# US 10,865,181 B2 · Small molecule inhibitors of the mitochondrial permeability transition pore (mtPTP)

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- Number: US 10,865,181 B2
- Document ID: US10865181B2
- Status: Granted
- Kind: B2
- Application number: 15/524,595
- Filed: 2015-11-04
- Published: 2018-10-04
- Granted: 2020-12-15
- Earliest claimed: 2014-11-05
- Assignees: University of Kansas; Oregon Health & Science University
- Applicants: University of Kansas; Oregon Health & Science University
- Inventors: Sudeshna Roy; Paolo Bernardi; Michael Forte; Frank Schoenen; Justina Sileikyte
- Web page: https://patentgrep.com/patent/US10865181B2

## CPC

- C07C 235/42: having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- A61K 31/415: 1,2-Diazoles
- A61K 31/42: Oxazoles
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- C07C 235/38: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 235/56: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07D 203/04: not condensed with other rings
- C07D 211/14: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 261/18: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/185: from aliphatic carboxylic acids
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present technology relates to compounds of any one of Formula I, II, IIa, III, IV, and/or V as described herein and their tautomers and/or pharmaceutically acceptable salts, compositions, and methods of uses thereof.

## Claims

### Claim 1

A compound according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y1 is O;
W1 is N;
Z1, Z2, and Z3 are each independently CH, C—R9, or N;
m is 1;
G1 is C═O;
R1 is
R2, R4, R5, and R9 are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, heterocyclyl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R4, R5, and R9 together form an aryl, heteroaryl, or heterocyclyl ring;
R3 is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl; and
R21 is F or Cl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2, R4, R5, and R9 are independently at each occurrence hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkenyl, C2-C8 alkynyl, aryl, cyano, carboxyl, carboxyl ester, acyl, formyl, C3-C7 heteroaryl, or C3-C7 heterocyclyl, or two adjacent R4, R5, and R9 together form an aryl, heteroaryl, or heterocyclyl ring.

### Claim 3 (depends on 2)

The compound of claim 2, wherein Z1 is CH.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Z1 is CH.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula-IIa:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the compound is a compound of Formula-IIa:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 6)

A composition comprising a compound of claim 6 and a pharmaceutically acceptable excipient.

### Claim 10 (depends on 1)

A method for treating a disease in a subject having said disease, wherein the method comprises administering an effective amount of a compound of claim 1 to the subject, wherein the disease is multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis, type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, or stroke.

### Claim 11 (depends on 10)

The method of claim 10, wherein the compound is a compound of Formula-IIa:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A method for inhibiting a mitochondrial permeability transition pore, wherein the method comprises contacting a cell with an effective amount of a compound of claim 1.

### Claim 13 (depends on 1)

A method for treating a condition in a subject having said condition, wherein the method comprises administering to a patient an effective amount of a compound of claim 1; and the condition in the subject is mediated by [Ca2+] dysregulation or an accumulation of a reactive oxygen species.