# US 12,758,643 B2 · Modified proteins and protein degraders

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- Number: US 12,758,643 B2
- Document ID: US12758643B2
- Status: Granted
- Kind: B2
- Application number: 18/361,422
- Filed: 2023-07-28
- Published: 2024-02-29
- Granted: 2026-10-13
- Earliest claimed: 2020-05-28
- Assignees: Cullgen (Shanghai), Inc.
- Applicants: Cullgen (Shanghai), Inc.
- Inventors: Jing Liu; Michael Bruno Plewe; Matthew Randolph Lee; Xiaoran Han; Liqun Chen; Chengwei Zhang; Jialiang Wang
- Web page: https://patentgrep.com/patent/US12758643B2

## CPC

- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- 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)

## Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are compounds having a DNA damage-binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Further provided herein are ligand-DDB1 complexes. Further provided herein are in vivo modified DDB1 proteins.

## Claims

### Claim 1

A ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety, wherein the ligand is a heterobifunctional ligand comprising the structure of Formula (IIc), Formula (IId), or Formula (IIe):
or a pharmaceutically acceptable salt thereof,
wherein:
F2 is a 5-membered heteroaryl;
L2 is a bond, —C(═O)NR13—, —NR13C(═O)—, —C(═O)—, —C(═S)—, —S—, —S(═O), —S(═O)2—, —S(═O)NR13—, —NR13S(═O)—, —S(═O)2NR13—, —NR13S(═O)2—, —O—, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, wherein each R13 is independently hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyclyl, C2-C8 heterocyclyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
each R11 and R12 is independently hydrogen, halogen, —CN, —Ra, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORaC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyclyl, C2-C8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —Ra, —ORa, or NRcRd; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —Ra, —ORa, or —NRcRd;
each Ra is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyclyl, C2-C8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyclyl, C2-C8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyclyl, C2-C8 heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
each Rc and Rd, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
q is an integer of 1-4;
s is an integer of 1-5;
L1 is a linker; and
Z1 is a target protein binding moiety.

### Claim 2 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein the linker comprises —(CH2)p2NH(CH2)p1NH—, —(CH2)p2NH(CH2)p1C(═O)NH—, —(CH2)p2NH(CH2)p1NHC(═O)—, —(CH2)p2NH(CH2CH2)(OCH2CH2)p1NH—, —(CH2)p2NH(CH2CH2)(OCH2CH2)p1C(═O)NH—, or —(CH2)p2NH(CH2CH2)(OCH2CH2)p1NHC(═O)—, wherein pl is 1-15, and p2 is 0-15.

### Claim 3 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein L2 is —C(═O)NH—.

### Claim 4 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein L2 is —C(═O)N(C1-C5 alkyl)-.

### Claim 5 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein F2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.

### Claim 6 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein F2 is thiazolyl, oxazolyl, furyl, or thiophenyl.

### Claim 7 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein F2 is thiazolyl.

### Claim 8 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein F2 is thiophenyl.

### Claim 9 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

### Claim 10 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

### Claim 11 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R11 is independently hydrogen, —NRaC(═O)Rb, or C1-C3 alkyl.

### Claim 12 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Ra is independently hydrogen.

### Claim 13 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently C1-C3 alkyl.

### Claim 14 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently methyl.

### Claim 15 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently —NO2 or C1-C6 alkyl.

### Claim 16 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently —NO2 or methyl.

### Claim 17 (depends on 1)

The ligand of claim 1, or a pharmaceutically acceptable salt thereof, wherein Zi is a target protein binding moiety that binds to CBP or P300.

### Claim 18 (depends on 1)

The ligand of claim 1, selected from the group consisting of:
2-(6-aminohexanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(3-(2-(3-(2-aminoethoxy)propoxy)ethoxy)propanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-N4-(6-aminohexyl)-N1-(4-methyl-5-nitrothiazol-2-yl)terephthalamide;
2-acetamido-N4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-N1-(4-methyl-5-nitrothiazol-2-yl)terephthalamide;
2-acetamido-N4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-N1-(5-nitrothiazol-2-yl)terephthalamide;
2-acetamido-4-((7-aminoheptyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-N-(5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-aminoethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((4-aminobutyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((6-aminohexyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((8-aminooctyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((10-aminodecyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-aminoethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((17-amino-3,6,9,12, 15-pentaoxaheptadecyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((20-amino-3,6,9,12,15,18-hexaoxaicosyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((4-aminobutyl)amino)-N-(5-nitrothiophen-2-yl)benzamide;
2-acetamido-4-((3-aminopropyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((5-aminopentyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((11-aminoundecyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
3-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)propanoic acid;
7-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)heptanoic acid;
3-(2-(2-(2-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)ethoxy)ethoxy)ethoxy)propanoic acid;
(3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl) glycine;
6-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)hexanoic acid;
10-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)decanoic acid;
11-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)undecanoic acid;
3-(2-(2-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)ethoxy)ethoxy)propanoic acid;
2-acetamido-4-((9-aminononyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
4-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)butanoic acid;
5-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)pentanoic acid;
3-(2-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)ethoxy)propanoic acid;
1-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid;
1-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid;
8-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)octanoic acid;
9-((3-acetamido-4-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)nonanoic acid;
4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-methyl-N-(5-nitrothiazol-2-yl)benzamide;
4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-methyl-N-(5-nitrothiazol-2-yl)benzamide;
4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-nitrothiazol-2-yl)benzamide;
4-((20-amino-3,6,9,12,15,18-hexaoxaicosyl)amino)-2-methyl-N-(5-nitrothiazol-2-yl)benzamide;
4-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-4-oxobutanoic acid;
5-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-5-oxopentanoic acid;
6-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-6-oxohexanoic acid;
7-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-7-oxoheptanoic acid;
8-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-8-oxooctanoic acid;
9-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-9-oxononanoic acid;
10-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-10-oxodecanoic acid;
11-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-11-oxoundecanoic acid;
12-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-12-oxododecanoic acid;
13-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-13-oxotridecanoic acid;
3-(3-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-3-oxopropoxy)propanoic acid;
3-(2-(3-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-3-oxopropoxy) ethoxy)propanoic acid;
3-(2-(2-(3-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-3-oxopropoxy) ethoxy)ethoxy)propanoic acid;
16-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-16-oxo-4,7,10,13-tetraoxahexadecanoic acid;
19-((2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)amino)-19-oxo-4,7,10, 13, 16-pentaoxanonadecanoic acid;
2-(2-aminoacetamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(3-aminopropanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(4-aminobutanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(5-aminopentanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(7-aminoheptanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(8-aminooctanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(9-aminononanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(10-aminodecanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(11-aminoundecanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(3-(2-aminoethoxy) propanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-(3-(2-(2-aminoethoxy)ethoxy) propanamido)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
1-amino-N-(2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide; and
1-amino-N-(2-((4-methyl-5-nitrothiazol-2-yl)carbamoyl)phenyl)-3,6,9,12,15-pentaoxaoctadecan-18-amide;
or a pharmaceutically acceptable salt thereof.

### Claim 19

A heterobifunctional compound selected from the group consisting of:
2-acetamido-4-((2-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)butyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((6-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)hexyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((7-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)heptyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((8-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)octyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((10-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)decyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((2-(2-(2-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosan-20-yl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide;
2-acetamido-4-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxo-6,9,12,15,18,21-hexaoxa-3-azatricosan-23-yl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide; and
2-acetamido-4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)acetamido)butyl)amino)-N-(5-nitrothiophen-2-yl)benzamide;
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising the ligand of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.