Sos1 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:
• L is a linker;
• one of U, V, X, and Y is —C═ or —N—;
• and the remaining three of U, V, X, and Y are each independently —C(R4)═ or —N═;
• R1 and R3 are each 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;
• R2 is C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heteroaryl-C1-6 alkylene, or heterocyclyl;
• each R4 is independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo;
• (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, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(O)SR1d, —NR1aC(N1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —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;
• 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;
• RE 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, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclyl 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) 0-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, 0-15 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)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, —OP(O)(ORb)ORc, —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, —NR C(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)R, —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, 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)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, —OP(O)(ORf)ORg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(O)SRf, —NReC(NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NfRg, —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 R9 together with the N atom to which they are attached form heterocyclyl.