Antiparasitic Agents Based On mTOR Inhibitors

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (VI),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein
• R1, R2, R3, and R4 are each independently hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, NRaRb, C(O)Ra, or C(O)NRaRb;
• R5 and R6 are each independently hydrogen or C1-C4 alkyl;
• X1 and X2 are each independently CRaRb, O, S, NRa, NC(O)Ra, or NC(O)ORa;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl, or —C1-C4 alkyl O—C1-C4 alkyl;
• and
• n1, n2, and n3 are each independently 0, 1, 2, 3, or 4.

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (II),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein
• R7, R8, R9, and R10 are each independently hydrogen, C1-C4 alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C(O)Ra, C(O)ORa, or C(O)NRaRb;
• R11, R12 and R13 are each independently hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, NRaRb, C(O)Ra, or C(O)NRaRb;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl;
• and
• n4 is 0, 1, 2, 3, or 4.

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (III),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein R14 is hydrogen, —C1-C4 alkyl-NRaC(O)ORa, or
• R15 is hydrogen, C1-C4 alkyl, aryl, heteroaryl, NRaRb, or
• Rc and R16 are each independently hydrogen or C1-C4 alkyl;
• R17 is hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, OC(O)Ra, NRaRb, NRaC(O)Ra, NRaC(O)ORa, C(O)Ra, or C(O)NRaRb;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl, or —C1-C4 alkyl O—C1-C4 alkyl;
• X is C or N;
• X3 and X4 are each independently CRaRb, O, S, NRa, NC(O)Ra, or NC(O)ORa;
• and
• n5, n6, and n7 are each independently 0, 1, 2, 3, or 4.

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (IV),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein
• R18, R19, and R20 are each independently hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, OC(O)Ra, NRaRb, NRaC(O)Ra, NRaC(O)ORa, C(O)Ra, or C(O)NRaRb;
• R21 is hydrogen or C1-C4 alkyl;
• X5 and X6 are each independently CRaRb, O, S, NRa, NC(O)Ra, or NC(O)ORa;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl, or —C1-C4 alkyl O—C1-C4 alkyl;
• and
• n8, n9, and n10 are each independently 0, 1, 2, 3, or 4.

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (V),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein
• R24 is hydrogen, C1-C4 alkyl, aryl, heteroaryl, NRaRb,
• R22 and R23 are each independently hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, C1-C4 alkyl-ORa, OC(O)Ra, NRaRb, NRaC(O)Ra, NRaC(O)ORa, C(O)Ra, or C(O)NRaRb;
• R25 and R26 are each independently hydrogen or C1-C4 alkyl;
• X7 and X8 are each independently CRaRb, O, S, NRa, NC(O)Ra, or NC(O)ORa;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl, or —C1-C4 alkyl-O—C1-4 alkyl;
• Y is C or N;
• and
• n11, n12, n13, and n14 are each independently 0, 1, 2, 3, or 4.

A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (VII),

• or a pharmaceutically acceptable salt or hydrate thereof,
• wherein
• R35, R36, R37, and R38 are each independently hydrogen, halogen, OH, CF3, C1-C4 alkyl, ORa, OC(O)Ra, NRaRb, NRaC(O)Ra, NRaC(O)ORa, C(O)Ra, or C(O)NRaRb;
• R39 is hydrogen or C1-C4 alkyl;
• X9 is CRaRb, O, S, NRa, NC(O)Ra, or NC(O)ORa;
• Ra and Rb are each independently hydrogen, C1-C4 alkyl, benzyl, pyridin-3-ylmethyl, —O—C1-C4 alkyl, or —C1-C4 alkyl O—C1-C4 alkyl;
• and
• n18 and n19 are each independently 0, 1, 2, 3, or 4.