Small molecule degraders of STAT3

A compound of Formula I:

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• R1a and R1b are independently selected from the group consisting of hydrogen, C1-C4 alkyl, and —CH2OC(═O)R1e;
• R1e is C1-C6 alkyl;
• M is selected from the group consisting of —O— and —C(R2a)(R2b)—;
• R2a and R2b are independently selected from the group consisting of hydrogen and fluoro;
• or
• R2a and R2b taken together with the carbon atom to which they are attached form a —C(═O)— group;
• A is selected from the group consisting of:
• wherein the bond designated with an “*” is attached to —C(═O)-E-QA,
• G1 is selected from the group consisting of —O—, —S—, and —NR17—;
• G2 is —CR18a═;
• G3 is —CR18b═;
• G4 is —CR18c═;
• G5 is —CR18d═;
• G6 is —CR18e═;
• G is selected from the group consisting of —N═ and —CR18f═;
• R3 is hydrogen;
• R3b is C1-C4 alkyl;
• R3c is hydrogen;
• R17 is selected from the group consisting of hydrogen and C1-C4 alkyl;
• R18a, R18b, R18c, R18d, R18e, and R18f are hydrogen;
• E is:
• wherein the bond designated with an “*” is attached to QA;
• R3g is hydrogen;
• XA is selected from the group consisting of —N(R8)CH2—, —CH2N(R8)—, and —CH2CH2—;
• R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (optionally substituted 5- to 8-membered heterocyclo)C1-C6 alkyl-, C1-C6 alkylsulfonyl, —C(═O)R9, and -L-B;
• R9 is selected from the group consisting of C1-C6 alkyl, amino, C1-C6 alkoxy, optionally substituted 4- to 8-membered heterocyclo, and optionally substituted 5- to 10-membered heteroaryl;
• QA is selected from the group consisting of:
• X1 is selected from the group consisting of —CH2—, —O—, and —N(R11a)—;
• or
• X1 is absent;
• R10 is hydrogen;
• R11a is hydrogen;
• s is 2 or 3;
• X2 is selected from the group consisting of —CH2—, —O—, and —N(R11b)—;
• or
• X2 is absent;
• t is 2 or 3;
• R11b is hydrogen;
• R12a is selected from the group consisting of hydrogen, C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6-cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, and (amino)(C6-C14 aryl)C1-C6 alkyl-;
• R12b is selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted C6-C14 aryl, and (optionally substituted C6-C14 aryl)C1-C6 alkyl;
• or
• R12a and R12b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo,
• R12c is hydrogen;
• X4 is —CH2—;
• or
• X4 is absent;
• v is 0, 1, or 2;
• R12d is hydrogen;
• R13a is selected from the group consisting of hydrogen, optionally substituted C6-C14 aryl, (optionally substituted C6-C14 aryl) C1-C6 alkyl-, (optionally substituted C3-C6 cycloalkyl)C1-C6 alkyl-, and optionally substituted 5- to 9-membered heteroaryl;
• R13b is hydrogen;
• R13c is hydrogen;
• or
• R13a and R13b taken together form an optionally substituted C3-C8 cycloalkyl or an optionally substituted C4-C9 heterocyclo;
• or
• R13b and R13c taken together form an optionally substituted 4- to 9-membered heterocyclo;
• A2* is selected from the group consisting of —C(R14b)— and —N—;
• R14b is hydrogen;
• g is 2;
• h is 2;
• X5 is —CH2—;
• or
• X5 is absent;
• y is 1 or 2;
• R15 is optionally substituted C6-C14 aryl;
• L is -J1-Y1-J2-Y2-J3-Z—;
• J1 is selected from the group consisting of C1-12 alkylenyl, 4- to 8-membered heterocyclenyl, and 5- to 9-membered heteroarylenyl;
• or
• J1 is absent;
• Y1 is selected from the group consisting of —(CH2)m— and —C≡C—;
• m is 0, 1, or 2;
• J2 is C1-12 alkylenyl;
• or
• J2 is absent;
• Y2 is selected from the group consisting of —(CH2)n—;
• n is 0, 1, 2, 3, or 4;
• J3 is C1-12 alkylenyl, 4- to 8-membered heterocyclenyl, and 5- to 9-membered heteroarylenyl;
• or
• J3 is absent;
• Z is selected from the group consisting of —(CH2)d—, —C≡C—, and, —N(R16c);
• d is 0, 1, 2, or 3;
• R16c is hydrogen;
• wherein Z is attached to B;
• B is selected from the group consisting of:
• A5 is —C(R19a)═;
• A2 is —C(R19a)±;
• A3 is —C(R19a)═;
• A4 is —C(R19a)═;
• Z1 is —CH2 and —C(═O)—;
• R5a is selected from the group consisting of hydrogen, methyl, and fluoro;
• R5b is selected from the group consisting of hydrogen and methyl;
• R19a, R19b, R19c, and R19d are each hydrogen;
• R20 is C4 alkyl;
• R21 is C1 alkyl;
• R23 is C1-C6 alkyl;
• and
• R24 is selected from the group consisting of, optionally substituted C3-C6 cycloalkyl and optionally substituted 5- to 14-membered heteroaryl,
• with the provisos:
• (1) when XA is —CH2CH2—, then QA is selected from the group consisting of Q-3, Q-5, Q-6, and Q-7;
• (2) when XA is —N(R8)CH2— or —CH2N(R8)—, and R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (optionally substituted 5- to 8-membered heterocyclo)C1-C6 alkyl-, C1-C6 alkylsulfonyl, and —C(═O) R9, then QA is selected from the group consisting of Q-3, Q-4, Q-5, Q-6, and Q-7;
• and
• (3) when XA is —N(R8)CH2— or —CH2N(R8)—, and R8 is-L-B, then QA is selected from the group consisting of Q-1 and Q-2.