# US 10,370,338 B2 · Benzazepine dicarboxamide compounds with tertiary amide function

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- Number: US 10,370,338 B2
- Document ID: US10370338B2
- Status: Granted
- Kind: B2
- Application number: 16/189,646
- Filed: 2018-11-13
- Published: 2019-03-14
- Granted: 2019-08-06
- Earliest claimed: 2016-05-23
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Lisha Wang; Hongying Yun; Weixing Zhang; Wei Zhu; Zhiwei Zhang
- Web page: https://patentgrep.com/patent/US10370338B2

## CPC

- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- A61P 11/06: Antiasthmatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/08: Bridged systems
- C07D 487/10: Spiro-condensed systems
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to new benzazepine dicarboxamide compounds of the formula wherein R1 to R3 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.

## Claims

### Claim 1

A benzazepine-4-carboxamide compound of the formula
wherein
R1 is C3-7-alkyl;
R2 is C3-7-alkyl or C3-7-cycloalkyl-C1-7-alkyl;
R3 is a heterocycle selected from
wherein
X1 is (CH2)m wherein m is 1 or 2;
X2 is (CH2)n wherein n is 1 or 2;
X3 is (CH2)o wherein o is 1 or 2;
X4 is (CH2)p wherein p is 1 or 2; and
Z1 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl; or
wherein
X5 is (CH2)q wherein q is 1 or 2;
X6 is (CH2)r wherein r is 1 or 2;
Y1 is a carbon or nitrogen atom and
Z2 is hydrogen and
Z3 is selected from the group consisting of hydrogen, C1-7-alkoxy, C2-7-alkenyloxy, phenyl, phenyl-C1-7-alkyl, phenyl-C1-7-alkyloxy, phenyl-C1-7-alkylamino, phenylamino-C1-7-alkyl, phenylamino, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl;
wherein
X7 is (CH2)s wherein s is 1 or 2; and
Z4 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl; or
wherein
X8 is (CH2)t wherein t is 1 or 2; and
Z5 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 and R2 are n-propyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 has the formula a)
wherein
X1 is (CH2)m wherein m is 1 or 2;
X2 is (CH2)n wherein n is 1 or 2;
X3 is (CH2)o wherein o is 1 or 2;
X4 is (CH2)p wherein p is 1 or 2; and
Z1 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein Z1 is phenyl or C1-7-alkylphenyl.

### Claim 5 (depends on 3)

The compound of claim 3, wherein m is 1 and n is 1.

### Claim 6 (depends on 3)

The compound of claim 3, wherein o is 1 and p is 1 or wherein o is 2 and p is 2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein m is 2, n is 2, o is 1 and p is 1.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 has the formula b)
wherein
X5 is (CH2)q wherein q is 1 or 2;
X6 is (CH2)r wherein r is 1 or 2;
Y1 is a carbon or nitrogen atom and
Z2 is hydrogen and
Z3 is selected from the group consisting of hydrogen, C1-7-alkoxy, C2-7-alkenyloxy, phenyl, phenyl-C1-7-alkyl, phenyl-C1-7-alkyloxy, phenyl-C1-7-alkylamino, phenylamino-C1-7-alkyl, phenylamino, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein Y1 is C.

### Claim 10 (depends on 8)

The compound of claim 8, wherein Y1 is N.

### Claim 11 (depends on 8)

The compound of claim 8, wherein Z3 is selected from the group consisting of phenyl, phenyl-C1-7-alkyl, phenyl-C1-7-alkyloxy, phenyl-C1-7-alkylamino, phenylamino-C1-7-alkyl, phenylamino and amino-C1-7-alkylphenyl.

### Claim 12 (depends on 8)

The compound of claim 8, wherein Z3 is C1-7-alkoxy or C2-7-alkenyloxy.

### Claim 13 (depends on 8)

The compound of claim 8, wherein q is 1 and r is 1.

### Claim 14 (depends on 8)

The compound of claim 8, wherein q is 2 and r is 2.

### Claim 15 (depends on 8)

The compound of claim 8, wherein q is 2 and r is 1.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R3 has the formula c)
wherein
X7 is (CH2)s wherein s is 1 or 2; and
Z4 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R3 has the formula d)
wherein
X8 is (CH2)t wherein t is 1 or 2; and
Z5 is phenyl, wherein phenyl is unsubstituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxy, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkyl-amino-C1-7-alkyl and di-C1-7-alkyl-amino-C1-7-alkyl.

### Claim 18 (depends on 1)

The compound of formula I according to claim 1, selected from:
2-amino-N,N-dipropyl-8-[6-(p-tolyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-3H-1-benzazepine-4-carboxamide;
2-amino-8-(4-anilinopiperidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(3-anilinoazetidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[3-(anilinomethyl)azetidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(3-anilinopyrrolidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(4-phenylpiperazine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(7-phenyl-2,7-diazaspiro[3.4]octane-2-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-N,N-dipropyl-8-(pyrrolidine-1-carbonyl)-3H-1-benzazepine-4-carboxamide;
2-amino-8-(4-anilinopiperidine-1-carbonyl)-N-(cyclopropylmethyl)-N-propyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(4-benzylpiperazine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(3-benzyloxyazetidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(6-phenyl-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(2-phenyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(7-phenyl-2,7-diazaspiro[3.5]nonane-2-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(8-phenyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(6-phenyl-3,6-diazabicyclo[3.2.0]heptane-3-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[3-(benzylamino)azetidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide,
2-amino-8-[3-[4-(aminomethyl)anilino]pyrrolidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[3-(benzylamino)pyrrolidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[4-(anilinomethyl)piperidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[3-(anilinomethyl)pyrrolidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-[3-[(E)-but-2-enoxy]azetidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide;
2-amino-8-(3-anilinopiperidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide,
2-amino-8-[3-(benzylamino)piperidine-1-carbonyl]-N,N-dipropyl-3H-1-benzazepine-4-carboxamide; or
2-amino-8-(3-butoxyazetidine-1-carbonyl)-N,N-dipropyl-3H-1-benzazepine-4-carboxamide,
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or adjuvant.

### Claim 20 (depends on 1)

A method of treating cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, or infectious diseases, the method comprising administering to a subject a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

A process for the manufacture of a compound of formula I as defined in claim 1, which process comprises:
a) coupling a compound of the formula II
wherein R1 and R2 are as defined in claim 1 and PG is a protecting group, with an amine of the formula III
R3H III
wherein R3 is defined herein before, under basic conditions in the presence of a coupling agent and removing the protecting group PG under acidic conditions to obtain a compound of the formula I
wherein R1 to R3 are as defined in claim 1, and, if desired, converting the compound obtained into a pharmaceutically acceptable salt.