# US 10,117,864 B2 · Substituted N-bicyclo-2-aryl-quinolin-4-carboxamides and use thereof

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- Number: US 10,117,864 B2
- Document ID: US10117864B2
- Status: Granted
- Kind: B2
- Application number: 15/552,997
- Filed: 2016-03-15
- Published: 2018-02-08
- Granted: 2018-11-06
- Earliest claimed: 2015-03-18
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Hartmut Beck; Tobias Thaler; Raimund Kast; Mark Meininghaus; Carsten Terjung; Uwe Muenster; Britta Olenik
- Web page: https://patentgrep.com/patent/US10117864B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/195: having an amino group
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/52: with aryl radicals attached in position 2
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present application relates to novel substituted N-bicyclo-2-arylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and inflammatory disorders.

## Claims

### Claim 1

A compound of the formula (I)
in which
the ring Q represents a group of the formula
where
#1 represents the point of attachment to the carbonyl group,
#2 represents the point of attachment to the nitrogen atom,
Y represents a group of the formula —O—, —CF2—, —C(H)(OH)—, —CHF— or —C(═O)—
Z represents —OH or represents a group of the formula —NH—R6 or —NH—SO2—R7 in which
R6 represents hydrogen, methyl or ethyl which is up to trisubstituted by fluorine, and
R7 represents (C1-C2)-alkyl which is up to trisubstituted by fluorine,
R1 represents halogen, (C1-C4)-alkyl which is up to pentasubstituted by fluorine, methoxy which is up to trisubstituted by fluorine, (trifluoromethyl)sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,
R2, R3 and R4 independently of one another represent hydrogen, halogen or methyl which is up to trisubstituted by fluorine,
R5 represents halogen, (C1-C4)-alkyl which is up to pentasubstituted by fluorine, methoxy which is up to trisubstituted by fluorine, represents hydroxy, methylsulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine, and
Ar represents phenyl which may be up to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, methyl, which is up to trisubstituted by fluorine, and methoxy, which is up to trisubstituted by fluorine, or represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine, or represents thiazolyl or pyridyl,
and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

### Claim 2 (depends on 1)

The compound of the formula (I) as claimed in claim 1 in which
the ring Q represents a group of the formula
where
#1 represents the point of attachment to the carbonyl group,
#2 represents the point of attachment to the nitrogen atom,
Y represents a group of the formula —C(H)(OH)— or —CHF—
Z represents —OH,
R1 represents chlorine, bromine, iodine, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoronnethyl, trifluoronnethoxy, (trifluoromethyl)sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,
R2 represents hydrogen,
R3 and R4 independently of one another represent hydrogen, chlorine or methyl,
R5 represents fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl, and
Ar represents phenyl which may be mono- or disubstituted by fluorine, represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine or represents a group of the formula
where
#3 represents the point of attachment to the quinoline ring,
R8 represents chlorine or methyl, and
R9 represents chlorine or methoxy,
and the salts, solvates and solvates of the salts thereof.

### Claim 3 (depends on 1)

The compound of the formula (I) as claimed in claim 1, in which
the ring Q represents a group of the formula
Z represents a group of the formula —OH,
R1 represents chlorine, bromine, iodine, methyl, tert-butyl, difluoromnethyl, trifluoromethyl, trimethylsilyl, ethynyl or cyclopropyl,
R2 represents hydrogen,
R3 and R4 independently of one another represent hydrogen, chlorine or methyl,
where at least one of the radicals R3 and R4 represents hydrogen,
R5 represents fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl, and
Ar represents phenyl which may be monosubstituted by fluorine,
and the salts, solvates and solvates of the salts thereof.

### Claim 4 (depends on 1)

The compound of the formula (I) as claimed in claim 1 in which
the ring Q represents a group of the formula
Z represents a group of the formula —OH,
R1 represents ethynyl, bromine or iodine,
R2, R3 and R4 each represent hydrogen,
R5 represents chlorine, methyl, methylsulfanyl or cyclopropyl, and
Ar represents phenyl,
and the salts, solvates and solvates of the salts thereof.

### Claim 5 (depends on 1)

A process for preparing a compound as defined in claim 1, wherein a compound of the formula (II)
is coupled with an amine compound of the formula (III)
and
T represents an ester protective group,
to give a compound of the formula (IV)
and then the ester radical T is eliminated to give the carboxylic acid of the formula (I-A)
and the carboxylic acid (I-A) is optionally converted in a further step into the corresponding acid chloride of the formula (V)
and the latter is subsequently reacted with a compound of the formula (VI)
H2N—R6 (VI)
to give the carboxamide of the formula (I-B)
and the compounds of the formulae (I-A) and (I-B) thus obtained are optionally converted with the appropriate (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.

### Claim 6 (depends on 1)

A method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs in humans and animals by administration of an effective amount of a medicament comprising at least one compound as defined in claim 1.

### Claim 7 (depends on 1)

A medicament comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

### Claim 8 (depends on 1)

A medicament comprising a compound as defined in claim 1 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade and pirfenidone.

### Claim 9 (depends on 7)

A method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs in humans and animals by administration of an effective amount of a medicament of claim 7.

### Claim 10 (depends on 1)

A method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs in humans and animals by administration of an effective amount of at least one compound as defined in claim 1.

### Claim 11 (depends on 5)

The process of claim 5 wherein T represents (C1-C4)-alkyl, benzyl or 4-methylphenylsulfonylethyl.

### Claim 12 (depends on 2)

A medicament comprising a compound as defined in claim 2 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

### Claim 13 (depends on 3)

A medicament comprising a compound as defined in claim 3 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

### Claim 14 (depends on 4)

A medicament comprising a compound as defined in claim 4 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

### Claim 15 (depends on 2)

A medicament comprising a compound as defined in claim 2 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade and pirfenidone.

### Claim 16 (depends on 3)

A medicament comprising a compound as defined in claim 3 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade and pirfenidone.

### Claim 17 (depends on 4)

A medicament comprising a compound as defined in claim 4 in combination with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade and pirfenidone.

### Claim 18 (depends on 1)

Compound according to claim 1 which is 4-{[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}bicyclo[2.2.2]octane-1-carboxylic acid having the formula
and the salts, solvates and solvates of the salts thereof.

### Claim 19 (depends on 1)

Compound according to claim 1 which is 4-{[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]annino}bicyclo[2.2.2]octane-1-carboxylic acid having the formula
and the salts, solvates and solvates of the salts thereof.

### Claim 20 (depends on 1)

Compound according to claim 1 which is 4-{[(6-bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}bicyclo[2.2.2]octane-1-carboxylic acid having the formula
and the salts, solvates and solvates of the salts thereof.