# US 8,569,314 B2 · Triazolo and tetrazolo pyrimidine derivatives as HNE inhibitors for treating COPD

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- Number: US 8,569,314 B2
- Document ID: US8569314B2
- Status: Granted
- Kind: B2
- Application number: 13/143,323
- Filed: 2009-12-29
- Published: 2012-01-05
- Granted: 2013-10-29
- Earliest claimed: 2009-01-09
- Assignees: Bayer Intellectual Property GmbH
- Applicants: Franz Von Nussbaum; Dagmar Karthaus; Sonja Anlauf; Martina Delbeck; Volkhart Min-Jian Li; Daniel Meibom; Klemens Lustig
- Inventors: Franz Von Nussbaum; Dagmar Karthaus; Sonja Anlauf; Martina Delbeck; Volkhart Min-Jian Li; Daniel Meibom; Klemens Lustig
- Web page: https://patentgrep.com/patent/US8569314B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/08: Bronchodilators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/14: Ortho-condensed systems
- 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

## Abstract

The present invention relates to novel heterocyclically fused diaryldihydropyrimidine derivatives, to processes for their preparation, to their use alone or in combination for the treatment and/or prevention of diseases and also to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of disorders of the lung and the cardiovascular system.

## Claims

### Claim 1

A compound of formula (I)
in which
A represents C—H,
Y represents N,
Z represents C—R9 in which
R9 represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
where (C1-C6)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl or phenyl and up to three times by fluorine
and where
the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine
and
the phenyl and heteroaryl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
or
R9 represents a group of the formula —SO2—NR10R11 or —NR12R13 in which
R10 and R11 are identical or different and independently of one another represent hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
R12 represents hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or (C1-C6)-alkylsulfonyl,
where (C1-C6)-alkyl may be substituted by cyano, hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl, (C3-C6)-cycloalkyl or phenyl and up to three times by fluorine
and where
the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine
and
the phenyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
R13 represents hydrogen, (C1-C6)-alkyl or a group of the formula —C(═O)—R14, —C(═O)—O—R15 or —C(═O)—NR16R17 in which
R14 represents hydrogen, (C1-C8)-alkyl, (C3-C6)-cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
where (C1-C8)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy, benzyloxy, phenoxy, (C1-C4)-acyloxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-acylamino, (C1-C4)-alkoxycarbonylamino, (C3-C6)-cycloalkyl or phenyl and up to three times by fluorine and up to two CH2 groups in (C1-C8)-alkyl may be exchanged for an oxygen atom provided this results in a stable compound
and where
the cycloalkyl and heterocyclyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine
and
the phenyl and heteroaryl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy, trifluoromethoxy and hydroxycarbonyl,
R15 represents (C1-C6)-alkyl which may be substituted by (C3-C6)-cycloalkyl or phenyl,
R16 and R17 are identical or different and independently of one another represent hydrogen or (C1-C6)-alkyl which may be substituted by hydroxyl or (C1-C4)-alkoxy,
or
R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N, O and S and which may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl, hydroxyl, (C1-C4)-alkoxy and oxo and may be fused to a phenyl ring,
or in which
R7 and R9, if both are present, are attached to one another and together with the carbon atoms to which they are attached form a fused phenyl, pyridyl or pyrimidyl ring which may in each case be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
R1 represents hydrogen
or —S(O)n—R20 in which
R20 represents (C1-C6)-alkyl
and
n represents the number 2,
R2 represents cyano or a group of the formula —C(═O)—R21, —C(═O)—O—R21 or —C(═O)—NH—R21 in which
R21 represents hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl or (C3-C6)-cycloalkyl,
where (C1-C6)-alkyl and (C3-C6)-cycloalkyl for their part may be substituted up to two times by identical or different substituents from the group consisting of hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, mono- and di-(C1-C4)-alkylamino and in (C1-C6)-alkyl and (C3-C6)-cycloalkyl in each case one CH2 group may be replaced by an oxygen atom provided this results in a chemically stable compound,
R3 represents methyl or ethyl
or
R2 and R3 are attached to one another and together form a fused group of the formula
in which
* denotes the point of attachment to the 5-position, marked in formula (I), of the dihydropyrimidine ring
and
** denotes the point of attachment to the 6-position, marked in formula (I), of the dihydropyrimidine ring
and
R22 represents hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl,
where (C1-C6)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy, aminocarbonyl, aminocarbonylamino, (C1-C4)-acylamino or (C3-C6)-cycloalkyl,
R4 represents nitro or trifluoromethyl
and
R5 represents hydrogen, fluorine or chlorine,
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 in which
A represents CH,
Y represents N,
Z represents C—R9,
in which
R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxycarbonyl, (C3-C6)-cycloalkyl or 5- or 6-membered heteroaryl,
where (C1-C4)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy or (C3-C6)-cycloalkyl and up to three times by fluorine
and where
the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine
and
the heteroaryl group mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
or
R9 represents a group of the formula —SO2—NR10R11 or —NR12R13 in which
R10 and R11 are identical or different and independently of one another represent hydrogen, (C1-C4)-alkyl or (C3-C6)-cycloalkyl,
R12 represents hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or (C1-C4)-alkylsulfonyl,
where (C1-C4)-alkyl may be substituted by cyano, hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl or (C3-C6)-cycloalkyl and up to three times by fluorine
and
the cycloalkyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine,
R13 represents hydrogen, (C1-C4)-alkyl or a group of the formula —C(═O)—R14, —C(═O)—O—R15 or —C(═O)—NR16R17 in which
R14 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, 4- to 6-membered heterocyclyl or 5- or 6-membered heteroaryl,
where (C1-C6)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy, (C1-C4)-acyloxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-acylamino, (C1-C4)-alkoxycarbonylamino or (C3-C6)-cycloalkyl and up to three times by fluorine
and where
the cycloalkyl and heterocyclyl groups mentioned may be substituted up to two times by identical or different substituents from the group consisting of (C1-C4)-alkyl and up to two times by fluorine
and
the heteroaryl group mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
R15 represents (C1-C4)-alkyl which may be substituted by (C3-C6)-cycloalkyl or phenyl,
and
R16 and R17 are identical or different and independently of one another represent hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl or (C1-C4)-alkoxy,
R1 represents hydrogen or a group of the formula —SO2—R20 in which
R20 represents (C1-C4)-alkyl,
R2 represents cyano or a group of the formula —C(═O)—R21 or —C(═O)—O—R21 in which
R21 represents methyl, ethyl or 2-hydroxyethyl,
R3 represents methyl,
R4 represents trifluoromethyl
and
R5 represents hydrogen,
or a salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 in which
A represents CH,
Y represents N,
Z represents C—R9,
in which
R9 represents (C1-C4)-alkyl, (C1-C4)-alkoxy or (C3-C6)-cycloalkyl,
where (C1-C4)-alkyl may be substituted by hydroxyl, methoxy, ethoxy or (C3-C6)-cycloalkyl and up to three times by fluorine
and
the cycloalkyl groups mentioned may be substituted up to two times by methyl and up to two times by fluorine,
or
R9 represents a group of the formula —SO2—NR10R11 or —NR12R13 in which
R10 and R11 are identical or different and independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
R12 represents hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or (C1-C4)-alkylsulfonyl,
where (C1-C4)-alkyl may be substituted by cyano, hydroxyl, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl or (C3-C6)-cycloalkyl and up to three times by fluorine
and
the cycloalkyl groups mentioned may be substituted up to two times by methyl and up to two times by fluorine,
R13 represents hydrogen or a group of the formula —C(═O)—R14 or —C(═O)—NR16R17 in which
R14 represents (C1-C4)-alkyl, (C3-C6)-cycloalkyl or 5- or 6-membered heteroaryl,
where (C1-C4)-alkyl may be substituted by hydroxyl, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-acylamino or (C3-C6)-cycloalkyl and up to three times by fluorine
and where
the cycloalkyl groups mentioned may be substituted up to two times by methyl and up to two times by fluorine
and
the heteroaryl group mentioned may be substituted up to two times by identical or different substituents from the group consisting of fluorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy and trifluoromethoxy,
and
R16 and R17 are identical or different and independently of one another represent hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl, methoxy or ethoxy,
R1 represents hydrogen or methylsulfonyl,
R2 represents cyano, acetyl, ethoxycarbonyl or (2-hydroxyethoxy)carbonyl,
R3 represents methyl,
R4 represents trifluoromethyl
and
R5 represents hydrogen,
or a salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1 in which
A represents CH,
Y represents N,
Z represents C—R9 in which
R9 represents a group of the formula —NHR12 or —NH—C(═O)—R14 in which
R12 represents a group of the formula —CH2—C(═O)—OH or —CH2—C(═O)—NH2
and
R14 represents (C3-C6)-cycloalkyl which may be substituted up to two times by methyl and up to two times by fluorine, or (C1-C4)-alkyl,
R1 represents hydrogen or methylsulfonyl,
R2 represents cyano,
R3 represents methyl,
R4 represents trifluoromethyl
and
R5 represents hydrogen,
or a salt thereof.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and at least one inert non-toxic pharmaceutically acceptable excipient.

### Claim 6 (depends on 1)

A process for preparing a compound of claim 1, comprising reacting a compound of formula (II)
in which A, R1, R2 and R3 each have the meanings given in claim 1,
in the presence of a base with a compound of formula (III)
in which Y and Z have the meanings given in claim 1,
to give an intermediate of formula (IV)
in which A, Y, Z, R1, R2 and R3 each have the meanings given above,
cyclizing the intermediate of formula (IV) in situ or in a separate acid-catalyzed reaction step to give a compound of formula (V)
in which A, Y, Z, R1, R2 and R3 each have the meanings given above,
coupling the compound of formula (V) in the presence of a copper(II) catalyst and a base with a phenylboronic acid of formula (VI)
in which R4 and R5 have the meanings given in claim 1,
to give the compound of formula (I).