Drug conjugate of glucocorticoid receptor agonist, and application thereof in medicine

A compound of formula (III-A) or (III-B) or a pharmaceutically acceptable salt thereof,

• wherein,
• represents a single bond or a double bond;
• ring A is aryl or heteroaryl optionally substituted with one or more Q1 substituents;
• ring B is aryl or heteroaryl optionally substituted with one or more Q1 substituents;
• X1 is —(CR5aR5b)m- or is aryl or heteroaryl optionally substituted with one or more Q1 substituents;
• R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, nitro, cyano, and the following groups optionally substituted with one or more Q1 substituents:
• alkyl, —NRiRj, —C(O)Rk, —C(O)ORk, —S(O)Rk, —S(O)ORk, —S(O)(O)Rk, —S(O)(O)ORk, —C(S)Rk, alkoxy, alkylthio, alkenyl and alkynyl, or together R5a and R5b form oxo or thio;
• ring C and ring D are each independently selected from the group consisting of aryl and heteroaryl or fused heteroaryl optionally substituted with one or more Q1 substituents, and at least one of ring C and ring D is fused cycloaryl or fused heteroaryl optionally substituted with one or more Q1 substituents;
• X2 is selected from the group consisting of —(CR6aR6b)n-, aryl or heteroaryl optionally substituted with one or more Q1 substituents, —O—, —S—, —S(O)—, —S(O)(O)—, —NR6c—, —CH2S—, —CH2O—, —NHCR6dR6e—, —CR6f═CR6g— and —C≡C—, or X2 is absent;
• R6a and R6b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, nitro, cyano, and the following groups optionally substituted with one or more Q1 substituents:
• alkyl, —NRiRj, —C(O)Rk, —C(O)ORk, —S(O)Rk, —S(O)ORk, —S(O)(O)Rk, —S(O)(O)ORk, —C(S)Rk, alkoxy, alkylthio, alkenyl and alkynyl, or R6a and R6b, together with the carbon atom to which they are attached, form 3- to 10-membered cycloalkyl;
• R6c, R6d, R6e, R6f and R6g are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy;
• each R1 is independently selected from the group consisting of hydrogen, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, deuterium, amino, cyano, nitro, hydroxy and hydroxyalkyl;
• each R2 is independently selected from the group consisting of —CH2OH, —CH2SH, —CH2Cl, —SCH2Cl, —SCH2F, —SCH2CF3, —OH, —OCH2CN, —OCH2Cl, —OCH2F, —OCH3, —OCH2CH3, —SCH2CN,
• each R2a is independently hydrogen or C1-C6 alkyl;
• each R2b is independently C1-C6 alkyl or C1-C6 alkoxy;
• each R2c is independently selected from the group consisting of hydrogen, C1-C6 alkyl, —CH2OH and C1-C6 alkoxy;
• R2d and R2e are each independently hydrogen or C1-C6 alkyl;
• each R3 is independently hydrogen or a halogen;
• each R4 is independently selected from the group consisting of hydrogen, halogen and hydroxy;
• m and n are each independently selected from an integer of 1 to 6;
• the Q1 substituents are each independently selected from the group consisting of C1-C6 alkyl, halogen, deuterium, hydroxy, sulfhydryl, —NRiRj, oxo, thio, —C(O)Rk, —C(O)ORk, —S(O)Rk, —S(O)ORk, —S(O)(O)Rk, —S(O)(O)ORk, —C(S)Rk, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused cycloaryl, and 5- to 12-membered fused heteroaryl;
• Ri and Rj are each independently selected from the group consisting of hydrogen, hydroxy, C1-C6 alkyl and C1-C6 alkoxy;
• Rk is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and —NRiRj, wherein the alkyl, alkoxy and haloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, sulfhydryl, —NRiRj, oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;
• each R1a is independently selected from the group consisting of hydrogen, alkyl and alkoxy, and the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, deuterium, amino, cyano, nitro, hydroxy and hydroxyalkyl;
• each R1b is independently selected from the group consisting of hydrogen, PG-, H-L1-, PG-L1-,
• or
• R1a and R1b, together with the nitrogen atom to which they are attached, form:
• or R1a and R1b, together with the nitrogen atom to which they are attached, form a nitro group;
• each p is independently 1, 2, 3, 4, 5 or 6;
• L1 is an amino acid unit;
• X is a halogen;
• PG is an amino protecting group;
• provided that when R5a is hydrogen or alkyl, R5b is not hydrogen or alkyl.