# US 2024/0197899 A1 · 2-amino-4-carboxamide-benzazepine immunoconjugates, and uses thereof

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- Number: US 2024/0197899 A1
- Document ID: US20240197899A1
- Status: Published application
- Kind: A1
- Application number: 18/283,071
- Filed: 2022-03-25
- Published: 2024-06-20
- Earliest claimed: 2021-03-26
- Assignees: Bolt Biotherapeutics, Inc.
- Applicants: Bolt Biotherapeutics, Inc.
- Inventors: Gary BRANDT; Romas KUDIRKA; Brian SAFINA
- Web page: https://patentgrep.com/patent/US20240197899A1

## CPC

- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6853: {Carcino-embryonic antigens}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- 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 35/00: Antineoplastic agents
- 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

## Abstract

The invention provides immunoconjugates of Formula I comprising an antibody linked by conjugation to one or more 2-amino-4-carboxamide-benzazepine derivatives. The invention also provides 2-amino-4-carboxamide-benzazepine derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the immunoconjugates through a linker or linking moiety. The invention further provides methods of treating cancer with the immunoconjugates.

## Claims

### Claim 1

An immunoconjugate comprising an antibody covalently attached to one or more 2-amino-4-carboxamide-benzazepine moieties by a linker, and having Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
Ab is the antibody;
p is an integer from 1 to 8;
X2 and X3 are independently selected from the group consisting of a bond, C(═O), C(═O)N(R5), O, N(R5), S, S(O)2, and S(O)2N(R5);
Y1 is CR1 or N;
Y2 is CH or N;
R1 is selected from the group consisting of H, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
R2 is selected from the group consisting of H, C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
R3 is selected from the group consisting of:
—(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-N(R5)—C(═O)*;
—(C1-C12 alkyldiyl)-N(R5)—C(═O)O—(C3-C12 carbocyclyldiyl)-*;
—(C1-C12 alkyldiyl)-N(R5)—(C1-C20 heteroaryldiyl)-*;
—(C1-C12 alkyldiyl)-N(R5)—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-*;
—(C1-C12 alkyldiyl)-N(R5)—S(O2)—*;
—(C1-C12 alkyldiyl)-OC(═O)—(C2-C9 heterocyclyldiyl)-*;
—(C1-C12 alkyldiyl)-O—*;
—(C1-C12 alkyldiyl)-(C3-C12 carbocyclyldiyl)-*;
—(C1-C12 alkyldiyl)-(C6-C20 aryldiyl)-*;
—(C1-C12 alkyldiyl)-(C6-C20 aryl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-*;
—(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-NR5—C(═NR5a)—N(R5)—*;
—(C6-C20 aryldiyl)-*;
—(C6-C20 aryldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-(C2-C20 heterocyclyldiyl)-*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
—(C2-C20 heterocyclyldiyl)-*;
—(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C2-C9 heterocyclyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
—(C1-C20 heteroaryldiyl)-*;
—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-O—*; and
—(C1-C20 heteroaryldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
where the asterisk * indicates the attachment site of the linker L;
R5 is selected from the group consisting of H, C6-C20 aryl and C1-C12 alkyl, or two R5 groups together form a 5- or 6-membered heterocyclyl ring;
R5a is selected from the group consisting of C6-C20 aryl and C1-C20 heteroaryl;
L is selected from the group consisting of:
—C(═O)-PEG-C(═O)—;
—C(═O)-PEG-C(═O)—PEP-;
—C(═O)-PEG-N(R5)—;
—C(═O)-PEG-N(R5)—C(═O)—;
—C(═O)-PEG-NR5-PEG-C(═O)—PEP-;
—C(═O)-PEG-N+(R5)2-PEG-C(═O)—PEP-;
—C(═O)-PEG-NR5CH(AA1)C(═O)-PEG-C(═O)—PEP-;
—C(═O)-PEG-O—;
—C(═O)-PEG-SS—(C1-C12 alkyldiyl)-OC(═O)—;
—C(═O)-PEG-SS—(C1-C12 alkyldiyl)-C(═O)—;
—C(═O)-PEG-;
—C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-;
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)—C(═O);
—C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-;
—C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
—C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
—C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
—C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
-succinimidyl-(CH2)m—C(═O)N(R5)-PEG-C(═O)—;
-succinimidyl-(CH2)m—C(═O)N(R5)-PEG-N(R5)—;
-succinimidyl-(CH2)m—C(═O)N(R5)-PEG-N(R5)—C(═O)—;
-succinimidyl-(CH2)m—C(═O)N(R5)-PEG-C(═O)—PEP-;
-succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
-succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—; and
-succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
PEG has the formula: —(CH2CH2O)n—(CH2)m— where m is an integer from 1 to 5, and n is an integer from 2 to 50;
PEP has the formula:
where AA1 and AA2 are independently selected from an amino acid side chain, or AA1 or AA2 and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment; and
where alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH═CH2, —C≡CH, —C≡CCH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)20H, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —O(CH2CH2O)n—(CH2)mCO2H, —O(CH2CH2O)nH, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, and —S(O)3H.

### Claim at position 2

2-9. (canceled)

### Claim 10 (depends on 1)

The immunoconjugate of claim 1 wherein R1 is optionally substituted C1-C20 heteroaryl.

### Claim 11 (depends on 1)

The immunoconjugate of claim 1 wherein R1 is pyrimidinyl or pyridinyl.

### Claim 12 (depends on 1)

The immunoconjugate of claim 1 wherein X2 and X3 are each a bond, and R2 and R3 are independently selected from C1-C8 alkyl, —O—(C1-C12 alkyl), —(C1-C12 alkyldiyl)-OR5, —(C1-C8 alkyldiyl)-N(R5)CO2R5, —(C1-C12 alkyl)-OC(O)N(R5)2, —O—(C1-C12 alkyl)-N(R5)CO2R5, and —O—(C1-C12 alkyl)-OC(O)N(R5)2.

### Claim 13 (depends on 1)

The immunoconjugate of claim 1 wherein X2 is a bond, and R2 is C1-C12 alkyl.

### Claim 14 (depends on 1)

The immunoconjugate of claim 1 wherein X3 is O and R3 is —(C1-C12 alkyldiyl)-N(R5)—*.

### Claim 15 (depends on 14)

The immunoconjugate of claim 14 wherein R3 is —CH2CH2CH2NH—.

### Claim 16 (depends on 14)

The immunoconjugate of claim 14 wherein L is selected from —C(═O)-PEG-C(═O)—, and —C(═O)-PEG-O—C(═O)—.

### Claim 17

(canceled)

### Claim 18 (depends on 1)

The immunoconjugate of claim 1 wherein n is 10 and m is 1.

### Claim at position 12

19-22. (canceled)

### Claim 23 (depends on 1)

The immunoconjugate of claim 1 having Formula Ia:

### Claim 24 (depends on 23)

The immunoconjugate of claim 23 wherein R1 is optionally substituted C1-C20 heteroaryl.

### Claim 25 (depends on 24)

The immunoconjugate of claim 24 wherein R1 is pyrimidinyl or pyridyl.

### Claim 26 (depends on 23)

The immunoconjugate of claim 23 wherein X2 is a bond, and R2 is C1-C12 alkyl.

### Claim 27 (depends on 23)

The immunoconjugate of claim 23 wherein R3 is —(C1-C12 alkyldiyl)-N(R5)—*.

### Claim 28 (depends on 1)

The immunoconjugate of claim 1 wherein X3—R3-L is selected from the group consisting of:
where the wavy line indicates the point of attachment to N.

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31 (depends on 1)

The immunoconjugate of claim 1 wherein Y1 is CR1 and Y2 is CH.

### Claim 32 (depends on 1)

The immunoconjugate of om claim 1 wherein Y1 is N and Y2 is CH.

### Claim 33 (depends on 1)

The immunoconjugate of claim 1 wherein Y1 is N and Y2 is N.

### Claim 34 (depends on 46)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 46 selected from the group consisting of:

### Claim 35 (depends on 34)

An immunoconjugate prepared by conjugation of an antibody with a 2-amino-4-carboxamide-benzazepine-linker compound of claim 34.

### Claim 36 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of an immunoconjugate according to claim 1, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient.

### Claim 37 (depends on 1)

A method for treating cancer comprising administering a therapeutically effective amount of an immunoconjugate according to claim 1, to a patient in need thereof, wherein the cancer is selected from bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, and breast cancer.

### Claim 38 (depends on 37)

The method of claim 37, wherein the cancer is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism.

### Claim 39 (depends on 37)

The method of claim 37, wherein the cancer is selected from triple-negative breast cancer, metastatic Merkel cell carcinoma, and gastroesophageal junction adenocarcinoma.

### Claim 40

(canceled)

### Claim 41

(canceled)

### Claim 42 (depends on 1, 34)

A method of preparing an immunoconjugate of Formula I of claim 1 wherein the 2-amino-4-carboxamide-benzazepine-linker of claim 34 is conjugated with the antibody.

### Claim 43

(canceled)

### Claim 44 (depends on 1)

The immunoconjugate of claim 1 selected from the formulae Ib-d:

### Claim 45 (depends on 1)

The immunoconjugate of claim 1 wherein the antibody binds to a target selected from the group consisting of PD-L1, HER2, TROP2, and CEA

### Claim 46 (depends on 45)

The immunoconjugate of claim 45 wherein the antibody is selected from the group consisting of trastuzumab, pertuzumab, labetuzumab, and sacituzumab.

### Claim 47 (depends on 1)

The immunoconjugate of claim 1 wherein L is selected from:
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-O—;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-O—C(═O)—;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)—;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-N(R5)—;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-N(R5)—C(═O)—;
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)—PEP-; and
-succinimidyl-(CH2)m—C(═O)N(R6)-PEG-SS-(C1-C12 alkyldiyl)-OC(═O)—.

### Claim 48

A 2-amino-4-carboxamide-benzazepine-linker compound having Formula II:
wherein
X2 and X3 are independently selected from the group consisting of a bond, C(═O), C(═O)N(R5), O, N(R5), S, S(O)2, and S(O)2N(R5);
Y1 is CR1 or N;
Y2 is CH or N;
R1 is selected from the group consisting of H, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
R2 is selected from the group consisting of H, C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
R3 is selected from the group consisting of:
—(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-N(R5)—C(═O)*;
—(C1-C12 alkyldiyl)-O—*;
—(C1-C12 alkyldiyl)-(C3-C12 carbocyclyldiyl)-*;
—(C1-C12 alkyldiyl)-(C6-C20 aryldiyl)-*;
—(C1-C12 alkyldiyl)-(C6-C20 aryl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C6-C20 aryl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-*;
—(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-*;
—(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C3-C12 carbocyclyldiyl)-NR5—C(═NR5a)—N(R5)—*;
—(C6-C20 aryldiyl)-*;
—(C6-C20 aryldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-(C2-C20 heterocyclyldiyl)-*;
—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
—(C2-C20 heterocyclyldiyl)-*;
—(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
—(C2-C9 heterocyclyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
—(C1-C20 heteroaryldiyl)-*;
—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*; and
—(C1-C20 heteroaryldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
where the asterisk * indicates the attachment site of the linker L;
R5 is selected from the group consisting of H, C6-C20 aryl and C1-C12 alkyl, or two R5 groups together form a 5- or 6-membered heterocyclyl ring;
R5a is selected from the group consisting of C6-C20 aryl and C1-C20 heteroaryl;
L-Q is selected from the group consisting of:
Q-C(═O)-PEG-C(═O)—;
Q-C(═O)-PEG-C(═O)—PEP-;
Q-C(═O)-PEG-N(R5)—;
Q-C(═O)-PEG-N(R5)—C(═O)—;
Q-C(═O)-PEG-NR5-PEG-C(═O)—PEP-;
Q-C(═O)-PEG-N+(R5)2-PEG-C(═O)—PEP-;
Q-C(═O)-PEG-NR5CH(AA1)C(═O)-PEG-C(═O)—PEP-;
Q-C(═O)-PEG-O—;
Q-C(═O)-PEG-SS-(C1-C12 alkyldiyl)-OC(═O)—;
Q-C(═O)-PEG-SS—(C1-C12 alkyldiyl)-C(═O)—;
Q-C(═O)-PEG-;
Q-C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
Q-C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-;
Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)—C(═O);
Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
Q-C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-;
Q-C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
Q-C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
Q-C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
Q-C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
Q-C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
Q-(CH2)m—C(═O)—PEP-N(R5)—;
Q-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
Q-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—; and
Q-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
PEG has the formula: —(CH2CH2O)n—(CH2)m— where m is an integer from 1 to 5, and n is an integer from 2 to 50;
PEP has the formula:
where AA1 and AA2 are independently selected from an amino acid side chain, or AA1 or AA2 and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment; and
Q is selected from the group consisting of N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, maleimide, and phenoxy substituted with one or more groups independently selected from F, Cl, NO2, and SO3;
where alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH═CH2, —C≡CH, —C≡CCH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)20H, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —O(CH2CH2O)n—(CH2)mCO2H, —O(CH2CH2O)nH, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, and —S(O)3H.

### Claim 49 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein R1 is optionally substituted C1-C20 heteroaryl.

### Claim 50 (depends on 49)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 49 wherein R1 is pyrimidinyl or pyridinyl.

### Claim 51 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein X2 and X3 are each a bond, and R2 and R3 are independently selected from C1-C8 alkyl, —O—(C1-C12 alkyl), —(C1-C12 alkyldiyl)-OR5, —(C1-C8 alkyldiyl)-N(R5)CO2R5, —(C1-C12 alkyl)-OC(O)N(R5)2, —O—(C1-C12 alkyl)-N(R5)CO2R5, and —O—(C1-C12 alkyl)-OC(O)N(R5)2.

### Claim 52 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein X2 is a bond, and R2 is C1-C12 alkyl.

### Claim 53 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein X3 is O and R3 is —(C1-C12 alkyldiyl)-N(R5)—*.

### Claim 54 (depends on 53)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 53 wherein R3 is —CH2CH2NH—.

### Claim 55 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein L is selected from —C(═O)-PEG-C(═O)—, and —C(═O)-PEG-O—C(═O)—.

### Claim 56 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein Y1 is CR1 and Y2 is CH.

### Claim 57 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein Y1 is N and Y2 is CH.

### Claim 58 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein Y1 is N and Y2 is N.

### Claim 59 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 wherein Q is selected from:

### Claim 60 (depends on 59)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 59 wherein Q is 2,3,5,6-tetrafluorophenoxy or 2,3,5,6-tetrafluoro, 4-sulfonate-phenoxy.

### Claim 61 (depends on 59)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 59 wherein Q is maleimide.

### Claim 62 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 having Formula IIa:

### Claim 63 (depends on 48)

The 2-amino-4-carboxamide-benzazepine-linker compound of claim 48 is selected from formula IIb-d: