# US 10,501,453 B2 · Benzothiazole or benzoxazole compounds as SUMO activators

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- Number: US 10,501,453 B2
- Document ID: US10501453B2
- Status: Granted
- Kind: B2
- Application number: 15/826,238
- Filed: 2017-11-29
- Published: 2018-05-10
- Granted: 2019-12-10
- Earliest claimed: 2012-08-29
- Assignees: Icahn School of Medicine at Mount Sinai
- Applicants: Icahn School of Medicine at Mount Sinai
- Inventors: Russell Dahl; Ah Young Lee; Changwon Kho; Roger J. Hajjar
- Web page: https://patentgrep.com/patent/US10501453B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4245: Oxadiazoles
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/433: Thidiazoles
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Provided are SUMO activators, which can enhance SUMOylation of SERCA2a, which are useful in the treatment of heart failure, cardiovascular diseases, cancer, neurodegenerative disorders, viral infection, bacterial infection, liver disease, inflammation, and other diseases.

## Claims

### Claim 1

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, neurodegenerative disorders, viral infection, liver disease, or inflammation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula II:
or a pharmaceutically acceptable salt thereof; wherein:
Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1a groups;
W is S or O;
Y is O;
each X is N;
Z is O, S, or NRA;
RA is H or C1-4 alkyl;
R1, R2, R3, and R4 are each independently selected from hydrogen, CN, nitro, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di-C1-4-alkylamino, carboxy, carbamyl, C1-6 alkylcarbamyl, di(C1-4alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylsulfonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di-C1-4 alkylamino sulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, and di-C1-4alkylaminosulfonylamino; wherein said C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylamino, di-C1-4-alkylamino, C1-6 alkylcarbamyl, di(C1-4alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-C1-3-alkylamino;
each R1a is hydrogen.

### Claim 2 (depends on 1)

A method according to claim 1, wherein Ar is phenyl.

### Claim 3 (depends on 1)

A method according to claim 1, wherein W is S.

### Claim 4 (depends on 1)

A method according to claim 1, wherein Z is NH.

### Claim 5 (depends on 1)

A method according to claim 1, wherein R1, R2, R3, and R4 are independently selected from hydrogen, CN, nitro, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di-C1-4-alkylamino.

### Claim 6 (depends on 1)

A method according to claim 1, wherein R1, R2, R3, and R4 are independently selected from hydrogen and C1-6 alkoxy.

### Claim 7 (depends on 1)

A method according to claim 1, wherein at least three of R1, R2, R3, and R4 are hydrogen.

### Claim 8

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, neurodegenerative disorders, viral infection, liver disease, or inflammation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula II:
or a pharmaceutically acceptable salt thereof; wherein:
Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1a groups;
W is S or O;
Y is O;
each X is N;
Z is O, S, or NRA;
RA is H or C1-4 alkyl;
R1, R2, R3, and R4 are each hydrogen;
each R1a is independently selected from halo, CN, nitro, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6 haloalkoxy, amino, C1-6 alkylamino, di-C1-4-alkylamino, carboxy, carbamyl, C1-6 alkylcarbamyl, di(C1-4alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylsulfonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6alklaminosulfonyl, di-C1-4 alklaminosulfonyl, aminosulfonylamino C1-6 alkylaminosulfonylamino, and di-C1-4alkylaminosulfonylamino; wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6 haloalkoxy, C1-6 alkylamino, di-C1-4-alkylamino, C1-6 alkylcarbamyl, di(C1-4 alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, alkylamino, and di-C1-3-alkylamino; or
two adjacent R1a taken together with the atoms to which they are attached can form a 3-7 membered carbocyclic or 4-6 membered heterocyclic ring, each of which is optionally substituted with 1, 2, 3, or 4 C1-3 alkyl groups.

### Claim 9 (depends on 8)

A method according to claim 8, wherein the compound is a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 8)

A method according to claim 8, wherein the compound is a compound of Formula Ib:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 8)

A method according to claim 8, wherein the compound is a compound of Formula Ic:
or a pharmaceutically acceptable salt thereof wherein:
R2a, R2b, R2c, R2d, and R2e are each independently selected from hydrogen, halo, CN, nitro, hydroxy, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6haloalkoxy, amino, C1-6alkylamino, carboxy, carbamyl, C1-6alkylcarbamyl, di(C1-4alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonyloxy, C1-6alkylsulfonyl, C1-6alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di-C1-4 alkylaminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino; wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6 haloalkoxy, C1-6 alkylamino, di-C1-4-alkylamino, C1-6alkylcarbamyl, di(C1-4alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-C1-3-alkylamino.

### Claim 12 (depends on 11)

A method according to claim 11, wherein R2a, R2b, R2c, R2d, and R2e are each independently selected from hydrogen, halo, CN, hydroxy, C1-6 alkyl, C1-6 haloalkyl, and C1-6 haloalkoxy.

### Claim 13

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, neurodegenerative disorders, viral infection, liver disease, or inflammation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of 5-(4 chlorophenyl)-N-(6-methoxybenzo[d]thiazol-2-yl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A method according to claim 1, wherein said heart failure is selected from congestive heart failure (CHF), chronic heart failure, and ischemic heart failure.

### Claim 15 (depends on 8)

A method according to claim 8, wherein the compound is a compound of Formula IIc:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 8)

A method according to claim 8, wherein the method further comprises administering to the patient an adeno-associated vector (AAV) comprising SERCA2a.