# US 2023/0054028 A1 · Pd-l1 antagonist compound

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- Number: US 2023/0054028 A1
- Document ID: US20230054028A1
- Status: Published application
- Kind: A1
- Application number: 17/780,979
- Filed: 2020-12-22
- Published: 2023-02-23
- Earliest claimed: 2019-12-26
- Assignees: Adlai Nortye Biopharma Co., Ltd.
- Applicants: Adlai Nortye Biopharma Co., Ltd.
- Inventors: Zhiyong YU; Pan LI; Beidi XU; Yu ZHOU; Wei PANG; Qiaodong WEN; Yongqiang SHI; Zhao SUN; Meng LV
- Web page: https://patentgrep.com/patent/US20230054028A1

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 37/02: Immunomodulators
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are a compound of Formula (I) and a pharmaceutical composition thereof, as well as a method for using the compounds of Formula (I) to prevent and/or treat immune-related disorders.

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, an isotopic derivative, an isomer, a solvate, or a metabolite thereof
wherein L1 is selected from —CRARB—and —C(O)—;
L2, L3 is selected from —(CRCRD)p, —(CRCRD)pNRa—(CRCRD)q—, —(CRCRD)p—O—(CRCRD)q— and —C(O)—;
W1, W2 each independently represents CRL or N;
R1 each independently represents hydrogen, halogen, nitro, cyano or —NRaRb, or C1-C6 alkyl, C3-C6 cycloalkyl, —O(C1-C6 alkyl), —O(C0-C6 alkylene)(C3-C6 cycloalkyl) or —O(C0-C6 alkylene)(3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from —ORa, cyano, oxo, halogen, C1-C6 alkyl, —(C1-C6 alkylene)ORa, cyano C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, —C(O)Ra, —(C1-C6 alkylene)C(O)Ra, —C(O)ORa, —(C1-C6 alkyl)C(O)ORa, —NRaRb, —(C1-C6 alkylene)NRaRb, —C(O)NRaRb, —SO2Ra, —C(O)NRaSO2Rb and —NRaC(O)Rb;
R2, R3, R4, R5 each independently represent hydrogen, halogen, nitro, cyano, —NRaRb, —SO2Ra, —S(O)Ra, —P(O)RaRb, C1-C6 alkyl, —O(C1-C6 alkyl), —O(C3-C6 cycloalkyl), halo(C1-C6 alkyl) or C3-C6 cycloalkyl;
Cy represents benzene ring or six-membered heteroaryl substituted by 0, 1, 2 or 3 R6, wherein the six-membered heteroaryl may optionally contain 1 or 2 nitrogen atoms; wherein the R6 represents hydrogen, halogen, nitro, cyano, —NRaRb, —SO2Ra, —S(O)Ra or —P(O)RaRb or C1-C6 alkyl, C3-C6 cycloalkyl, —O(C1-C6 alkyl), —O(C0-C6 alkylene)(C5-C10 aryl), —O(C0-C6 alkylene)(5-10 membered heteroaryl), —O(C0-C6 alkylene)(C3-C6 cycloalkyl) or —O(C0-C6 alkylene)(3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from —ORa, cyano, oxo, halogen, C1-C6 alkyl, —(C1-C6 alkylene)ORa, cyano C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, —C(O)Ra, —(C1-C6 alkylene)C(O)Ra, —C(O)ORa, —(C1-C6 alkylene)C(O)ORa, —NRaRb, —(C1-C6 alkylene)NRaRb, —C(O)NRaRb, —SO2Ra, —C(O)NRaSO2Rb or —NRaC(O)Rb;
wherein RL represents hydrogen, C1-C6 alkyl, —O(C1-C6 alkyl), —O(C3-C6 cycloalkyl), halogen, nitro, cyano, —NRaRb, halo(C1-C6 alkyl) or C3-C6 cycloalkyl;
T, A each independently represent —(C1-C6 alkyl), —(C0-C6 alkylene)-(C3-C12 cycloalkyl), —(C0-C6 alkylene)-(3-12 membered heterocycle), —(C0-C6 alkylene)-(C6-C10 aryl) or —(C0-C6 alkylene)-(5-10 membered heteroaryl) substituted with 0, 1, 2 or 3 substituents, wherein the substituents are selected from cyano, oxo, halogen, C1-C6 alkyl, —(C0-C6 alkylene)ORa, cyano C1-C6 alkyl, halo(C1-C6 alkyl), C3-C8 cycloalkyl, —(C0-C6 alkylene)C(O)Ra, —(C0-C6 alkylene)C(O)ORa, —(C0-C6 alkenyl)C(O)ORa, —(C0-C6 alkylene)NRaRb, —C(O)NRaRb, —NRaSO2Rb, —C(O)NRaSO2Rb and —NRaC(O)Rb;
wherein RA, RB each independently represent hydrogen, C1-C6 alkyl, —(C0-C3 alkylene)(C3-C12 cycloalkyl), —(C0-C3 alkylene)(3-12 membered heterocycle), halo(C1-C6 alkyl) or halogen, or RA and RB together with their co-attached carbon atom form a 3-6 membered ring;
RC, RD each independently represent hydrogen, C1-C6 alkyl, —(C0-C3 alkylene)(C3-C12 cycloalkyl), —(C0-C3 alkylene)(3-12 membered heterocycle), halo(C1-C6 alkyl) or halogen, or RC and RD together with their co-attached carbon atom form a 3-6 membered ring;
Ra, Rb each independently represent hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), —(C0-C6 alkylene)OH, —(C0-C3 alkylene)(C3-C12 cycloalkyl), —(C0-C3 alkylene)(3-12 membered heterocycle), —(C0-C3 alkylene)(C6-C10 aryl), —(C0-C3 alkylene)(5-10 membered heteroaryl) or halo(C1-C6 alkyl), or Ra and Rb together with their co-attached atom form a 3-6 membered ring;
wherein m, o each independently represent 0, 1 or 2; and
wherein p, q each independently represent 0, 1, 2 or 3.

### Claim 2 (depends on 1)

The compound of Formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, an isotopic derivative, an isomer, a solvate, or a metabolite thereof according to claim 1, wherein the compound of Formula (I) having the following structure of Formula (II):
wherein R1, R2, R3, R4, R5, R6, L1, L2, L3, T, A, W1, W2, m, o are as defined in claim 1;
and wherein r represents 0, 1, 2 or 3.

### Claim 3 (depends on 1)

The compound of Formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, an isotopic derivative, an isomer, a solvate, or a metabolite thereof according to claim 1, wherein the compound of Formula (I) having the following structure of Formula (III):
wherein R1, R2, R3, R4, R5, R6, L1, L2, L3, T, A, W1, W2, m, o as defined in claim 1;
wherein W3 represents CRM or N;
wherein RM represents hydrogen, C1-C6 alkyl, —O(C1-C6 alkyl), —O(C3-C6 cycloalkyl), halogen, nitro, cyano, —NRaRb, halo(C1-C6 alkyl) or C3-C6 cycloalkyl, and preferably hydrogen;
wherein r represents 0, 1 or 2.

### Claim 4

(canceled)

### Claim 5 (depends on 1)

The compound according to claim 1, wherein L1 is selected from —CRARB—, and wherein RA and RB are each independently selected from hydrogen, halogen, C1-C6 alkyl and halo(C1-C6 alkyl), preferably are hydrogen.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein L2 and L3 are each independently selected from —CRCRD— and —CRCRD—NRa— (CRCRD)q—, wherein q is selected from 0, 1 or 2, and wherein RC, RD are each independently selected from hydrogen, halogen, C1-C6 alkyl and halo(C1-C6 alkyl), preferably are hydrogen; Ra is each independently selected from hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl) and —(C0-C3 alkylene)C3-C12 cycloalkyl, and preferably from hydrogen, (C1-C6 alkyl) and halo(C1-C6 alkyl).

### Claim 7 (depends on 1)

The compound according to claim 1, wherein W1, W2 each independently represents CH or N.

### Claim 8 (depends on 3)

The compound according to claim 3, wherein W3 represents CH or N.

### Claim 9

(canceled)

### Claim 10 (depends on 1)

The compound according to claim 1, wherein T, A each independently represent —(C1-C6 alkyl), —(C0-C6 alkylene)-(C3-C12 cycloalkyl) or —(C0-C6 alkylene)-(3-12 membered heterocycle) substituted with 0, 1, 2 or 3 substituents, and wherein the substituents are selected from oxo, halogen, C1-C6 alkyl, —(C0-C6 alkylene)ORa, halo(C1-C6 alkyl), C3-C8 cycloalkyl, —(C0-C6 alkylene)C(O)Ra, —(C0-C6 alkylene)C(O)ORa, —(C0-C6 alkenyl)C(O)ORa, —(C0-C6 alkylene)NRaRb, —C(O)NRaRb, —NRaSO2Rb, —C(O)NRaSO2Rb and —NRaC(O)Rb;
or wherein T, A each independently represents C1-C6 alkyl, C3-C12 cycloalkyl or 3-12 membered heterocycle substituted with 0, 1 or 2 substituents, wherein the substituents are selected from oxo, —ORa, —(C0-C6 alkylene)C(O)ORa, —(C0-C6 alkenyl)C(O)ORa, —NRaSO2Rb, —C(O)NRaSO2Rb and —NRaC(O)Rb.

### Claim 11

(canceled)

### Claim 12 (depends on 11)

The compound of claim 11, wherein T, A each independently represents
optionally substituted with 0, 1 or 2 substituents, wherein the substituents are selected from C1-C6 alkyl, —ORa, —(C0-C6 alkylene)C(O)ORa and —(C0-C6 alkenyl)C(O)ORa, wherein α represents 1, 2 or 3;
preferably wherein T, A each independently represents the following groups:
and more preferably wherein T, A each independently represents:

### Claim 13

(canceled)

### Claim 14 (depends on 11)

The compound of claim 11, wherein T, A each independently represent
optionally substituted with 0, 1 or 2 substituents, wherein the substituents are selected from: C1-C6 alkyl, —ORa and halogen, wherein Re represents hydrogen or C1-C6 alkyl; wherein α represents 1, 2, 3 or 4;
or wherein T, A each independently represents
wherein Re represents hydrogen or C1-C6 alkyl; wherein α represents 1, 2, 3 or 4.

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17 (depends on 1)

The compound according to claim 1, wherein R1 represents —O(C1-C6 alkyl), —O(C0-C6 alkylene)(C3-C6 cycloalkyl) or —O(C0-C6 alkylene)(3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, cyano C1-C6 alkyl and C1-C6 haloalkyl, preferably halogen.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein R2 represents hydrogen, halogen, nitro, cyano, —SO2Ra, C1-C6 alkyl, halo(C1-C6 alkyl) or C3-C6 cycloalkyl.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein R3, R4 each independently represent hydrogen or halogen.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein R5 represents hydrogen, halogen, nitro, cyano, C1-C6 alkyl, halo(C1-C6 alkyl) or C3-C6 cycloalkyl.

### Claim 21 (depends on 1)

The compound according to claim 1, wherein R6 represents hydrogen, halogen, C1-C6 alkyl, halo(C1-C6 alkyl) or C3-C6 cycloalkyl or —O(C1-C6 alkyl), O(C0-C6 alkylene)(C3-C6 cycloalkyl) or —O(C0-C6 alkylene)(3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, cyano C1-C6 alkyl and C1-C6 haloalkyl, preferably halogen.

### Claim 22 (depends on 1)

The compound according to claim 1, RL represents hydrogen or halogen.

### Claim 23

(canceled)

### Claim 24 (depends on 1)

The compound according to claim 1, having the following structures:

### Claim 25 (depends on 1)

A pharmaceutical composition, comprising a compound according to claim 1 and optionally a pharmaceutically acceptable carrier.

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28 (depends on 1, 25)

A method of treating a disease or condition responsive to inhibition of PD-L1 binding to PD-1, comprising administering the compound of claim 1 or the pharmaceutical composition of claim 25 to a mammal in need thereof; wherein the disease or condition is preferably selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.

### Claim 29

(canceled)

### Claim 30 (depends on 10)

The compound according to claim 10, wherein T represents: —(C1-C6 alkyl), —(C0-C6 alkylene)-(C3-C12 cycloalkyl) or —(C0-C6 alkylene)-(3-12 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents, and wherein the substituents are selected from oxo, —(C0-C6 alkylene)ORa, —(C0-C6 alkylene)C(O)ORa, —(C0-C6 alkylene)NRaRb, —C(O)NRaRb, —NRaSO2Rb and —NRaC(O)Rb.