Gpx4 inhibitors, pharmaceutical compositions thereof, and their use for treating gpx4-mediated diseases

A compound of Formula (I):

• or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
• or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• E is O, S, NRa, or NOR1a;
• L is a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, C7-15 aralkylene, heteroarylene, or heterocyclylene;
• X and Y are:
• (i) X is a bond, —NRX—, or —O—;
• and Y is —NRY—, —NRYO—, or —O—;
• or (ii) X is —NRX— or —O—;
• and Y is a bond;
• wherein each RX and RY is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• R1 is
• or —CH2—R2b, wherein R2a is hydrogen, deuterium, or C1-6 alkyl;
• and R2b is halo, —OS(O)2R1a, or —OS(O)2OR1a;
• R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• R4 and R5 together with the carbon atom to which they are attached form C3-10 cycloalkyl or heterocyclyl;
• or R4 and R5 are each independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• R6 is hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• and
• each R1a is independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, wherein each Q is independently selected from:
• (a) deuterium, cyano, halo, nitro, and oxo;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Qa;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SRa, —OC(NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(NRd)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa;
• or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more substituents Qa;
• wherein each Qa is independently selected from:
• (a) deuterium, cyano, halo, nitro, and oxo;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRfRg, —NReC(O)SRf—NReC(NRh)NRfRg, —NReC(S)Rh—NReC(S)OR, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
• wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) R and Rg together with the N atom to which they are attached form heterocyclyl.