Asymmetric triazole benzamide derivatives and the compositions and methods of treatment regarding the same

A method of modulating a Parkin ligase, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• L1, L2 and Care each independently selected from a bond, alkylene, or alkenylene,
• M1 and M2 are each independently selected from —NR4—, —NR4C(O)—, —N(C(O)R1)—, —C(O)NR4—, —NR4C(O)NR4—, —C(O)—, —C(═NR4)—, —C(═NOR4)—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NR4—, —NR4C(O)O—, —S(O)m—, —S(O)mNR4—, or —NR4S(O)m—, provided that M1 and M2 are not both —NR4—,
• R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
• R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
• R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
• R5 is each independently I, Br, Cl, F, —CH2F, —CF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NH2, —NHR6, —NO2, —NR6R6, —N3, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, or —SR6;
• R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl;
• or alternatively two R6 on the same N atom can together form a 3-6 membered N-heterocyclyl;
• R7 is each independently I, Br, Cl, F, —CH2F, —CHF2, —CF3, —OCF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NH2, —NHR6, —NO2, —NR6R6, —N3, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, —SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
• m is 0, 1, or 2;
• and
• wherein the compound is not N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)dibenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)furan-2-carboxamide, N-(5-cinnamamido-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N-(1-phenyl-5-(phenylamino)-1H-1,2,4-triazol-3-yl)benzamide, 4-fluoro-N-(5-(4-methoxybenzamido)-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)bis(4-methylbenzamide), N-(5-((2-chlorobenzyl)amino)-1-phenyl-1H-1,2,4-triazol-3-yl)-2-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-nitrobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)carbamoyl)benzoic acid.

A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• L1, L2 and L3 are each independently selected from a bond, alkylene, or alkenylene;
• M1 and M2 are each independently selected from —NR4—, —NR4C(O)—, —N(C(O)R1)—, —C(O)NR4—, —NR4C(O)NR4—, —C(O)—, —C(═NR4)—, —C(═NOR4)—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NR4—, —NR4C(O)O—, —S(O)m—, —S(O)mNR4—, or —NR4S(O)m—, provided that M1 and M2 are not both —NR4—;
• R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
• R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
• R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
• R5 is each independently I, Br, Cl, F, —CH2F, —OCF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NH2, —NHR6, —NO2, —NR6R6, —N3, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, or —SR6;
• R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl;
• or alternatively two R6 on the same N atom can together form a 3-6 membered N-heterocyclyl;
• R7 is each independently I, Br, Cl, F, —CH2F, —CHF2, —CF3, —OCF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NH2, —NHR6, —NO2, —NR6R6, —N3, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, —SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
• m is 0, 1, or 2;
• and
• wherein the compound is not N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)dibenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)furan-2-carboxamide, N-(5-cinnamamido-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N-(1-phenyl-5-(phenylamino)-1H-1,2,4-triazol-3-yl)benzamide, 4-fluoro-N-(5-(4-methoxybenzamido)-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)bis(4-methylbenzamide), N-(5-((2-chlorobenzyl)amino)-1-phenyl-1H-1,2,4-triazol-3-yl)-2-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-nitrobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)carbamoyl)benzoic acid.

A method of treating Parkinson's Disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• L1, L2 and L3 are each independently selected from a bond, alkylene, or alkenylene,
• M1 and M2 are each independently selected from —NR4—, —NR4C(O)—, —N(C(O)R1)—, —C(O)NR4—, —NR4C(O)NR4—, —C(O)—, —C(═NR4)—, —C(═NOR4)—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NR4—, —NR4C(O)O—, —S(O)m—, —S(O)mNR4—, or —NR4S(O)m—, provided that M1 and M2 are not both —NR4—;
• R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
• R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
• R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
• R5 is each independently I, Br, Cl, F, —CH2F, —CHF2, —CF3, —OCF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NHR6, —NO2, —NR6R6, —N, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, or —SR6;
• R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl;
• or alternatively two R6 on the same N atom can together form a 3-6 membered N-heterocyclyl;
• R7 is each independently I, Br, Cl, F, —CH2F, —CF, —OCF3, —CN, -alkyl-CN, —CONH2, —CONHR6, —CONR6R6, —COOH, —NH2, —NHR6, —NO2, —NR6R6, —N3, —OH, OR6, —COOR6, —OSO3R6, oxo, R6, —SH, —SO2R6, —SO3H, —SO3R6, —SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
• m is 0, 1, or 2;
• and
• wherein the compound is not N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)dibenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)furan-2-carboxamide, N-(5-cinnamamido-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N-(1-phenyl-5-(phenylamino)-1H-1,2,4-triazol-3-yl)benzamide, 4-fluoro-N-(5-(4-methoxybenzamido)-1-phenyl-1H-1,2,4-triazol-3-yl)benzamide, N,N′-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)bis(4-methylbenzamide), N-(5-((2-chlorobenzyl)amino)-1-phenyl-1H-1,2,4-triazol-3-yl)-2-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-fluorobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-4-nitrobenzamide, N-(3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido-1-phenyl-1H-1,2,4-triazol-5-yl)carbamoyl)benzoic acid.