Compound for degradation of bcl-2 family proteins and medical application thereof

A compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from a compound of general formula (I),

• B-L-K (I);
• L is selected from a bond or —C1-50 hydrocarbyl-, wherein the hydrocarbyl has 0 to 20 methylene units optionally further replaced by -Ak- or -Cy-;
• each -Ak- is independently selected from —(CH2)q—, —(CH2)q—O—, —O—(CH2)q—, —(CH2)q—NRL, —NRL—(CH2)q—, —(CH2)q—NRLC(═O)—, —NRL(CH2)qC(═O)—, —(CH2)q—C(═O)NRL, —C(═O)—, —C(═O)—(CH2)q—NRL—, —(C≡C)q—, —CH═CH—, —Si(RL)2—, —Si(OH)(RL)—, —Si(OH)2—, —P(═O)(ORL)—, —P(═O)(RL)—, —S—, —S(═O)—, —S(═O)2— or a bond, wherein the —CH2— is optionally further substituted with 0 to 2 substituents selected from H, halogen, OH, CN, NH2, C1-6 alkyl, C1-6 alkoxy, halogen-substituted C1-6 alkyl, hydroxyl-substituted C1-6 alkyl, or cyano-substituted C1-6 alkyl;
• each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
• each RL is independently selected from H, C1-6 alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered cycloalkyl, phenyl or 5- to 6-membered heteroaryl;
• each -Cy- is independently selected from a bond, a 4- to 8-membered mono-heterocyclic ring, a 4- to 10-membered fused-heterocyclic ring, a 5- to 12-membered spiro-heterocyclic ring, a 7- to 10-membered bridged-heterocyclic ring, 3- to 7-membered monocycloalkyl, 4- to 10-membered fused cycloalkyl, 5- to 12-membered spiro cycloalkyl, 7- to 10-membered bridged cycloalkyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl, mono-heterocyclic ring, fused-heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, ═O, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxyl-substituted C1-4 alkyl or C1-4 alkoxy, and the heteroaryl, mono-heterocyclic ring, fused-heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N, and is optionally further substituted with 0, 1 or 2 ═O when the heteroatom is selected from S;
• B is selected from
• W is selected from W1 or W2;
• W1 is selected from —CRw1Rw2—, —(CRw1Rw2)3—, —(CRw1Rw2)4—, —CH2CRw3Rw4—, —CRw3Rw4CH2—, —CRw1Rw2O—, —OCRw1Rw2—, —CRw1Rw2NRw5—, or —NRw5CRw1Rw2—;
• W2 is selected from —(CRw1Rw2)2—;
• D is selected from C1-4 alkylene;
• B1 and Z are each independently selected from a 4- to 7-membered mono-heterocyclic ring, a 5- to 12-membered fused-heterocyclic ring, a 6- to 12-membered spiro-heterocyclic ring, or a 7- to 12-membered bridged-heterocyclic ring, the B1 is optionally further substituted with 0 to 4 RB1, and the Z is optionally further substituted with 0 to 4 RQ, wherein the fused-heterocyclic ring, spiro-heterocyclic ring, or bridged-heterocyclic ring contains 1 to 3 heteroatoms selected from O, S or N, and is optionally further substituted with 0, 1 or 2 ═O when the heteroatom is selected from S;
• B2, B3, B4, and B5 are each independently selected from C6-10 aryl or 5- to 10-membered heteroaryl, the B2 is optionally further substituted with 0 to 4 RB2, the B3 is optionally further substituted with 0 to 5 RB3, the B4 is optionally further substituted with 0 to 4 RB4, and the B5 is optionally further substituted with 0 to 5 RB5, wherein the heteroaryl contains 1 to 3 heteroatoms selected from O, S or N;
• RB1, RQ, RB2, RB3, and RB5 are each independently selected from halogen, OH, oxo, CN, C1-4 alkyl or C1-4 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN or C1-4 alkyl;
• each RB4 is independently selected from —SO2—C1-4 alkyl, nitro, halogen, CN, OH, C1-4 alkyl or C1-4 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN or C1-4 alkyl;
• Rw1, Rw2 and Rw5 are each independently selected from H, halogen, CN, OH, C1-4 alkyl or C1-4 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN or C1-4 alkyl;
• alternatively, Rw1 and Rw2 are directly connected to form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN or C1-4 alkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
• Rw3 and Rw4 are directly connected to form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN or C1-4 alkyl, and the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
• alternatively, RB1 and RB2 are directly connected to form C5-7 carbocycle or 5- to 7-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 3 Rc, and the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
• each Rc is independently selected from halogen, OH, CN, ═O, C1-4 alkyl, C1-4 alkoxy, C3-6 carbocycle or 3- to 7-membered heterocycle, wherein the alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl, and the heterocycle or heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S or N,
• provided that when W2 is selected from —(CRw1Rw2)2—, and Rw1 and Rw2 are each independently selected from F, methyl or methoxy, B at least satisfies any one of the following conditions:
• 1) B1 is not piperazine;
• 2) Z is not piperazine, piperidine,
• 3) B3 is selected from phenyl substituted with 1 RB3, when RB3 is at the para-position of the phenyl, RB3 is not halogen, methyl or trifluoromethyl;
• 4) when B2 is selected from phenyl, the phenyl is substituted with 1 to 4 RB2;
• 5) RB1 and RB2 are directly connected to form C5-7 carbocycle or 5- to 7-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 3 Rc, and the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
• 6) when B5 is selected from phenyl, the phenyl is substituted with 1 to 4 RB5;
• K is selected from
• each Q is independently selected from a bond, —O—, —S—, —CH2—, —NRq—, —CO—, —NRqCO—, —CONRq— or 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-4 alkyl or C1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N;
• Rq is selected from H or C1-6 alkyl;
• A is selected from C3-10 carbocyclyl, C6-10 aryl, 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;
• each F is independently selected from C3-20 carbocyclyl, C6-20 aryl, 3- to 20-membered heterocyclyl or 5- to 20-membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;
• each Rk2 is independently selected from a bond, —CO—, —SO2—, —SO— or —C(Rk3)2—;
• each Rk1 is independently selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-4 alkyl or C1-4 alkoxy;
• each Rk3 is independently selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or 3- to 8-membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-4 alkyl or C1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N;
• or two Rk3 together with the carbon atoms or ring backbones to which they are directly attached form 3- to 8-membered carbocycle or 3- to 8-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-4 alkyl or C1-4 alkoxy, and the heterocycle contains 1 to 4 heteroatoms selected from O, S or N;
• each Rk4 is independently selected from H, OH, NH2, CN, CONH2, C1-6 alkyl, C3-8 cycloalkyl or 3- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C1-4 alkyl or C1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N;
• M1 is selected from a bond, —C(═O)NH—, —NHC(═O)—, —CH2—C(═O)NH—, —C(═O)CH2NH—, or 5- to 6-membered heteroaryl, wherein the heteroaryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, CF3, NH2, CN, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxyl-substituted C1-4 alkyl or C1-4 alkoxy, and the heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;
• M2 is selected from —NHC(═O)—C1-6 alkyl, —NHC(═O)—C3-6 cycloalkyl or 4- to 10-membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, ═O, OH, NH2, C1-4 alkyl or C1-4 alkoxy, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N;
• M3 is selected from —NH— or —O—;
• Rk10 is selected from C1-6 alkyl, wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, ═O, OH, C1-6 alkyl or C3-6 cycloalkyl;
• each Rk11 is independently selected from H, F, Cl, Br, I, ═O, OH, SH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio or —O—C(═O)—C1-6 alkyl, wherein the alkyl, alkoxy or alkylthio is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C1-4 alkyl or C1-4 alkoxy;
• Rk12 and Rk13 are each independently selected from H, C1-6 alkyl or C3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, ═O, OH, NH2, C1-4 alkyl or C1-4 alkoxy;
• Rk14 is selected from 5- to 6-membered heteroaryl, wherein the heteroaryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, CF3, CN, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxyl-substituted C1-4 alkyl, C1-4 alkoxy or C3-6 cycloalkyl, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O or S;
• G is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, CF3, CN, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxyl-substituted C1-4 alkyl, C1-4 alkoxy or C3-6 cycloalkyl, and the heteroaryl contains 1 to 4 heteroatoms selected from N, O or S;
• optionally, 1 to 20 H of the compound of general formula (I) are replaced by 1 to 20 deuterium;
• n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
• each p1 or p2 is independently selected from 0, 1, 2, 3, 4 or 5.