# US 2019/0169165 A1 · Benzazepine compounds, conjugates, and uses thereof

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- Number: US 2019/0169165 A1
- Document ID: US20190169165A1
- Status: Published application
- Kind: A1
- Application number: 16/274,132
- Filed: 2019-02-12
- Published: 2019-06-06
- Earliest claimed: 2017-03-15
- Assignees: Silverback Therapeutics, Inc.
- Applicants: Silverback Therapeutics, Inc.
- Inventors: Craig Alan COBURN; Peter Robert BAUM; Sean Wesley SMITH
- Web page: https://patentgrep.com/patent/US20190169165A1

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- 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}
- A61P 35/00: Antineoplastic agents
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07F 5/00: Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F 5/025: {Boronic and borinic acid compounds}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/2887: {against CD20}
- C07K 16/30: from tumour cells
- C07K 16/3007: {Carcino-embryonic Antigens}
- C07K 16/32: against translation products of oncogenes
- C07K 2317/31: multispecific
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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

Benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. The disclosed benzazepine compounds are useful, among other things, in the treating of cancer and modulating TLR8. Additionally, benzazepine compounds incorporated into a conjugate with an antibody construct are described herein.

## Claims

### Claim 1

A compound represented by the structure of Formula (IIB):
or a pharmaceutically acceptable salt thereof, wherein:
L10 is selected from —C(O)—, and —C(O)N(R10)—*, wherein * represents where L10 is bound to R5—;
L2 is selected from —C(O)— and —C(O)N(R10)—;
R1 and R2 are independently selected from hydrogen; and C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)2, —S(O)R10, —S(O)2R10, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), and —CN;
R4 is selected from:
—OR10, —N(R10)2, —C(O)N(R10)2, —C(O)R10, —C(O)OR10, —S(O)R10, and —S(O)2R10; and
C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)C(O)N(R10)2, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)C(O)N(R10)2, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R5 is selected from unsaturated C4-8 carbocycle; bicyclic carbocycle; and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, wherein R5 is optionally substituted and wherein substituents are independently selected at each occurrence from:
halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)C(O)N(R10)2, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), and —CN; and
C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)C(O)N(R10)2, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; and
C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)C(O)N(R10)2, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R10 is independently selected at each occurrence from:
hydrogen, —NH2, —C(O)OCH2C6H5; and
C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2, —NH2, ═O, ═S, —C(O)OCH2C6H5, —NHC(O)OCH2C6H5, C1-10 alkyl, —C1-10 haloalkyl, —O—C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and haloalkyl;
R20, R21, R22, and R23 are independently selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —S(O)R10, —S(O)2R10—C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; and
R24 and R25 are independently selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —S(O)R10, —S(O)2R10, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, ═S, ═N(R10), —CN, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; or R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R20, R21, R22, and R23 are independently selected from hydrogen, halogen, —OH, —OR10, —NO2, —CN, and C1-10 alkyl.

### Claim 3 (depends on 2)

The compound or salt of claim 2, wherein R20, R21, R22, and R23 are each hydrogen.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein R24 and R25 are each hydrogen.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein R1 and R2 are each hydrogen.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein L10 is selected from —C(O)N(R10)—*.

### Claim 7 (depends on 6)

The compound or salt of claim 6, wherein R10 of —C(O)N(R10)—* is selected from hydrogen and C1-6 alkyl.

### Claim 8 (depends on 7)

The compound or salt of claim 7, wherein L10 is —C(O)NH—*.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein R5 is an optionally substituted 8- to 12-membered bicyclic carbocycle.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein R5 is an optionally substituted 8- to 12-membered bicyclic carbocycle substituted with one or more substituents independently selected from —OR10, —N(R10)2, and ═O.

### Claim 11 (depends on 10)

The compound or salt of claim 10, wherein R5 is an optionally substituted indane, and optionally substituted tetrahydronaphthalene.

### Claim 12 (depends on 1)

The compound or salt of claim 1, wherein R5 is selected from an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle.

### Claim 13 (depends on 12)

The compound or salt of claim 12, wherein R5 is an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle with one or more substituents independently selected from —C(O)OR10, —N(R10)2, —OR10, and optionally substituted C1-10 alkyl.

### Claim 14 (depends on 1)

The compound or salt of claim 1, wherein R5 is an optionally substituted fused 6-6 bicyclic heterocycle.

### Claim 15 (depends on 14)

The compound or salt of claim 14, wherein the fused 6-6 bicyclic heterocycle is an optionally substituted pyridine-piperidine.

### Claim 16 (depends on 15)

The compound or salt of claim 15, wherein L10 is bound to a carbon atom of the pyridine of the fused pyridine-piperidine.

### Claim 17 (depends on 1)

The compound or salt of claim 1, wherein R5 is selected from tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthyridine, cyclopentapyridine, and dihydrobenzoxaborole, any one of which is optionally substituted.

### Claim 18 (depends on 17)

The compound or salt of claim 17, wherein substituents on R5 are independently selected at each occurrence from:
halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)2, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, ═O, and —CN; and
C1-10 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —N(R10)2, —C(O)R10, —C(O)OR10, —NO2, ═O, and —CN.

### Claim 19 (depends on 1)

The compound or salt of claim 1, wherein R5 is not substituted.

### Claim 20 (depends on 1)

The compound or salt of claim 1, wherein L2 is —C(O)—.

### Claim 21 (depends on 1)

The compound or salt of claim 1, wherein R4 is —N(R10)2.

### Claim 22 (depends on 21)

The compound or salt of claim 21, wherein R10 of —N(R10)2 is independently selected at each occurrence from optionally substituted C1-6 alkyl.

### Claim 23 (depends on 22)

The compound or salt of claim 22, wherein -L2-R4 is CH3

### Claim 24 (depends on 1)

The compound or salt of claim 1, wherein the compound is selected from:
and a salt of any one thereof.

### Claim 25 (depends on 1)

The compound or salt of claim 1, wherein
L10 is —C(O)N(H)—*,
L2 is —C(O)—,
R1 and R2 are hydrogen;
R4 is —N(R10)2, wherein R10 of —N(R10)2 is independently selected at each occurrence from optionally substituted C1-6 alkyl; and
R20, R21, R22, R23, R24 and R25 are independently selected from hydrogen.

### Claim 26 (depends on 25)

The compound or salt of claim 25, wherein R5 is an optionally substituted 8- to 12-membered bicyclic carbocycle.

### Claim 27 (depends on 25)

The compound or salt of claim 25, wherein R5 is selected from an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle.

### Claim 28 (depends on 1)

The compound or salt of claim 1, wherein the compound is further covalently bound to a linker, L3.

### Claim 29 (depends on 28)

The compound or salt of claim 28, wherein L3 is attached, valence permitting, to a substitutable nitrogen atom of the compound represented by the structure of Formula (IIB).

### Claim 30 (depends on 28)

The compound or salt of claim 28, wherein L3 is a noncleavable linker.

### Claim 31 (depends on 28)

The compound or salt of claim 28, wherein L3 is a cleavable linker.

### Claim 32 (depends on 31)

The compound or salt of claim 31, wherein L3 is cleavable by a lysosomal enzyme.

### Claim 33 (depends on 28)

The compound of claim 28, wherein L3 is represented by the formula:
wherein:
L4 represents the C-terminus of the peptide and L5 is selected from a bond, alkylene and heteroalkylene, wherein L5 is optionally substituted with one or more groups independently selected from R32, and RX is a reactive moiety; and
R32 is independently selected at each occurrence from halogen, —OH, —CN, —O— alkyl, —SH, ═O, ═S, —NH2, —NO2; and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —O-alkyl, —SH, ═O, ═S, —NH2, —NO2.

### Claim 34 (depends on 33)

The compound or salt of claim 33, wherein RX comprises a maleimide.

### Claim 35 (depends on 33)

The compound or salt of claim 33, wherein the peptide of L3 comprises Val-Cit or Val-Ala.

### Claim 36 (depends on 28)

The compound or salt of claim 28, wherein L3 is represented by the formula:
RX, wherein RX comprises a reactive moiety, and n=0-9.

### Claim 37 (depends on 28)

The compound or salt of claim 28, wherein L3 is further covalently bound to an antibody construct.

### Claim 38 (depends on 37)

The compound or salt of claim 37, wherein L3 is attached to the antibody construct at a lysine or cysteine residue.

### Claim 39 (depends on 1)

A pharmaceutical composition comprising the compound or salt of claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 40 (depends on 39)

A method of treating cancer, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 39.

### Claim 41 (depends on 1)

A method of preparing an antibody conjugate of the formula
wherein Antibody is an antibody construct and D is a compound or salt of claim 1, wherein L3-D is contacted with an antibody construct.