Mitochondrial uncouplers for treatment of metabolic diseases and cancer

A compound of Formula Ia

• wherein R1a is selected from the group consisting of —CH3, —CH2CH3, —(CH2)N(CH2CH2OCH3)2,
• and
• R4d is selected from the group consisting of CH2OH, —CH2OCH2CH3, —CH2OCH3, —CH2O(CH2)2OH, —CH2O(CH2)2OCH3, —CH2O(CH2)2NHCH3, —CH2O(CH2)2N(CH3)2, —CH2O(CH2)2NHSO2CH3,
• —OCH3;
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

A compound of Formula IIa

• wherein
• R10a is selected from the group consisting of —OCH3, —CH2OCH3, —CH2OCH2OCH3, —CH2O(CH2)2OH, —CH2O(CH2)2OCH3, —(CH2)NH(CH2)2OCH3, —CH2NHC(O)CH3,
• CH2N(CH3)(CH2)2OCH3, —(CH2)N(CH2CH2OCH3)2, —CH2N(CH3)(CH2)2O(CH2)2OCH3,
• and C(O)N(CH2CH2OCH3)2;
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

A compound of Formula IIIa

• wherein R100a is selected from the group consisting of —CH3, —(CH2)N(CH2CH2OCH3)2, CH3,
• and
• R400d is selected from the group consisting of —CH2NHC(O)CH2CH3, —CH2NHC(O)CH2OCH3, —CH2NHSO2CH3, —CH2N(CH3)2
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

A method of preparing a mitochondrial membrane-retaining mitochondrial uncoupler comprising:

• 1. identifying a conventional mitochondrial uncoupler;
• 2. designing a compound that covalently links at least one secondary or tertiary amino moiety to a conventional mitochondrial uncoupler;
• and
• 3. preparing the compound of step 2, wherein the compound is a mitochondrial membrane retaining uncoupler compound.

A mitochondrial membrane-retaining uncoupler compound of the Formula:

• or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• wherein RA and RB are covalently linked;
• each RA is independently a moiety containing a secondary or tertiary amine;
• u is an integer selected from the group consisting of 1 and 2;
• and
• RB is a conventional mitochondrial uncoupler prior to being covalently linked to RA;
• provided the mitochondrial membrane-retaining uncoupler compound is not