Crbn ligand, preparation method therefor, and application

A compound having a structure represented by formula I, or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, a nitrogen oxide, a metabolite, a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isotope-labeled compound, or a prodrug thereof:

• wherein
• X1, X2, X3, X4, X5, and X6 are each independently a bond, carbon, nitrogen, oxygen, or sulfur;
• ring W is a 5-, 6-, or 7-membered ring;
• the bonds connected to X1, X2, X3, X4, X5, and X6 each independently represent a single bond or a double bond;
• two bonds connected to the same atom are not simultaneously double bonds;
• when X1, X2, X3, X4, X5, or X6 is oxygen or sulfur, the bonds connected thereto are single bonds;
• each Ra is independently hydrogen, deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, carboxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl C1-6 alkyl, 5- to 10-membered heteroaryl C1-6 alkyl, C3-6 cycloalkyl C1-6 alkyl, 3- to 6-membered heterocyclyl C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C6-10 aryloxy, 5- to 10-membered heteroaryloxy, C3-6 cycloalkyloxy, 3- to 6-membered heterocyclyloxy, C6-10 arylamino, 5- to 10-membered heteroarylamino, C3-6 cycloalkylamino, or 3- to 6-membered heterocyclylamino;
• optionally, two Ra are connected to form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl C1-6 alkyl, 5- to 10-membered heteroaryl C1-6 alkyl, C3-6 cycloalkyl C1-6 alkyl, 3- to 6-membered heterocyclyl C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C6-10 aryloxy, 5- to 10-membered heteroaryloxy, C3-6 cycloalkyloxy, 3- to 6-membered heterocyclyloxy, C6-10 arylamino, 5- to 10-membered heteroarylamino, C3-6 cycloalkylamino, 3- to 6-membered heterocyclylamino, and the 3- to 7-membered monocyclic carbocycle or 3- to 7-membered monocyclic heterocycle formed by the connection of two Ra are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
• Rb is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl;
• optionally, Rb and Ra are connected to form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and the 3- to 7-membered monocyclic carbocycle or 3- to 7-membered monocyclic heterocycle formed by the connection of Rb and Ra are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• Y is a bond, NH, CH2, CH2CH2, NHCH2, or CH2NH;
• optionally, Y is substituted with 1, 2, 3, or 4 RY;
• each R′ is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O═), thio (S═), C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• Z is NH, O, S, or CH2;
• optionally, Z is substituted with 1 or 2 RZ;
• each RZ is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O═), thio (S═), C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• optionally, RZ and Ra, or RZ and Rb, are connected to form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, and the 3- to 7-membered monocyclic carbocycle or 3- to 7-membered monocyclic heterocycle formed by the connection of RZ and Rb are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• Rc is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• U is CH2, NH, O, or S;
• E and A are each independently a bond, CH2, NH, O, or S, wherein E and A are not simultaneously a bond, NH, or O;
• optionally, U, E, and A are each independently substituted with 1 or 2 Re;
• each Rc is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo (O═), thio (S═), C1-6 alkyl, NH2C(═O)—, C1-6 alkyl C(═O)—, C1-6 alkyl S(═O)—, C1-6 alkyl S(═O)2—, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• optionally, two Rc attached to the same carbon atom, together with the atom to which they are attached, form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle;
• the C1-6 alkyl, NH2C(═O)—, C1-6 alkyl C(═O)—, C1-6 alkyl S(═O)—, C1-6 alkyl S(═O)2—, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• Q1, Q2, Q3, and Q4 are each independently CH or N;
• each Rd is independently hydrogen, deuterium, halogen, cyano, hydroxyl, sulfhydryl, nitro, amino, carboxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl C1-6 alkyl, 5- to 10-membered heteroaryl C1-6 alkyl, C3-6 cycloalkyl C1-6 alkyl, 3- to 6-membered heterocyclyl C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C6-10 aryloxy, 5- to 10-membered heteroaryloxy, C3-6 cycloalkyloxy, 3- to 6-membered heterocyclyloxy, C6-10 arylamino, 5- to 10-membered heteroarylamino, C3-6 cycloalkylamino, 3- to 6-membered heterocyclylamino, NH2C(═O)—, C1-6 alkyl NHC(═O)—, C1-6 alkyl C(═O)NH—, C1-6 alkyl C(═O)—, C1-6 alkyl S(═O)—, C1-6 alkyl S(═O)2—, C1-6 alkyl OC(═O)—, C1-6 alkyl S(═O)NH—, C1-6 alkyl S(═O)2NH—, C6-10 aryl C(═O)—, C6-10 aryl S(═O)—, C6-10 aryl S(═O)2—, C6-10 aryl OC(═O)—, C6-10 aryl S(═O)NH—, or C6-10 aryl S(═O)2NH—;
• optionally, two adjacent Rd are connected to form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl C1-6 alkyl, 5- to 10-membered heteroaryl C1-6 alkyl, C3-6 cycloalkyl C1-6 alkyl, 3- to 6-membered heterocyclyl C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C6-10 aryloxy, 5- to 10-membered heteroaryloxy, C3-6 cycloalkyloxy, 3- to 6-membered heterocyclyloxy, C6-10 arylamino, 5- to 10-membered heteroarylamino, C3-6 cycloalkylamino, 3- to 6-membered heterocyclylamino, NH2C(═O)—, C1-6 alkyl NHC(═O)—, C1-6 alkyl C(═O)NH—, C1-6 alkyl C(═O)—, C1-6 alkyl S(═O)—, C1-6 alkyl S(═O)2—, C1-6 alkyl OC(═O)—, C1-6 alkyl S(═O)NH—, C1-6 alkyl S(═O)2NH—, C6-10 aryl C(═O)—, C6-10 aryl S(═O)—, C6-10 aryl S(═O)2—, C6-10 aryl OC(═O)—, C6-10 aryl S(═O)NH—, C6-10 aryl S(═O)2NH—, and the 3- to 7-membered monocyclic carbocycle or 3- to 7-membered monocyclic heterocycle formed by the connection of two adjacent Rd are each independently optionally substituted with 1, 2, 3, 4, or 5 Rd1, each Rd1 being independently selected from deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and C1-6 alkyl OC(═O)—;
• optionally, two Rd1 are connected to form a 3- to 7-membered monocyclic carbocycle or a 3- to 7-membered monocyclic heterocycle, wherein the 3- to 7-membered monocyclic carbocycle or 3- to 7-membered monocyclic heterocycle formed by the connection of two Rd1 is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from hydrogen, deuterium, oxo (O═), thio (S═), halogen, cyano, hydroxyl, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl;
• m is 0, 1, 2, 3, or 4.