Benzothiazole or benzoxazole compounds as sumo activators

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, cancer, neurodegenerative disorders, viral infection, bacterial 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 6independently selected R1a groups;
• W is S or O;
• Y is S or O;
• each X is CH;
• Z is O, S, or NRA;
• RA is H or C1-4 alkyl;
• R1, R2, R3, and R4 are each independently selected from hydrogen, halo, 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(C1-4 alkyl)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 alkylaminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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(C1-4 alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3alkoxy, amino, C1-3 alkylamino, and di-C1-3- alkylamino;
• and
• each R1a is independently selected from halo, CN, nitro, hydroxy, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di-C1-4-alkylamino, carboxy, carbamyl, C1-6 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6alkylcarbonyloxy, C1-6 alkylsulfonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di-C1-4 alkylaminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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 alkoxy, 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 3groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-C1-3 -alkylamino;
• or two adjacent R1a taken together with the atoms to which they are attached can form a 3-7membered carbocyclic or 4-6 membered heterocyclic ring, each of which is optionally substituted with 1, 2, 3, or 4 C1-3 alkyl groups.

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, cancer, 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 IIc:

• 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 6independently selected R1a groups;
• Z is O, S, or NRA;
• RA is H or C1-4 alkyl;
• R1, R2, R3, and R4 are each independently selected from hydrogen, halo, 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(C1-4 alkyl)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 alkylaminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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(C1-4 alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3alkoxy, amino, C1-3 alkylamino, and di-C1-3- alkylamino;
• and
• each R1a is independently selected from halo, CN, nitro, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl,C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di-C1-4-alkylamino, carboxy, carbamyl, C1-6 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6alkylcarbonyloxy, C1-6 alkylsulfonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di-C1-4 alkylaminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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 alkoxy, 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 3groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-C1-3- alkylamino;
• or
• two adjacent R1a taken together with the atoms to which they are attached can form a 3-7membered carbocyclic or 4-6 membered heterocyclic ring, each of which is optionally substituted with 1, 2, 3, or 4 C1-3 alkyl groups.

A method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, cancer, 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 6independently selected R1a groups;
• W is S or O;
• Y is S or O;
• each X is independently CH or 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, halo, 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(C1-4 alkyl)carbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylsulfonyl, C1-6 alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di-C1-4 alkylaminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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(C1-4 alkyl)carbamyl, and C1-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3alkoxy, amino, C1-3 alkylamino, and di-C1-3- alkylamino;
• and
• each R1a is independently selected from halo, CN, nitro, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino,di-C1-4-alkyiamino, carboxy, carbamyl, C1-6 alkylcarbamyl, di(C1-4 alkyl)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 alkylaminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino;
• 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 alkoxy, 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 3groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-C1-3- alkylamino;
• or
• two adjacent R1a taken together with the atoms to which they are attached can form a 3-7membered carbocyclic or 4-6 membered heterocyclic ring, each of which is optionally substituted with 1, 2, 3, or 4 C1-3 alkyl groups;
• wherein the method further comprises administering to the patient an adeno-associated vector (AAV) comprising SERCA2a.