Bifunctional chimeric heterocyclic compound and use thereof as androgen receptor degrader

A compound represented by formula I, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or a mesomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a metabolite thereof, or a metabolic precursor thereof, or an isotope-substituted form thereof:

• wherein TB is a target recognition/binding moiety, L is a linker, and U is a ubiquitin protease recognition/binding moiety;
• the three moieties are linked by a chemical bond;
• Wherein, the above TB moiety has a structure represented by formula I-A:
• wherein, A is absent, aromatic ring, heteroaromatic ring, non-aromatic heterocycle, non-aromatic carbon ring, bridged ring, spiral ring, fused heterocycle, and fused heteroaromatic ring;
• the aromatic ring comprises a benzene ring;
• the heteroaromatic ring comprises 5-6 membered heteroaromatic rings;
• the non-aromatic heterocycles comprise 3-7 membered non-aromatic heterocycles;
• the non-aromatic carbon ring comprises 3-7 membered non-aromatic carbon rings;
• the fused heterocycle comprises a (5-6-membered heterocycle)-fused 5-6-membered heterocycle;
• the fused heteroaromatic ring comprises a (5-6-membered heteroaromatic ring)-fused 5-6-membered heterocycle, and a (5-6-membered heteroaromatic ring)-fused 5-6-membered heteroaromatic ring;
• wherein, R1 and R2 are each independently selected from the group consisting of absence, hydrogen, halogen, cyano, amino, hydroxyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthiol, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylcarbonyl, C1-C6 alkylaminocarbonyl, —NR3R4, —CRaR3R4, —NR3—CO—R4, —CO—NR3R4, —NR3—SO2—R4, —SO2—NR3R4, —CO—R3, —SO—R3, —SO2—R3, —CR3═CH2, —OR3, —SR3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted fused heterocyclyl, substituted or unsubstituted spiro-heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, and substituted or unsubstituted phenyl;
• R1 and R2 can be linked to form a ring;
• wherein, the substituted substituents are Ra, R3, and R4, which are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted phenylcarbonyl, and sulfonyl;
• any two of R3, R3, and R4 can be linked to form a 3-8-membered ring, the substituted substituents are selected from the group consisting of halogen, amino, hydroxyl, and hydroxyl-substituted C1-6 alkyl;
• wherein, G1 and G2 are each independently linked to A by a chemical bond;
• wherein G1 is selected from the group consisting of absence, —(CH2)y—, —(CH2)m—CRg1Rg2—, —(CH2)m—CO—, O, S, SO, SO2 and NRg1;
• G2 is selected from the group consisting of absence, —(CH2)n—CRg3Rg4—, —(CH2)n—O—, O, S, SO, SO2, and NRg2;
• wherein y, m, and n are integers from 0 to 3;
• Rg1, Rg2, Rg3, and Rg4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and hydroxyl;
• Rg1 and Rg2, Rg3 and Rg4 can be linked to form a ring;
• when G1 and G2 are both absent, X is directly linked to A by a chemical bond;
• wherein, X is selected from the group consisting of —N—, —NR5—, —O—, —S—, —CO—, —SO—, —SO2—, —CONR5—, —NR5CO—, —CH—, —CHR5—, and —CR5R5′—;
• said R5 and R5′ are each independently selected from the group consisting of H and C1-C6 alkyl;
• wherein, rings B and C are each independently selected from the group consisting of substituted or unsubstituted benzene ring, thiophene, pyridine, pyrimidine, 5-6-membered aromatic heterocycle, 3-8-membered cycloalkane, and 3-8-membered heterocycle;
• the substituted substituents are halogen and cyano;
• wherein, B1 and B2 are each independently selected from the group consisting of H, halogen, and C1-C6 alkyl;
• or B1, B2 and X are linked to form a ring;
• wherein, Z is selected from the group consisting of —C—, —CO—, —CH—, —CH2—, —O—, —N—, —S—, —SO—, and —SO2—;
• wherein, T1 and T2 are each independently selected from the group consisting of absence, H, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, C1-C6 oxaalkyl, C1-C6 azaalkyl, C3-C6 cycloalkyl, acyl, C1-C6 alkoxy, and C1-C6 alkylamino;
• or T1 and T2 can be linked to each other to form a ring;
• the substituted substituent is hydroxyl or amino;
• wherein, L1 and L2 are each independently selected from the group consisting of H, halogen, cyano, amino, hydroxyl, and C1-C6 alkyl;
• wherein, said L moiety has a structure as represented by formula I-L:
• wherein, Q, J, Y, W, and V are each independently selected from the group consisting of absence, —O—, —S—, —SO—, —SO2—, —NRg1—, —NRj1—, —C═C—, —C═C—, —NRq1CO—, —NRj1CO—, —CO—, —CONH—, —NRq11SO2—, —CRg1Rq2—, —CRy1Ry2, —CRw1Rw2—, —CRv1Rv2—, —CRj1Rj2—, —[(OCH2CH2O)2]n5—, —[(OCH2CH2O)3]n6—, (Rc,Rd)-substituted or unsubstituted 3-7-membered cycloalkyl, (Rc,Rd)-substituted or unsubstituted 3-7-membered heterocyclyl, (Rc,R4)-substituted or unsubstituted phenyl, (Rc,Rd)-substituted or unsubstituted aromatic heterocyclyl, (Rc,Rd)-substituted or unsubstituted fused aromatic heterocyclyl;
• said Rc and Rd are each independently selected from H, halogen, and C1-3 alkyl;
• or Rc and Rd can be linked to each other to form a ring;
• wherein, Rq1, Rq2, Ry1, Ry2, Rw1, Rw2, Rv1, Rv2, Rj1, and Rj2 are each independently selected from the group consisting of H;
• halo-substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 oxaalkyl, C1-C6 azaalkyl, C3-C6 oxacycloalkyl, and C3-C6 azacycloalkyl;
• wherein, Rq1 and Rq2, Ry1 and Ry2, Rw1 and Rw2, Rv1 and Rv2, and Rj1 and Rj2 can be linked to each other to form a ring;
• wherein, n1, n2, n3, n4, n5, and n6 are each independently selected from an integer of 0 to 6;
• wherein, Q and J can freely linked to TB moiety or U moiety;
• wherein, said U moiety has a structure as represented by formula I-U:
• wherein, M is selected from the group consisting of —O—, —S—, —CRm—, and —NRm—;
• wherein, Rm is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and C3-6 heteocyclyl, and
• said Rm1 is selected from the group consisting of H, C1-6 alkyl, and C3-6 cycloalkyl;
• Xm is selected from the group consisting of —CRm2Rm3—, —ORm2—, and —NRm2Rm3—, wherein, Rm2 and Rm3 are each independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and C3-6 heteocyclyl, and C1-6 oxaalkyl;
• Rm2 and Rm3 can be linked to form a ring;
• E1 and E2 are each independently selected from the group consisting of —CO—, —CS—, —NRc1—, —O—, —S—, —SO2—, —CH2—, —CD2-, —CRc2Rc3—,
• Rc1, Rc2, and Rc3 are each independently selected from the group consisting of C1-6 alkyl, H, halogen, hydroxyl, and amino;
• Y1, Y2, and Y3 are each independently selected from the group consisting of H, O, S, and C1-3 alkyl;
• J and k are each independently selected from an integer of 0 to 3, and J and k are not both 0;
• U1, U2, U3, and U4 are each independently selected from the group consisting of O, S, N, —CRg1—, —CRg2—, —CRg3, and —CRg4, wherein Rg1, Rg2, Rg3, and Rg4 are each independently selected from the group consisting of H, halogen, hydroxyl, amino, thiol, sulfonyl, sulfinyl, nitro, cyano, CF3, heterocyclyl, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, and C2-6 alkynyl.