Combination therapy using a chemokine receptor 2 (ccr2) antagonist and a pd-1/pd-l1 inhibitor

A method of treating colorectal cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor to the subject, wherein the CCR2 chemokine receptor antagonist has the formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X3 and X4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, —C(O)R18, —CO2R18, —C(O)NR18R19, —OR18, —OC(O)R19, —OC(O)NR18R19, —NO2, —NR18C(O)R19, —NR18C(O)NR19R20, —NR18R19, —NR18CO2R19, —NR18S(O)2R19, —SR18, —S(O)R18, —S(O)2R18, —S(O)2NR18R19, substituted or unsubstituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
• R18, R19, and R20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
• or
• R18 and R19, R19 and R20, or R18 and R20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
• Y9 is selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR21, —CO2R21, —OC(O)R21, —OC(O)NR21R22, —C(O)NR21R22, —C(O)R21, —SR21, —S(O)R21, —S(O)2R21, —NR21R22, —NR21C(O)R22, —NR21C(O)2R22, —NR21S(O)2R22, —NR21C(O)NR22R23, substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
• R21, R22, and R23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
• or
• R21 and R22, R22 and R23, or R21 and R23 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
• and
• Y11 is —CH—, —N—, and —N+(O)−—.