 220 nm. 1 H NMR:400MHz MeOD-d4 δ:7.25-7.11(m,5H),3.91-3.47(m,1H),3.17-3.13(m,2H),2.62-2.59(m,2H),1.99-1.97(m,1H) ,1.76-1.65(m,2H),1.63-1.61(m,2H),1.53-1.50(m,2H),1.49-1.34(m,5H),1.33-1.20(m,3H). 13 C NMR:400MHz MeOD-d4 δ:(179,178,143,130,129,126,70.7,66.6,45.6,45.4,40.2,36.9,35.7,32.9,32.5,32.4,30.4,30.3,29.2,27.5,24.9)ppm.

[0192] Synthesis of (1r,4r)-4-hydroxy-N-(4-phenylbutoxy)cyclohexane-1-carboxamide (Formula 86, diastereomer of Formula 86)

[0193] [ka]

[0194]

[0104] To a mixture of (4-bromobutyl)benzene (300 mg, 1.41 mmol) and 2-hydroxyisoindoline-1,3-dione (275 mg, 1.69 mmol) in DMF (10.00 mL), K 2 CO 3 (389 mg, 2.82 mmol) was added at 20° C. The mixture was stirred at 80° C. for 1 h to give (191 mg, 646 μmol, 45.9% yield). To a solution of 2-(4-phenylbutoxy)isoindoline-1,3-dione (190 mg, 643 μmol) in DCM (10.0 mL), NH 2 -NH 2 H 2 O (322 mg, 6.43 mmol) was added at 25° C. The mixture was stirred for 2 h to give O-(4-phenylbutyl)hydroxylamine (95.0 mg, 574 μmol, 89.3% yield). O-(4-phenylbutyl)hydroxylamine was combined with (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (124 mg, 862 μmol) in THF (10.0 mL) at 25° C., followed by HATU (327 mg, 862 μmol) and TEA (174 mg, 1.72 mmol, 3.00 mL). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC (neutral conditions, column: Waters Xbridge 150x25 mmx5 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 26%-56%, 10 min). The title compound was obtained as an off-white solid (83.72 mg, 286 μmol, 49.7% yield, 99.6% purity). LCMS: RT=0.730 min, m / z=292.2 (M+H)+. HPLC: RT=1.803 min, 99.6% purity at 220 nm. 1 H NMR: 400MHz, DMSO-d 6δ:10.9-10.5(m,1H),7.28-7.25(m,2H),7.19-7.14(m,3H),4.63-4.52(m,1H),3.73-3.70(m,2H),3.34-3.30(m,1H) ,2.59-2.56(m,2H),1.84-1.81(m,3H),1.64-1.62(m,4H),1.60-1.51(m,2H),1.43-1.28(m,2H),1.09-1.06(m,2H).

[0195] Synthesis of (1r,4R)-4-hydroxy-N-((1R,2R)-2-(3-phenylpropyl)cyclopropyl)cyclohexane-1-carboxamide (Formula 87, diastereomer of Formula 87)

[0196] [ka]

[0197]

[0106] To a solution of 4-phenylbutanal (3.34 g, 22.5 mmol), tert-butyl 2-(triphenyl-15-phosphinylidene)acetate (10.1 g, 27.0 mmol) was added with N 2 The mixture was added at 25°C under atmospheric pressure. The mixture was stirred for 12 hours to give (E)-tert-butyl 6-phenylhex-2-enoate (3.54 g, 14.3 mol, yield 63.7%). BLAH iodomethane [(CH3) 3 To a mixture of [SOI] (1.61 g, 7.31 mmol) in DMSO (10.0 mL), NaH (292 mg, 7.31 mmol) was added 2At 25° C., the mixture was stirred for 1 hour at 25° C. After 1 hour, (E)-tert-butyl 6-phenylhex-2-enoate (1.50 g, 6.09 mmol) was added to the mixture and stirred for another 1 hour to give tert-butyl (1S,2S)-2-(3-phenylpropyl)cyclopropane-1-carboxylate (790 mg, 3.03 mmol, 49.8% yield). To a mixture of tert-butyl (1S,2S)-2-(3-phenylpropyl)cyclopropane-1-carboxylate (790 mg, 3.03 mmol) in DCM (10.0 mL), TFA (14.1 g, 124 mmol, 9.19 mL) was added at 25° C. and stirred for 1 hour to give (1S,2S)-2-(3-phenylpropyl)cyclopropane-1-carboxylic acid (576 mg, 2.82 mmol, 92.9% yield). To a mixture of (1S,2S)-2-(3-phenylpropyl)cyclopropane-1-carboxylic acid (576 mg, 2.82 mmol) in toluene (10.0 mL), DPPA (776 mg, 2.82 mmol), TFA (428 mg, 4.23 mmol) and N 2 The mixture was heated to 105° C. and stirred for 2 h to give (1S,2S)-2-(3-phenylpropyl)cyclopropan-1-amine (73.0 mg, 416 μmol, 14.7% yield). HATU (237 mg, 625 μmol) and TEA (361 mg, 3.57 mmol, 0.50 mL) were added to a mixture of (1S,2S)-2-(3-phenylpropyl)cyclopropan-1-amine (73.0 mg, 416 μmol) and (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (72.1 mg, 500 μmol) in THF (10.0 mL) at 25° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by HPLC (TFA condition, column: Phenomenex Synergi Polar-RP 100x25mmx4μm; mobile phase: [water (TFA)-ACN]; B%: 43%-63%, 7 min) to give the title compound as a white solid (8.29mg, 26.6μmol, yield 6.38%, purity 96.6%). LCMS: RT=0.892min, m / z=302.2(M+H)+. HPLC: RT=2.309min, purity 96.6% at 220nm. 1H NMR: 400MHz, DMSO-d 6 δ:7.72(d,J=4.0,1H),7.28-7.24(m,2H),7.19-7.13(m,3H),4.51(d,J=4 .4,1H),3.30-3.26(m,1H),2.60-2.56(m,2H),2.32-2.27(m,1H),1.83-1 .79(m,3H),1.65-1.60(m,4H),1.34-1.30(m,2H),1.20-1.19(m,2H),1.0 7-1.04(m,2H),0.75-0.70(m,1H),0.51-0.49(m,1H),0.38-0.36(m,1H).

[0198] Synthesis of (1r,4r)-4-hydroxy-N-(2-(4-phenylbutyl)cyclopropyl)cyclohexane-1-carboxamide (Formula 88, diastereomer of Formula 88)

[0199] [ka]

[0200] The title compound was synthesized as outlined in Scheme 89.

[0201] [ka]

[0202] Briefly, 5-phenylpentan-1-ol was converted to the corresponding aldehyde using Dess-Martin periodinane, and the crude aldehyde was then converted to the corresponding t-butyl-α,β-unsaturated ester using tert-butyl 2-(triphenyl-15-phosphinylidene)acetate (overall yield approx. 75%). 3Cyclopropanation was carried out using SOI (overall yield ca. 36%). After cleavage of the t-butyl ester with trifluoroacetic acid, the crude cyclopropylcarboxene was converted to the corresponding BOC-protected amine with diphenylphosphoryl azide in t-butanol (overall yield ca. 48%). Free amine with HCl gas in dioxane (ca. 91%) was then coupled with (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid using EDCI to give the title compound in 50% yield. LCMS: RT=0.521 min, m / z=316.2 (M+H)+. HPLC: RT=2.738 min, 96.2% purity at 220 nm. 1 H NMR: 400MHz, DMSO-d 6 δ:7.69(d,J=4.4Hz,1H),7.27-7.24(m,2H),7.18-7.13(m,3H),4.51(d,J =4.4Hz,1H),3.30-3.26(m,1H),2.57-2.53(m,2H),2.32-2.31(m,1H),1. 89-1.80(m,3H),1.63-1.57(m,4H),1.37-1.31(m,6H),1.08-1.04(m,2H) ,0.70-0.68(m,1H),0.48-0.46(dt,J=8.8,4.8Hz,1H),0.37-0.36(m,1H).

[0203] Synthesis of (1r,4r)-4-hydroxy-N-(3-(3-phenylpropyl)cyclobutyl)cyclohexane-1-carboxamide (Formula 90, diastereomer of Formula 90)

[0204] [ka]

[0205] The title compound was synthesized in a similar manner to that of formula 30A, except that 3-(3-phenylpropyl)cyclobutan-1-amine was prepared as a coupling intermediate. The product was analyzed by LC-MS, HPLC, and HPLC. 1 Identification was performed by 1 H NMR.

[0206] Synthesis of (1r,4S)-4-hydroxy-N-((1S,2S)-2-phenethoxycyclopropyl)cyclohexane-1-carboxamide (Formula 91, diastereomer of Formula 91)

[0207] [ka]

[0208]

[0102] Ethyl (1S,2S)-2-phenethoxycyclopropane-1-carboxylate (440 mg, 1.88 mmol) in MeOH (5.00 mL), THF (5.00 mL) and H 2 To the mixture, LiOH H 2 2H2O (157 mg, 3.76 mmol) was added at 25° C. The mixture was heated to 70° C. and stirred for 2 h to give (1S,2S)-2-phenethoxycyclopropane-1-carboxylic acid (284 mg, 1.38 mmol, 73.3% yield). To a mixture of (1S,2S)-2-phenethoxycyclopropane-1-carboxylic acid (264 mg, 1.28 mmol) in toluene (10.0 mL), DPPA (352 mg, 1.28 mmol) and TFA (194 mg, 1.92 mmol, 1.50 eq) were added. 2 The mixture was heated to 105°C and stirred for 2 hours to give (1S,2S)-2-phenethoxycyclopropan-1-amine (54.0 mg, 304 μmol, 23.8% yield). HATU (151 mg, 397 μmol) and TEA (727 mg, 7.18 mmol, 1.00 mL) were added to a mixture of (1S,2S)-2-phenethoxycyclopropan-1-amine (47.0 mg, 265 μmol) and (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (45.8 mg, 318 μmol) in THF (10.0 mL) at 25°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by HPLC (neutral conditions, column: Waters Xbridge 150x25mmx5 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 25%-55%, 10 min, TFA conditions, column: Phenomenex Synergi Polar-RP 100x25mmx4μm; mobile phase: [water (TFA)-ACN]; B%: 36%-56%, 7 min), affording the title compound as a white solid (7.89mg, 25.7μmol, yield 9.69%, purity 98.8%). LCMS: RT=0.716min, m / z=304.2(M+H)+. HPLC: RT=1.709min, purity 98.8% at 220nm. 1 H NMR: 400MHz, DMSO-d 6 δ:7.74(d,J=3.6,1H),7.29-7.25(m,2H),7.23-7.16(m,3H),4.55(d,J=4.4,1H),3.77-3.66(m,2H),3.33-3.29(m,2H),3.07-3.06(m,1H) ),2.81-2.77(m,2H),1.88-1.79(m,3H),1.64-1.60(m,2H),1.33-1.30(m,2H),1.13-1.07(m,2H),0.84-0.82(m,1H),0.65-0.64(m,2H).

[0209] Synthesis of (1r,4r)-N-(2-(benzyloxy)cyclopropyl)-4-hydroxycyclohexane-1-carboxamide (Formula 92, diastereomer of Formula 92)

[0210] [ka]

[0211]

[0104] Ethyl 2-(benzyloxy)cyclopropane-1-carboxylate (750 mg, 3.41 mmol) in MeOH (5.00 mL), THF (5.00 mL) and H 2 To the mixture, LiOH H 22-(Benzyloxy)cyclopropane-1-carboxylic acid (485 mg, 2.52 mmol), DPPA (694 mg, 2.52 mmol), TFA (382 mg, 3.78 mmol) were added at 25° C. The mixture was heated to 70° C. and stirred for 2 h to give 2-(benzyloxy)cyclopropane-1-carboxylic acid (485 mg, 2.52 mmol, 74.1% yield). To a mixture of 2-(benzyloxy)cyclopropane-1-carboxylic acid (485 mg, 2.52 mmol) in toluene (10.0 mL), DPPA (694 mg, 2.52 mmol), TFA (382 mg, 3.78 mmol) were added with N 2 The mixture was heated to 105°C and stirred for 2 hours to give 2-(benzyloxy)cyclopropan-1-amine (108 mg, 661 μmol, 26.2% yield). HATU (377 mg, 992 μmol) and TEA (1.81 g, 17.9 mmol, 2.50 mL) were added to a mixture of 2-(benzyloxy)cyclopropan-1-amine (108 mg, 661 μmol) and (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (114 mg, 794 μmol) in THF (10.0 mL) at 25°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (TFA conditions, column: Phenomenex Synergi Polar-RP 100x25mmx4μm; mobile phase: [water (TFA)-ACN]; B%: 32%-52%, 7 min) and (neutral conditions, column: Waters Xbridge 150x25mmx5μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 21%-51%, 9 min) to give the title compound as a white solid (5.97 mg, 20.1 umol, 3.05% yield, 97.8% purity). LCMS: RT=0.671 min, m / z=290.1 ​​(M+H)+. HPLC: RT=1.821 min, 97.8% purity at 220 nm. 1 H NMR: 400MHz, DMSO-d 6δ:7.76(d,J=3.2,1H),7.26-7.30(m,5H),4.62-4.53(m,3H),3.31-3.29(m,1H),3.14-3.12(m,1H),2.64-2.63(m,1H) ),1.91-1.80(m,3H),1.64-1.62(m,2H),1.36-1.33(m,2H),1.09-1.05(m,2H),1.01-0.97(m,1H),0.71-0.70(m,1H).

[0212] Synthesis of (1r,4r)-4-hydroxy-N-(2-(3-phenylpropoxy)cyclopropyl)cyclohexane-1-carboxamide (Formula 93, diastereomer of Formula 93)

[0213] [ka]

[0214]

[0106] Ethyl 2-(3-phenylpropoxy)cyclopropane-1-carboxylate (870 mg, 3.50 mmol) in MeOH (5.00 mL), THF (5.00 mL) and H 2 To the mixture, LiOH H 2 2-(3-phenylpropoxy)cyclopropane-1-carboxylic acid (690 mg, 3.13 mmol, 89.4% yield) was obtained. To a mixture of 2-(3-phenylpropoxy)cyclopropane-1-carboxylic acid (690 mg, 3.13 mmol) in toluene (10.0 mL), DPPA (862 mg, 3.13 mmol), TFA (475 mg, 4.70 mmol) were added with N 2The mixture was heated to 105° C. and stirred for 2 hours to give 2-(3-phenylpropoxy)cyclopropan-1-amine (154 mg, 805 μmol, 25.7% yield). HATU (459 mg, 1.21 mmol) and TEA (727 mg, 7.18 mmol, 1.00 mL) were added to a mixture of 2-(3-phenylpropoxy)cyclopropan-1-amine (154 mg, 805 μmol) and (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (139 mg, 966 μmol) in THF (5.00 mL) at 25° C. and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (TFA conditions, column: Phenomenex Synergi Polar-RP 100x25mmx4μm; mobile phase: [water (TFA)-ACN]; B%: 41%-61%, 7 min) and (neutral conditions, column: Waters Xbridge 150x25mmx5μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 31%-61%, 10 min), affording the title compound as an off-white solid (7.29 mg, 22.5 μmol, 2.80% yield, 98.1% purity). LCMS: RT=0.830 min, m / z=318.2 (M+H)+. HPLC: RT=1.814 min, 98.1% purity at 220 nm. 1 H NMR: 400MHz, DMSO-d 6 δ:7.71(d,J=3.6,1H),7.28-7.25(m,2H),7.19-7.16(m,3H),4.52(d,J=4 .4,1H),3.54-3.45(m,2H),3.43-3.30(m,1H),3.07-3.06(m,1H),2.59-2 .55(m,3H),1.89-1.82(m,1H),1.80-1.76(m,4H),1.73-1.61(m,2H),1.3 4-1.30(m,2H),1.08-1.05(m,2H),0.90-0.87(m,1H),0.65-0.64(m,1H).

[0215] Mitofusin Activity and In Vitro Pharmacology Table 1 summarizes the biological activity of compounds of formulas 80-83, 84, 24, 85, 86, and 87-93 in comparison to the mitofusin activator of formula 1.

[0216] [Table 1]

[0217] As shown in the table, the compounds of formulas 9-12, which have an endocyclic amide nitrogen atom, unexpectedly exhibited a sharp increase in PAMPA values ​​compared to the compound of formula 1. Some of these compounds had low EC values ​​comparable to that of the compound of formula 1. 50 The urea analogues corresponding to the compounds of formula 9 (i.e., the urea compounds of formula 18) had EC 50 The EC of the corresponding amide analog with the amide nitrogen atom on the opposite side of the carbonyl group (i.e., the amide of formula 28) was 50 The EC and PAMPA values ​​were comparable to those of the compound of formula 1. The compounds of formulas 86 to 93, which have different linkers between the amide nitrogen atom and the phenyl group in the compound of formula 28, had low EC 50 Although some of the compounds maintained their potency, with the exception of compounds of formulas 88 and 90, the PAMPA assay values ​​did not improve.

[0218]

[0108] Unless otherwise indicated, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the desired properties sought to be obtained by 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 claims, each numerical parameter should at least be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0219]

[0109] One or more exemplary embodiments incorporating various features are presented herein. For clarity, not all of the features of the physical examples are described in this application. It is understood that in the development of a physical embodiment incorporating an embodiment of the present invention, numerous example-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 from example to example and over time. Although the developer's efforts may take time, such efforts are routine for those of ordinary skill in the art and who have the benefit of this disclosure.

[0220]

[0110] Although various systems, tools, and methods are described herein using words "comprising" various components or steps, the systems, tools, and methods may "consist essentially of" or "consist of" the various components and steps.

[0221]

[0111] In this specification, the phrase "at least one of" before consecutive items, together with the term "and" or "or" separating the items, modifies the list as a whole and not each member (i.e., each item) of the list. The phrase "at least one of" can mean at least 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. For example, the phrase "at least one of A, B, and C" or "at least one of A, B, or C" refers, respectively, to only A, only B, or only C; any combination of A, B, and C; and / or at least one of A, at least one of B, and at least one of C.

[0222]

[0112] Thus, the disclosed system, tool and method are well adapted to achieve the stated objects and advantages, as well as those inherent therein. The specific embodiments disclosed above are merely illustrative, and the teachings of the disclosure may be modified and implemented in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings. Moreover, no limitations are intended to the details of construction or design shown herein, other than as set forth in the following claims. Thus, the specific exemplary embodiments disclosed above may be altered, combined or modified, and all such modifications are clearly within the scope of the present disclosure. The systems, tools and methods illustratively disclosed herein may suitably be practiced in the absence of any elements not specifically disclosed herein and / or any elements disclosed herein. Although the systems, tools and methods are described using the terms "comprising," "containing" or "including" various components or steps, the systems, tools and methods may "consist essentially of" or "consist of" various components and steps. There may be some variation in all of the values ​​and ranges disclosed above. Whenever a range of values ​​is disclosed with a lower limit and an upper limit, any value or range falling within the range is specifically disclosed. In particular, any range of values ​​disclosed herein (in the form of "about a to about b" or, equivalently, "approximately a to b" or, equivalently, "approximately a to b") shall be understood to describe all values ​​and ranges falling within the broader range. Moreover, terms in the claims shall have their plain and ordinary meaning unless expressly and unambiguously defined by the patent owner. Moreover, the indefinite article "a" or "an" as used in the claims is defined herein to mean one or more of the elements that follow it. If there is a discrepancy between the usage of a word or term in this specification and one or more patents or other documents incorporated herein by reference, the consistent definition in this specification shall control.

Claims

1. 【Chemical 94】 A composition comprising a mitofusin activator having a structure represented by the formula: G is N or CH; A is an optionally substituted 5- or 6-membered cycloalkyl or heterocycloalkyl ring; X is (CH ２ ) ３ , OCH ２ CH ２ , CH ２ OCH ２ , CH ２ CH ２ O, Cyc, CH ２ Cyc, NR １ (CH ２ ) ３ , NR １ OCH ２ CH ２ , NR １ CH ２ OCH ２ , NR １ CH ２ CH ２ O, or NR １ Cyc, wherein R １ is H or C １ ~C ６ alkyl, and Cyc is 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, or 1,4-cyclohexyl; Z is (CH ２ ) ｎ Or (CH ２ ) ｎ１ O (CH ２ ) ｎ２ And, n is an integer from 1 to 5; １ is an integer from 0 to 4, and n ２ is an integer from 0 to 4, and n １ +n ２ = n - 1, R ２ is an optionally substituted aryl or heteroaryl group.

2. R ２ The composition of claim 1 , wherein is an optionally substituted phenyl group.

3. 2. The composition of claim 1, wherein G is N and A represents an optionally substituted piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl group.

4. The mitofusin activator 【Chemistry 95】 or a stereoisomer thereof, In the formula, J is a bond, CH(hal), CHOR ３ , CHR ４ , C.H.N.R. ４ R ５ , O, or NR ４ and Q is any substitution, hal is a halogen; R ３ is H or C １ ~C ６ alkyl, R ４ and R ５ are independently H, C １ ~C ６ Alkyl, or C １ ~C ６ The composition of claim 3 which is acyl.

5. J is CHOR ３ or CHR ４ The composition of claim 4 ,

6. X is (CH ２ ) ３ 6. The composition of claim 3, wherein the aryl group is 1,2-cyclopropyl, 1,2-cyclobutyl, or 1,3-cyclobutyl.

7. Z is (CH ２ ) ｎ Or O(CH ２ ) ｎ－１ 7. The composition of claim 6, wherein n is an integer from 2 to 5.

8. The composition of claim 6, wherein A is 4-hydroxypiperidinyl.

9. R ２ The composition of claim 6 , wherein is optionally substituted phenyl.

10. The mitofusin activator 【Chemistry 96】 【Chemistry 97】 【Chemistry 98】 【Chemistry 99】 【Chemistry 100】 【Chemistry 101】 【Chemistry 102】 【Chemistry 103】 6. The composition of claim 3 , having a structure represented by the formula:

11. X is NR １ (CH ２ ) ３ , N.R. １ (1,2-cyclopropyl), NR １ (1,2-cyclobutyl), or NR １ The composition according to any one of claims 3 to 5, wherein the aryl group is 1,3-cyclobutyl.

12. Z is (CH ２ ) ｎ Or O(CH ２ ) ｎ－１ and n is an integer from 1 to 4.

13. The composition of claim 6, wherein A is 4-hydroxypiperidinyl.

14. R ２ The composition of claim 6 , wherein is optionally substituted phenyl.

15. The mitofusin activator 【Chemistry 104】 6. The composition of claim 3 , having a structure represented by the formula:

16. 2. The composition of claim 1, wherein G is CH and A represents an optionally substituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopentyl, or cyclohexyl group.

17. The mitofusin activator 【Chemistry 105】 or a stereoisomer thereof, In the formula, J is a bond, CH(hal), CHOR ３ , CHR ４ , C.H.N.R. ４ R ５ , O, or NR ４ and Q is any substitution, hal is a halogen; R ３ is H or C １ ~C ６ alkyl, R ４ and R ５ are independently H, C １ ~C ６ Alkyl, or C １ ~C ６ The composition of claim 16 which is acyl.

18. J is CHOR ３ or CHR ４ 18. The composition of claim 17, wherein

19. X is NR １ (CH ２ ) ３ , N.R. １ (1,2-cyclopropyl), NR １ (1,2-cyclobutyl), or NR １ 19. The composition of any one of claims 16 to 18, wherein the aryl group is (1,3-cyclobutyl).

20. Z is (CH ２ ) ｎ Or O(CH ２ ) ｎ－１ 20. The composition of claim 19, wherein n is an integer from 2 to 4.

21. The composition of claim 19, wherein A is 4-hydroxycyclohexyl.

22. R ２ 20. The composition of claim 19, wherein is optionally substituted phenyl.

23. The mitofusin activator 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemistry 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 19. The composition of any one of claims 16 to 18, having a structure represented by:

24. 19. The composition of any one of claims 1 to 5 or 16 to 18, further comprising a pharma- ceutically acceptable excipient.

25. A method comprising administering a therapeutically effective amount of a composition, stereoisomer thereof, or pharma- ceutically acceptable salt thereof described in any one of claims 1 to 5 or 16 to 18 to a subject having or suspected of having a mitochondrial-associated disease, disease, or condition.

26. 26. The method of claim 25, wherein the mitochondrial associated disease, illness or condition is a genetic or non-genetic disease of the peripheral nervous system (PNS) or central nervous system (CNS), physical injury, and / or chemical injury.

27. The PNS or CNS disease may be a chronic neurodegenerative condition in which mitochondrial fusion, adaptation, and / or trafficking is impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, and / or movement disorders; a degenerative neuromuscular condition; Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis; Huntington's disease; Alzheimer's disease; Parkinson's disease; hereditary motor and sensory neuropathies; autism; autosomal dominant optic atrophy (ADOA); muscular dystrophy; Lou Gehrig's disease; cancer; mitochondrial myopathy; diabetic deafness (DAD); Leber's hereditary optic neuropathy (LHON); Leigh's syndrome; subacute sclerosing encephalopathy; neuropathy, ataxia, 27. The method of claim 26, wherein the condition is one or more selected from the group consisting of retinitis pigmentosa-ptosis (NARP); myoclonus pigmentosa-ptosis (MARP); myoclonus neurogenic gastrointestinal encephalopathy (MNGIE); myoclonus epilepsy with ragged red fibers (MERRF); mitochondrial myopathy, encephalomyopathy, hyperlactatemia and stroke-like episodes (MELAS); mtDNA depletion; mitochondrial neurogenic gastrointestinal encephalomyopathy (MNGIE); autonomic neuropathy 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 involving axonal transection; and combinations thereof.

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