Substituted dihydropyrazolones and use thereof as HIF-prolyl-4-hydroxylase inhibitors
View Patent ↗The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases, and for promoting wound healing.
1. A compound of the formula (I)
in which
R 1 represents a heteroaryl group of the formula
where
* represents the point of attachment to the dihydropyrazolone ring,
A in each individual occurrence represents C—R 4 or N, where at most two ring members A represent N at the same time,
and
E in each individual occurrence represents C—R 5 or N, where at most two ring members E represent N at the same time,
R 2 represents a heteroaryl group of the formula
where
# represents the point of attachment to the dihydropyrazolone ring,
G in each individual occurrence represents C—R 6 or N,
J represents O, S or N—R 7 ,
L in each individual occurrence represents C—R 8 or N, where at most two ring members L represent N at the same time,
and
M in each individual occurrence represents C—R 9 or N, where in total one or two ring members M represent N,
where
R 4 , R 6 , R 8 and R 9 are identical or different and in each individual case independently of one another represent hydrogen or a substituent selected from the group consisting of halogen, cyano, nitro, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C(═O)—R 10 , —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —SO 2 —R 26 , —SO 2 —NR 27 R 28 , —OR 29 , —SR 30 and —NR 31 R 32 , where
(i) (C 1 -C 6 )-alkyl for its part may be mono- to trisubstituted by identical or different radicals selected from the group consisting of halogen, cyano, oxo, (C 3 -C 7 )-cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C(═O)—R 10 , —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —SO 2 —R 26 , —SO 2 —NR 27 R 28 , —OR 29 , —SR 30 and —NR 31 R 32 ,
where the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals for their part may in each case be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
(ii) (C 3 -C 7 )-cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be mono- to trisubstituted by identical or different radicals selected from the group consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, halogen, cyano, oxo, —C(═O)—R 10 , —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —SO 2 —R 26 , —SO 2 —NR 27 R 28 , —OR 29 , —SR 30 and —NR 31 R 32 ,
where the last-mentioned alkyl radical for its part may be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl,
(iii) R 10 , R 11 , R 12 , R 14 , R 15 , R 18 , R 20 , R 22 , R 25 , R 26 , R 27 , R 29 , R 30 and R 31 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where
(C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl
and
(C 1 -C 6 )-alkyl may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl,
where the last-mentioned heterocycloalkyl radical for its part may be substituted up to two times by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl,
(iv) R 13 , R 16 , R 17 , R 19 , R 21 , R 23 , R 24 , R 28 and R 32 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and/or where
(v) R 12 and R 13 , R 15 and R 16 , R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 22 and R 23 , R 24 and R 25 , R 27 and R 28 and also R 31 and R 32 in each case as a pair together with the atoms to which they are attached may form a 5- or 6-membered heterocycloalkyl ring which may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
R 5 in each individual case, independently of one another, represents hydrogen or a substituent selected from the group consisting of halogen, cyano, nitro, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxycarbonyl and (C 1 -C 6 )-alkoxycarbonyl
and
R 7 represents hydrogen or a substituent selected from the group consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where
(i) (C 1 -C 6 )-alkyl for its part may be mono- to trisubstituted by identical or different radicals selected from the group consisting of halogen, cyano, oxo, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C(═O)—R 10 , —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —SO 2 —R 26 , —SO 2 —NR 27 R 28 , —OR 29 , —SR 30 and —NR 31 R 32 ,
where the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals for their part may in each case be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and
(ii) (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be mono- to trisubstituted by identical or different radicals selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, cyano, oxo, —C(═O)—R 10 , —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —SO 2 —R 26 , —SO 2 —NR 27 R 28 , —OR 29 , —SR 30 and —NR 31 R 32 ,
where the last-mentioned alkyl radical for its part may be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl,
where
(a) R 10 , R 11 , R 12 , R 14 , R 15 , R 18 , R 20 , R 22 , R 25 , R 26 , R 27 , R 29 , R 30 and R 31 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where
(C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be substituted up to three times by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl
and
(C 1 -C 6 )-alkyl may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl,
(b) R 13 , R 16 , R 17 , R 19 , R 21 , R 23 , R 24 , R 28 and R 32 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and/or
(c) R 12 and R 13 , R 15 and R 16 , R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 22 and R 23 , R 24 and R 25 , R 27 and R 28 and also R 31 and R 32 in each case as a pair together with the atoms to which they are attached may form a 5- or 6-membered heterocycloalkyl ring which may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and
R 3 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
and salts, solvates and solvates of the salts thereof.
2. The compound of claim 1 in which
R 1 represents a heteroaryl group of the formula
where
* represents the point of attachment to the dihydropyrazolone ring
and
R 4A and R 4B are identical or different and independently of one another represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxycarbonyl and (C 1 -C 6 )-alkoxycarbonyl,
where the (C 1 -C 6 )-alkyl radical mentioned for its part may be substituted up to three times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents a heteroaryl group of the formula
where
# represents the point of attachment to the dihydropyrazolone ring,
G represents in each case C—R 6 or N, where not more than one of the two ring members G represents N,
J represents O or S,
M represents in each case C—R 9 or N, where one of the two ring members M represents N and the other represents C—R 9 ,
where
R 6 and R 9 in each individual case independently of one another represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —OR 29 and —NR 31 R 32 , where
(i) (C 1 -C 6 )-alkyl for its part may be mono- to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C(═O)—OR 11 , —C(═O)—NR 12 R 13 , —O—C(═O)—R 14 , —O—C(═O)—NR 15 R 16 , —NR 17 —C(═O)—R 18 , —NR 19 —C(═O)—OR 20 , —NR 21 —C(═O)—NR 22 R 23 , —NR 24 —SO 2 —R 25 , —OR 29 and —NR 31 R 32 ,
where the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals for their part may in each case be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
(ii) (C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
(iii) R 11 , R 12 , R 14 , R 15 , R 18 , R 20 , R 22 , R 25 , R 29 and R 31 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where
(C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be substituted up to three times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl
and
(C 1 -C 6 )-alkyl may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 6 )-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl,
(iv) R 13 , R 16 , R 17 , R 19 , R 21 , R 23 , R 24 and R 32 independently of one another in each individual occurrence represent a radical selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and/or where
(v) R 12 and R 13 , R 15 and R 16 , R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 22 and R 23 , R 24 and R 25 and also R 31 and R 32 in each case as a pair together with the atoms to which they are attached may form a 5- or 6-membered heterocycloalkyl ring which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and
R 8 represents hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxycarbonyl and (C 1 -C 6 )-alkoxycarbonyl,
and
R 3 represents hydrogen or methyl,
and salts, solvates and solvates of the salts thereof.
3. The compound of claim 1 in which
R 1 represents a heteroaryl group of the formula
where
* represents the point of attachment to the dihydropyrazolone ring
and
R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents a heteroaryl group of the formula
where
# represents the point of attachment to the dihydropyrazolone ring
and
R 9 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl, where
(C 1 -C 4 )-alkyl for its part may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and
R 3 represents hydrogen,
and salts, solvates and solvates of the salts thereof.
4. The compound of claim 1 in which
R 1 represents a heteroaryl group of the formula
where
* represents the point of attachment to the dihydropyrazolone ring
and
R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents a heteroaryl group of the formula
where
# represents the point of attachment to the dihydropyrazolone ring
and
R 6 , R 6A and R 6B are identical or different and independently of one another represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where
(C 1 -C 4 )-alkyl for its part may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl for their part may in each case be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
and
R 3 represents hydrogen,
and salts, solvates and solvates of the salts thereof.
5. A method of making a compound of the formula (I) as defined in claim 1 , characterized in that a compound of the formula (II)
in which R 1 and R 3 have the meanings given in claim 1 and
Z 1 represents methyl or ethyl,
is reacted in an inert solvent, if appropriate in the presence of an acid, with a compound of the formula (III)
in which R 2 has the meaning given in claim 1 ,
to give compounds of the formula (IV)
in which Z 1 , R 1 , R 2 and R 3 have the meanings given above,
which, already under these reaction conditions or in a subsequent reaction step under the action of a base, cyclize to the compounds of the formula (I),
and the compounds of the formula (I) are, if appropriate with the appropriate (i) solvents and/or (ii) bases or acids, converted into their solvates, salts and/or solvates of the salts.
6. A process for the preparation of a compound of the formula (I) as defined in claim 1 in which R 3 represents hydrogen, comprising:
condensing a compound of the formula (V)
in which R 1 has the meaning given in claim 1 and
Z 1 represents methyl or ethyl,
with a compound of the formula (VI)
in which
Z 2 represents methyl or ethyl,
to give compounds of the formula (VII)
in which Z 1 and R 1 have the meanings given above, reacting the compound of formula (VII) in the presence of an acid with a compound of the formula (III)
in which R 2 has the meaning given in claim 1 ,
to give compounds of the formula (IV-A)
in which Z 1 , R 1 and R 2 have the meanings given above,
which, already under these reaction conditions or in a subsequent reaction step under the action of a base, cyclize to the compounds of the formula (I) in which R 3 represents hydrogen.
7. A pharmaceutical composition comprising the compound of claim 1 in combination with an inert, non-toxic, pharmaceutically suitable auxiliary.
8. A pharmaceutical composition comprising the compound of claim 1 and at least one active compound selected from the group consisting of an ACE inhibitor, an angiotensin II receptor antagonist, a beta receptor blocker, a calcium antagonist, a PDE inhibitor, a mineralocorticoid receptor antagonist, a diuretic, an aspirin, an iron supplement, a vitamin B12 and folic acid supplement, a statin, a digitalis (digoxin) derivative, a tumor chemotherapeutic, and an antibiotic.
9. A method for the treatment of anemia, chronic kidney disease, renal insufficiency, coronary heart disease, angina pectoris, myocardial infarction, arteriosclerosis, pulmonary hypertension, malignant hypertension, and peripheral arterial occlusive disease, comprising administering an effective amount of at least one compound of claim 1 , to a human or animal in need thereof.
10. A method for the treatment of anemia, chronic kidney disease, renal insufficiency, coronary heart disease, angina pectoris, myocardial infarction, arteriosclerosis, pulmonary hypertension, malignant hypertension, and peripheral arterial occlusive disease, comprising administering an effective amount of the pharmaceutical composition of claim 7 , to a human or animal in need thereof.