# US 2024/0189438 A1 · Drug conjugate of glucocorticoid receptor agonist, and application thereof in medicine

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- Number: US 2024/0189438 A1
- Document ID: US20240189438A1
- Status: Published application
- Kind: A1
- Application number: 18/264,072
- Filed: 2022-01-28
- Published: 2024-06-13
- Earliest claimed: 2021-02-04
- Assignees: Shanghai Senhui Medicine Co., Ltd.; Shanghai Shengdi Pharmaceutical Co., Ltd.; Jiangsu Hengrui Pharmaceuticals Co., Ltd.
- Applicants: Shanghai Senhui Medicine Co., Ltd.; Shanghai Shengdi Pharmaceutical Co., Ltd.; Jiangsu Hengrui Pharmaceuticals Co., Ltd.
- Inventors: Lingjian Zhu; Min Hong; Manping Tang; Lu Su; Mengdie Deng; Jingyang Zhang; Wenming Ren; Kan Lin; Jian Huang; Cheng Liao; Lianshan Zhang
- Web page: https://patentgrep.com/patent/US20240189438A1

## CPC

- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- C07J 71/0031: {at positions 16, 17}
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 2317/21: from primates, e.g. man
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07J: STEROIDS (seco-steroids C07C)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A drug conjugate of a glucocorticoid receptor agonist, and an application thereof in medicine. Specifically, the present invention relates to an antibody-drug conjugate as represented by formula (I): Ab-(L-D)k (I), wherein Ab is an antibody or an antigen-binding fragment thereof, L is a linker covalently linking Ab to D, k is 1 to 20, and D is as represented by formula (II-A) or (II-B). The groups in the formulas are as defined in the description. The antibody-drug conjugate can effectively treat autoimmune diseases.

## Claims

### Claim 1

An antibody-drug conjugate of formula (I),
Ab-(L-D)k (I)
wherein Ab is an antibody or an antigen-binding fragment thereof;
L is a linker covalently linking Ab to D, and k is 1 to 20;
D is represented by formula (II-A) or (II-B):
wherein,
represents a single bond or a double bond;
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;
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 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, or together R6a and R6b form oxo or thio;
R6c, R6a, 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 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;
each 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;
provided that when R5a is hydrogen or alkyl, R5b is not hydrogen or alkyl.

### Claim 2 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom; ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein X1 is —(CR5aR5b)m- or is 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom; R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk, —S(O)Rk, —S(O)ORk, —S(O)(O)Rk, —S(O)(O)ORk, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl and C2-C6 alkynyl, or together R5a and R5b form oxo or thio.

### Claim 5 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein ring C and ring D are each independently selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused cycloaryl and 5- to 12-membered fused heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl or fused heteroaryl comprises at least one nitrogen atom

### Claim 6 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein X2 is selected from the group consisting of —(CR6aR6b)n-, —O—, —S—, —NR6c—, —CH2S—, —CH2O—, —NHCR6dR6e—, and 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom; R6a and R6b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk, —S(O)Rk, —S(O)(O)Rk, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl, or R6a and R6b, together with the carbon atom to which they are attached, form 3- to 10-membered cycloalkyl.

### Claim 7 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein D is represented by formula (II-A′) or (II-B′):
wherein,
each R1a is independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 alkoxy;
ring A is
and the ring A is optionally substituted with one or more Q1 substituents;
ring B is
and the ring B is optionally substituted with one or more Q1 substituents;
X1 is —(CR5aR5b)m- or is 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom;
R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk and C1-C6 alkoxy, or together R5a and R5b form oxo or thio;
ring C is selected from the group consisting of
and the ring C is optionally substituted with one or more Q1 substituents;
ring D is
and the ring D is optionally substituted with one or more Q1 substituents;
X2 is selected from the group consisting of —(CR6aR6b)n-, —O—, —S—, —NR6c—, —CH2S—, —CH2O—, —NHCR6dR6e—, and 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents;
R6a and R6b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk and C1-C6 alkoxy;
R6c, R6d and R6e are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy;
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;
m and n are each independently an integer of 1 to 6;
the Q1 substituents are each independently selected from the group consisting of halogen, hydroxy, sulfhydryl, deuterium, oxo, thio, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkoxy;
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;
provided that when R5a is hydrogen or alkyl, R5b is not hydrogen or alkyl.

### Claim 8

(canceled)

### Claim 9

(canceled)

### Claim 10 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein k is 1-10.

### Claim 11 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker comprises amino acid unit L1, and the amino acid unit L1 comprises a peptide residue consisting of 2 to 7 amino acids selected from the group consisting of phenylalanine, glycine, valine, lysine, citrulline, serine, glutamic acid, aspartic acid, homolysine, n-methyl-valine and
wherein q is an integer of 1-6.

### Claim 12 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker comprises a stretcher unit, the stretcher unit is selected from the group consisting of
wherein each p is independently 1, 2, 3, 4, 5 or 6.

### Claim 13 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker is selected from the group consisting of

### Claim 14 (depends on 1)

The antibody-drug conjugate according to claim 1, being selected from the group consisting of:
wherein each p is independently 1, 2, 3, 4, 5 or 6; Ab, D and k are as defined in claim 1.

### Claim 15 (depends on 1)

The antibody-drug conjugate according to claim 1, being selected from the group consisting of
wherein k is 1 to 10; Ab is as defined in claim 1.

### Claim 16 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody is selected from the group consisting of a murine antibody, a chimeric antibody, a humanized antibody and a fully human-derived antibody.

### Claim 17 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody or the antigen-binding fragment thereof is selected from the group consisting of an anti-TNFα antibody, an anti-IL-4R antibody, an anti-IL-6/IL-6R antibody, an anti-IL-13R antibody, an anti-IL-17/IL-17R antibody, an anti-IL-23/IL23R antibody, an anti-IL-36R antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD28 antibody, an anti-CD40 antibody and an anti-TSLP antibody or antigen-binding fragments thereof.

### Claim 18

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.

### Claim 19 (depends on 18)

The compound or the pharmaceutically acceptable salt thereof according to claim 18, being a compound of formula (III-A′) or (III-B′) or a pharmaceutically acceptable salt thereof:
wherein,
ring A is
and the ring A is optionally substituted with one or more Q1 substituents;
ring B is
and the ring B is optionally substituted with one or more Q1 substituents;
X1 is —(CR5aR5b)m- or is 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents, and the heteroaryl comprises at least one nitrogen atom;
R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk and C1-C6 alkoxy, or together R5a and R5b form oxo or thio;
ring C is selected from the group consisting of
and N and the ring C is optionally substituted with one or more Q1 substituents;
ring D is
and the ring D is optionally substituted with one or more Q1 substituents;
X2 is selected from the group consisting of —(CR6aR6b)n-, —O—, —S—, —NR6c—, —CH2S—, —CH2O—, —NHCR6dR6e—, and 6- to 10-membered aryl or 5- to 10-membered heteroaryl optionally substituted with one or more Q1 substituents;
R6a and R6b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, sulfhydryl, deuterium, cyano, and the following groups optionally substituted with one or more Q1 substituents: C1-C6 alkyl, —NRiRj, —C(O)Rk, —C(O)ORk and C1-C6 alkoxy;
R6c, R6d and R6e are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy;
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;
m and n are each independently an integer of 1 to 6;
the Q1 substituents are each independently selected from the group consisting of halogen, hydroxy, sulfhydryl, deuterium, oxo, thio, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkoxy;
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;
each R1a is independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 alkoxy;
each R1b is independently selected from the group consisting of hydrogen, PG-, H-L1-, PG-L1-,
each p is independently 1, 2, 3, 4, 5 or 6;
L1 is an amino acid unit, preferably and L1 is -glycine-glutamic acid- or
X is a halogen;
PG is an amino protecting group;
provided that when R5a is hydrogen or alkyl, R5b is not hydrogen or alkyl.

### Claim 20 (depends on 18)

The compound or the pharmaceutically acceptable salt thereof according to claim 18, being selected from the group consisting of
or pharmaceutically acceptable salts thereof.

### Claim 21 (depends on 18)

The compound or the pharmaceutically acceptable salt thereof according to claim 18, being selected from the group consisting of
or pharmaceutically acceptable salts thereof, wherein X is a halogen.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1, and a pharmaceutically acceptable excipient.

### Claim 23 (depends on 1)

A method of treating an immune disease in a subject in need thereof, the method comprising administering to the subject the antibody-drug conjugate according to claim 1, wherein the immune disease is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, hidradenitis suppurativa, uveitis, Behçet's disease, spondyloarthropathy and psoriasis.