# US 11,026,904 B2 · Mitofusin activators and methods of use thereof

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- Number: US 11,026,904 B2
- Document ID: US11026904B2
- Status: Granted
- Kind: B2
- Application number: 17/087,971
- Filed: 2020-11-03
- Published: 2021-02-18
- Granted: 2021-06-08
- Earliest claimed: 2019-01-28
- Assignees: Mitochondria Emotion, Inc.
- Applicants: Mitochondria Emotion, Inc.
- Inventors: Gerald W. Dorn, II
- Web page: https://patentgrep.com/patent/US11026904B2

## CPC

- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- G01N 33/5035: {on sub-cellular localization}
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/351: not condensed with another ring
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07C 275/26: having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 2601/02: with a three-membered ring
- C07C 2601/04: with a four-membered ring
- C07C 2601/14: The ring being saturated
- G01N 2500/10: involving cells
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Compositions including small molecule mitofusin activators are described. The mitofusin activators are useful for treating diseases or disorders associated with a mitochondria-associated disease, disorder, or condition such as diseases or disorders associated with mitofusin 1 (MFN1) and/or mitofusin 2 (MFN2), or mitochondrial dysfunction. Methods of treatment, pharmaceutical formulations, and screening methods for identifying compounds that activate mitochondrial fusion are also described.

## Claims

### Claim 1

A method comprising:
administering a therapeutically effective amount of a composition comprising one or more of a mitofusin activator or a pharmaceutically acceptable salt thereof to a subject having or suspected of having a mitochondria-associated disease, disorder or condition, the mitofusin activator having a formula of
wherein:
X is
Z is optionally substituted phenyl;
Ra and Rb are independently H, F, alkyl, or C3-7 cycloalkyl, or Ra and Rb taken together form a C3-7 cycloalkyl or heterocycloalkyl;
Rc and Rd are independently H, F, alkyl, CORg, or C3-7 cycloalkyl, or Rc and Rd taken together form a C3-7 cycloalkyl or heterocycloalkyl;
Y is 0, CH2, cyclopropyl, or cyclobutyl;
Rg is H, alkyl, or C3-7 cycloalkyl;
o is 0 or 1;
p is 1; and
q is 1, 2, 3, or 4, provided that if Y is cyclopropyl or cyclobutyl, the sum of o+p+q is not less than 3 or greater than 5 and otherwise the sum of o+p+q is 5.

### Claim 2 (depends on 1)

The method of claim 1, wherein Ra, Rb, Rc, and Rd are each independently H or alkyl.

### Claim 3 (depends on 2)

The method of claim 2, wherein Y is CH2, cyclopropyl or cyclobutyl.

### Claim 4 (depends on 2)

The method of claim 2, wherein Ra, Rb, Rc, and Rd are each H.

### Claim 5 (depends on 2)

The method of claim 2, wherein X is

### Claim 6 (depends on 2)

The method of claim 2, wherein Z is phenyl having zero to four substituents independently selected from the group consisting of Rg, ORg, Cl, F, CN, CF3, NRgRh, SO2NRgRh, NRgSO2Ri, SO2Ri, CONRgRh, NRgCORi, C3-7 cycloalkyl, and heterocycloalkyl;
Ra, Rb, Rc, and Rd are each H;
Rh is H, alkyl, CORg, or C3-7 cycloalkyl, or Rg and Rh taken together form a C3-7 cycloalkyl; and
Ri is from alkyl or C3-7 cycloalkyl.

### Claim 7 (depends on 2)

The method of claim 2, wherein the mitofusin activator has a structure of
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein R1 is X and R2 is Z.

### Claim 8 (depends on 7)

The method of claim 7, wherein R2 is

### Claim 9 (depends on 2)

The method of claim 2, wherein the mitofusin activator is selected from the group consisting of

### Claim 10 (depends on 1)

The method of claim 1, wherein the mitochondria-associated disease, disorder or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-generic disorder, physical damage, and/or chemical injury.

### Claim 11 (depends on 10)

The method of claim 10, wherein the PNS or CNS disorder is selected from any one or a combination of:
a chronic neurodegenerative condition wherein mitochondrial fusion, fitness, or trafficking are impaired;
a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction;
a disease associated with mitochondrial fragmentation, dysfunction, or dysmotility;
a degenerative neuromuscular condition such as Charcot-Marie-Tooth disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease;
hereditary motor and sensory neuropathy, autism, autosomal dominant optic atrophy (ADOA), muscular dystrophy, Lou Gehrig's disease, cancer, mitochondrial myopathy, diabetes mellitus and deafness (DAD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome, subacute sclerosing encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), mtDNA depletion, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), dysautonomic mitochondrial myopathy, mitochondrial channelopathy, or pyruvate dehydrogenase complex deficiency (PDCD/PDH);
diabetic neuropathy;
chemotherapy-induced peripheral neuropathy; and
crush injury, spinal cord injury (SCI), traumatic brain injury, stroke, optic nerve injury, and related conditions that involve axonal disconnection.

### Claim 12

A composition comprising one or more of a mitofusin activator or a pharmaceutically acceptable salt thereof, the mitofusin activator having a formula of
wherein:
X is
Z is optionally substituted phenyl;
Ra and Rb are independently H, F, alkyl, or C3-7 cycloalkyl, or Ra and Rb taken together form a C3-7 cycloalkyl or heterocycloalkyl;
Rc and Rd are independently H, F, alkyl, CORg, or C3-7 cycloalkyl, or Rc and Rd taken together form a C3-7 cycloalkyl or heterocycloalkyl;
Y is 0, CH2, cyclopropyl or cyclobutyl;
Rg is H, alkyl, or C3-7 cycloalkyl;
o is 0 or 1;
p is 1; and
q is 1, 2, 3, or 4, provided that if Y is cyclopropyl or cyclobutyl, the sum of o+p+q is not less than 3 or greater than 5 and otherwise the sum of o+p+q is 5.

### Claim 13 (depends on 12)

The composition of claim 12, wherein Ra, Rb, Rc, and Rd are each independently H or alkyl.

### Claim 14 (depends on 13)

The composition of claim 13, wherein Y is CH2, cyclopropyl or cyclobutyl.

### Claim 15 (depends on 13)

The composition of claim 13, wherein Ra, Rb, Rc, and Rd are each H.

### Claim 16 (depends on 13)

The composition of claim 13, wherein X is

### Claim 17 (depends on 13)

The composition of claim 13, wherein Z is phenyl having zero to four substituents independently selected from the group consisting of Rg, ORg, Cl, F, CN, CF3, NRgRh, SO2NRgRh, NRgSO2Ri, SO2Ri, CONRgRh, NRgCORi, C3-7 cycloalkyl, and heterocycloalkyl;
Ra, Rb, Rc, and Rd are each H;
Rh is H, alkyl, CORg, or C3-7 cycloalkyl, or Rg and Rh taken together form a C3-7 cycloalkyl; and
Ri is alkyl or C3-7 cycloalkyl.

### Claim 18 (depends on 13)

The composition of claim 13, wherein the mitofusin activator has a structure of
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein R1 is X and R2 is Z.

### Claim 19 (depends on 18)

The composition of claim 18, wherein R2 is

### Claim 20 (depends on 13)

The composition of claim 13, wherein the mitofusin activator is selected from the group consisting of

### Claim 21 (depends on 13)

The composition of claim 13, further comprising:
a pharmaceutically acceptable excipient.