Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications

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:
• R4A is -A-L-RE and R4B is R4;
• or R4A is R4 and R4B is -A-L-RE;
• A is a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
• L is a linker;
• RE is a moiety having the structure of
• R1, R3, and R4 are each independently (i) hydrogen, deuterium, cyano, halo, or nitro;
• (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(NR1a)NR1bR1c—OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1aR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(O)SR1d, —N1aC(NR1dR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1e, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heterocyclyl, or C1-6 alkyl-heterocyclylene;
• each R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• XE is C(RE2) or N;
• YE is a bond, C1-6 alkylene, —O—, —S—, —S(O)—, —S(O2)—, or —N(RE3)—;
• ZE is C6-14 arylene, heteroarylene, or C6-14 arylene-heteroarylene;
• RE1 is hydrogen or C1-6 alkyl;
• RE2 is hydrogen, deuterium, halo, or C1-6 alkyl;
• RE3 is hydrogen or C1-6 alkyl;
• and
• m is an integer of 0, 1, or 2;
• wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from:
• (a) deuterium, cyano, halo, imino, nitro, and oxo;
• (b) C1-6 alkyl, C1-6 heteroalkyl, 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, in one embodiment, one, two, three, or four, substituents Qa;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NR1bR1c, —C(O)SRa, —C(NRa)NR1bR1c, —C(S)Ra, —C(S)ORa, —C(S)NR1bR1c, —OR, —OC(O)Ra, —OC(O)ORa, —OC(O)NR1bR1c, —OC(O)SRa, —OC(NRa)NR1bR1c, —OC(S)Ra, —OC(S)ORa, —OC(S)NR1bR1c, —OP(O)(ORb)ORc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NR1bR1c, —OS(O)2NR1bR, —NR1bR1c, —NRaC(O)R1d, —NRaC(O)OR, —NRaC(O)NR—Rc, —NRaC(O)SR1d, —NRaC(NR1d)NR1bR1c, —NRaC(S)R1d, —NRaC(S)OR1d, —NRaC(S)NR1bR1c, —NRaS(O)R1d, —NRaS(O)2Rb, —NRaS(O)NR1bR1c, —NRaS(O)2NR1bR1c, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NR1bR1c, and —S(O)2NR1bR1c, wherein each Ra, Rb, Rc, and R1d is independently (i) hydrogen or deuterium;
• (ii) C1-6 alkyl, C1-6 heteroalkyl, 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, in one embodiment, one, two, three, or four, 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, in one embodiment, one, two, three, or four, substituents Qa;
• wherein each Qa is independently selected from:
• (a) deuterium, cyano, halo, nitro, imino, and oxo;
• (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Rc, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRc)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRc, —OC(NRe)—NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OP(O)(ORf)ORg, —OS(O)Re, —OS(O)2R, —OS(O)NRfR—, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NRcC(O)ORf, —NRcC(O)NRfRg, —NReC(O)SRf, —NReC(NRh)NRfRg, —NReC(S)Rh, —NReC(S)OR, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NRS(O)NRfRg, —NReS(O)2NRfR, —SW, —S(O)R, —S(O)2, —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) Rf and Rg together with the N atom to which they are attached form heterocyclyl.