Novel mitochondrial uncouplers for treatment of metabolic diseases and cancer

A compound of formula (I) having the structure:

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R1 is selected from the group consisting of H, M, PO(OH)2, PO2(OH)M, PO3M2, PO(OH)Ra, PO(OM)Ra, PO(Ra)2, and C(O)Ra, wherein M is a metal cation or an organic amine;
• R2, R3, R4, and R5 are each independently selected from the group consisting of H, halogen, CF3, SF3, CN, NO2, alkyl, aryl, COOH, COORa, and CONHRa;
• X is a 9-membered ring having the structure:
• wherein T is O, S, or NRa;
• W3, X3, X3′, Y3, and Z3 are each independently CRb or N;
• each Ra is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
• each Rb is independently selected from the group consisting of H, halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRC(N(Rd)2);
• each Rc is independently selected from the group consisting of H, CN, O-alkyl, NH2, mono-alkyl substituted amino, and di-alkyl substituted amino;
• and
• each Rd is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, or CONHRa;
• and provided that said 9-membered ring contains at least one nitrogen and is not indole.

A compound of formula (I) having the structure:

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R1 is selected from the group consisting of H, M, PO(OH)2, PO2(OH)M, PO3M2, PO(OH)Ra, PO(OM)Ra, PO(Ra)2, and C(O)Ra, wherein M is a metal cation or an organic amine;
• R2, R3, R4, and R5 are each independently selected from the group consisting of H, halogen, SF3, CF3, OCF3, CN, NO2, alkyl, aryl, CO2H, CO2Ra, and CONHRa;
• X is a six-membered heteroaryl having the structure:
• wherein two of W2, X2, Y2 and Z2 are N and the other two are CRb, and W2 and Z2 are not both N;
• each Ra is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
• and
• each Rb is independently selected from the group consisting of H, halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRc(N(Rd)2);
• each Rc is independently selected from the group consisting of H, CN, O-alkyl, NH2, mono-alkyl substituted amino, and di-alkyl substituted amino;
• each Rd is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, or CONHRa;
• and
• provided that when said six-membered heteroaryl is a pyrazine, Rb is selected from halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRc(N(Rd)2).

A compound of formula (I) having the structure:

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R1 is selected from the group consisting of H, M, PO(OH)2, PO2(OH)M, PO3M2, PO(OH)Ra, PO(OM)Ra, PO(Ra)2 and C(O)Ra, wherein M is a metal cation or an organic amine;
• R2, R3, R4, and R5 are each independently selected from the group consisting of H, halogen, CF3, SF3, CN, NO2, alkyl, aryl, COOH, COORa, and CONHRa;
• X is a pyridine ring substituted with one or more Rb, wherein each Rb is independently selected from the group consisting of halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRc(N(Rd)2), provided that said halogen is not substituted ortho to the ring nitrogen;
• each Ra is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
• each Rc is independently selected from the group consisting of H, CN, O-alkyl, NH2, mono-alkyl substituted amino, and di-alkyl substituted amino;
• and
• each Rd is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, or CONHRa.

A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

• R1 is selected from the group consisting of H, M, PO(OH)2, PO2(OH)M, PO3M2, PO(OH)Ra, PO(OM)Ra, PO(Ra)2, and C(O)Ra, wherein M is a metal cation or an organic amine;
• R2, R3, R4, and R5 are each independently selected from the group consisting of H, halogen, CF3, SF3, CN, NO2, alkyl, aryl, COOH, COORa, and CONHRa;
• X is optionally substituted with at least one Rb and X is selected from the group consisting of imidazole, pyrrole, tetrazole, cyano-thiazole, triazine, indazole, purine, benzimidazole, benzoxazole, benzothiazole, isoquinoline, and quinazoline;
• each Ra is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
• each Rb is independently selected from the group consisting of H, halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRc(N(Rd)2);
• each Re is independently selected from the group consisting of H, CN, O-alkyl, NH2, mono-alkyl substituted amino, and di-alkyl substituted amino;
• and
• each Rd is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, or CONHRa;
• provided that when X is cyano-thiazole, said cyano-thiazole is not substituted with tent-butyl.

A compound of formula (I) having the structure:

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R1 is selected from the group consisting of PO(OH)2, PO2(OH)M, PO3M2, PO(OH)Ra, PO(OM)Ra, PO(Ra)2, and C(O)Re, wherein M is a metal cation or an organic amine;
• R2, R3, R4, and R5 are each independently selected from the group consisting of H, halogen, CF3, SF3, CN, NO2, alkyl, aryl, COOH, COORa, and CONHRa;
• X is a C6-10aryl optionally substituted with one or more Rb;
• each Ra is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
• each Rb is independently selected from the group consisting of H, halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, alkyl, haloalkyl, CONHRa, and C═NRc(N(Rd)2);
• each Rc is independently selected from the group consisting of H, CN, O-alkyl, NH2, mono-alkyl substituted amino, and di-alkyl substituted amino;
• each Rd is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO2, CO2H, CO2Ra, CF3, OCF3, SF3, C6-10aryl, or CONHRa;
• and
• Re is NH2 optionally substituted with one or two alkyl groups.

A compound selected from the group consisting of

• N-(5-Bromopyrazin-2-yl)-5-chloro-2-hydroxybenzamide,
• 5-Chloro-N-(5-cyanopyrazin-2-yl)-2-hydroxybenzamide,
• 5-Chloro-N-(3-chloro-5-cyanopyrazin-2-yl)-2-hydroxybenzamide,
• 5-chloro-2-hydroxy-N-(pyrimidin-5-yl)benzamide,
• 5-Chloro-N-(2,4-dichloropyrimidin-5-yl)-2-hydroxybenzamide,
• 5-Chloro-N-(2-chloropyrimidin-5-yl)-2-hydroxybenzamide,
• 5-Chloro-N-(2-cyanopyrimidin-5-yl)-2-hydroxybenzamide,
• 5-Chloro-2-hydroxy-N-(pyridazin-3-yl)benzamide,
• 5-Chloro-N-(6-chloropyridazin-3-yl)-2-hydroxybenzamide,
• 5-Chloro-N-(5-cyanopyridin-2-yl)-2-hydroxybenzamide,
• N-(Benzo[d]thiazol-5-yl)-5-chloro-2-hydroxybenzamide,
• 5-Chloro-N-(5-cyanothiazol-2-yl)-2-hydroxybenzamide,
• N-(Benzo[d]thiazol-2-yl)-5-chloro-2-hydroxybenzamide,
• 5-Chloro-N-(4-fluorobenzo[d]thiazol-2-yl)-2-hydroxybenzamide,
• 4-Chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl dihydrogen phosphate,
• Sodium 4-chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl phosphate phosphate,
• 5-Chloro-2-hydroxy-N-(isoquinolin-7-yl)benzamide,
• 5-Chloro-2-hydroxy-N-(quinoxalin-6-yl)benzamide,
• 4-Chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl dimethylcarbamate,
• 4-chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl [1,4′-bipiperidine]-1′-carboxylate,
• 4-chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl[1,4′-bipiperidine]-1′-carboxylate,
• 4-Chloro-2-((5-cyanopyrazin-2-yl)carbamoyl)phenyl ethylcarbamate,
• 5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-hydroxybenzamide,
• 4-Chloro-2-((6-fluorobenzo[d]thiazol-2-yl)carbamoyl)phenyl dimethylcarbamate,
• 5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide,
• 4-chloro-244-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamoyl)phenyl, dimethylcarbamate,
• 5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide,
• 4-chloro-246-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamoyl)phenyl, dimethylcarbamate,
• 4-chloro-2-((4-fluorobenzo[d]thiazol-2-yl)carbamoyl)phenyl dimethylcarbamate,
• 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl dimethylcarbamate,
• 5-chloro-2-hydroxy-N-(5-(trifluoromethyl)pyrazin-2-yl)benzamide,
• 5-chloro-N-(6-cyanobenzo[d]thiazol-2-yl)-2-hydroxybenzamide,
• 4-chloro-2-((2-chloro-4-cyanophenyl)carbamoyl)phenyl ethyl hydrogen phosphate,
• 4-chloro-2-((2-chloro-4-cyanophenyl)carbamoyl)phenyl dihydrogen phosphate, or
• sodium 4-chloro-2-((2-chloro-4-cyanophenyl)carbamoyl)phenyl phosphate, and pharmaceutically acceptable salt thereof.