Radiosensitization of tumors with indazolpyrrolotriazines for radiotherapy

A method of treating a tumor in a subject, comprising the steps of:

• (A) radiosensitizing the tumor by administering to the subject a radiosensitizing amount of an indazolpyrrolotriazine of Formula I:
• or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
• or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R is C6-14 aryl or heterocyclyl;
• R1 is C1-6 alkyl;
• R2 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• X is a bond, O, S, C(R3R4), or NR3;
• and
• each R3 and R4 is independently hydrogen, C1-6 alkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• wherein each alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl is optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(═NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRaRd, —NRaC(O)Rb, —NRaC(O)ORb, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rb, —NRaS(O)2Rb, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, and —S(O)2Ra;
• wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
• or (ii) Rb and Rc together with the N atom to which they are attached form heterocyclyl or heteroaryl;
• and
• (B) administering to the subject a therapeutically effective dose of radiation.

A method of radiosensitizing a cell, comprising contacting the cell with a radiosensitizing amount of an indazolpyrrolotriazine of Formula I:

• or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
• or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R is C6-14 aryl or heterocyclyl;
• R1 is C1-6 alkyl;
• R2 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• X is a bond, O, S, C(R3R4), or NR3;
• and
• each R3 and R4 is independently hydrogen, C1-6, alkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• wherein each alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl is optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(═NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRaRd, —NRaC(O)Rb, —NRaC(O)ORb, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rb, —NRaS(O)2Rb, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, and —S(O)2Ra;
• wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
• or (ii) Rb and Rc together with the N atom to which they are attached form heterocyclyl or heteroaryl.

A method of inhibiting the growth of a cell, comprising the steps of:

• (A) radiosensitizing the cell by contacting the cell with a radiosensitizing amount of an indazolpyrrolotriazine of Formula I:
• or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
• or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R is C6-14 aryl or heterocyclyl;
• R1 is C1-6 alkyl;
• R2 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• X is a bond, O, S, C(R3R4), or NR3;
• and
• each R3 and R4 is independently hydrogen, C1-6 alkyl, C6-14 aryl, C7-20 aralkyl, or heterocyclyl;
• wherein each alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl is optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(═NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRaRd, —NRaC(O)Rb, —NRaC(O)ORb, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rb, —NRaS(O)2Rb, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, and —S(O)2Ra;
• wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
• or (ii) Rb and Rc together with the N atom to which they are attached form heterocyclyl or heteroaryl;
• and
• (B) exposing the cell to an effective fraction of radiation sufficient to inhibit the cell growth.