Oxygen-substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals

The present invention relates to compounds of the formula I,

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wherein A, D, E, G, R¹⁰, R³⁰, R⁴⁰, R⁵⁰and R⁶⁰have the meanings indicated below, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

Cathepsin A (EC=3.4.16.5; gene symbol CTSA) is a protease also known as lysosomal carboxypeptidase A or protective protein. It belongs to a family of serine carboxypeptidases which contains only two other mammalian representatives, retinoid-inducible serine carboxypeptidase and vitellogenic carboxypeptidase-like protein. Within the cell cathepsin A resides in lysosomes where it forms a high molecular weight complex with beta-galactosidase and neuraminidase. The interaction of cathepsin A with these glycosidases is essential for their correct routing to the lysosome and protects them from intralysosomal proteolysis. A deficiency of cathepsin A resulting from various mutations in the ctsa gene leads to a secondary deficiency of beta-galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis (cf. A. d'Azzo et al., in “The Metabolic and Molecular Bases of Inherited Disease”, vol. 2 (1995), 2835-2837). The majority of identified mutations in ctsa are missense mutations affecting the folding or the stability of the protein. None of them was shown to occur in the active site of the enzyme (G. Rudenko et al., Proc. Natl. Acad. Sci. USA 95 (1998), 621-625). Accordingly, the lysosomal storage disorder can be corrected with catalytically inactive cathepsin A mutants (N. J. Galjart et al., J. Biol. Chem. 266 (1991), 14754-14762). The structural function of cathepsin A is therefore separable from its catalytic activity. This is also underscored by the observation that in contrast to mice deficient in the ctsa gene, mice carrying a catalytically inactivating mutation in the ctsa gene do not develop signs of the human disease galactosialidosis (R. J. Rottier et al., Hum. Mol. Genet. 7 (1998), 1787-1794; V. Seyrantepe et al., Circulation 117 (2008), 1973-1981).

Cathepsin A displays carboxypeptidase activity at acidic pH and deamidase and esterase activities at neutral pH against various naturally occurring bioactive peptides. In vitro studies have indicated that cathepsin A converts angiotensin I to angiotensin 1-9 and bradykinin to bradykinin 1-8, which is the ligand for the bradykinin B1 receptor. It hydrolyzes endothelin-1, neurokinin and oxytocin, and deamidates substance P (cf. M. Hiraiwa, Cell. Mol. Life Sci. 56 (1999), 894-907). High cathepsin A activity has been detected in urine, suggesting that it is responsible for tubular bradykinin degradation (M. Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). However, the enzyme can also be released from platelets and lymphocytes and is expressed in antigen-presenting cells where it might be involved in antigen processing (W. L. Hanna et al., J. Immunol. 153 (1994), 4663-4672; H. Ostrowska, Thromb. Res. 86 (1997), 393-404; M. Reich et al., Immunol. Lett. (online Nov. 30, 2009)). Immunohistochemistry of human organs revealed prominent expression in renal tubular cells, bronchial epithelial cells, Leydig's cells of the testis and large neurons of the brain (O. Sohma et al., Pediatr. Neurol. 20 (1999), 210-214). It is upregulated during differentiation of monocytes to macrophages (N. M. Stamatos et al., FEBS J. 272 (2005), 2545-2556). Apart from structural and enzymatic functions, cathepsin A has been shown to associate with neuraminidase and an alternatively spliced beta-galactosidase to form the cell-surface laminin and elastin receptor complex expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes and certain cancer cell types (A. Hinek, Biol. Chem. 377 (1996), 471-480).

The importance of cathepsin A for the regulation of local bradykinin levels has been demonstrated in animal models of hypertension. Pharmacological inhibition of cathepsin A activity increased renal bradykinin levels and prevented the development of salt-induced hypertension (H. Ito et al., Br. J. Pharmacol. 126 (1999), 613-620). This could also be achieved by antisense oligonucleotides suppressing the expression of cathepsin A (I. Hajashi et al., Br. J. Pharmacol. 131 (2000), 820-826). Besides in hypertension, beneficial effects of bradykinin have been demonstrated in various further cardiovascular diseases and other diseases (cf. J. Chao et al., Biol. Chem. 387 (2006), 665-75; P. Madeddu et al., Nat. Clin. Pract. Nephrol. 3 (2007), 208-221). Key indications of cathepsin A inhibitors therefore include atherosclerosis, heart failure, cardiac infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, renal diseases such as renal fibrosis, renal failure and kidney insufficiency; liver diseases such as liver fibrosis and liver cirrhosis, diabetes complications such as nephropathy, as well as organ protection of organs such as the heart and the kidney.

As indicated above, cathepsin A inhibitors can prevent the generation of the bradykinin B1 receptor ligand bradykinin 1-8 (M. Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). This offers the opportunity to use cathepsin A inhibitors for the treatment of pain, in particular neuropathic pain, and inflammation, as has been shown for bradykinin B1 receptor antagonists (cf. F. Marceau et al., Nat. Rev. Drug Discov. 3 (2004), 845-852). Cathepsin A inhibitors can further be used as anti-platelet agents as has been demonstrated for the cathepsin A inhibitor ebelactone B, a propiolactone derivative, which suppresses platelet aggregation in hypertensive animals (H. Ostrowska et al., J. Cardiovasc. Pharmacol. 45 (2005), 348-353).

Further, like other serine proteases such as prostasin, elastase or matriptase, cathepsin A can stimulate the amiloride-sensitive epithelial sodium channel (ENaC) and is thereby involved in the regulation of fluid volumes across epithelial membranes (cf. C. Planes et al., Curr. Top. Dev. Biol. 78 (2007), 23-46). Thus, respiratory diseases can be ameliorated by the use of cathepsin A inhibitors, such as cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections and lung carcinoma. Cathepsin A modulation in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.

Besides for the above-mentioned compound ebelactone B, an inhibitory effect on cathepsin A has been found for certain dipeptidic phenylalanine derivatives which are described in JP 2005/145839. There is a need for further compounds which inhibit cathepsin A and offer an opportunity for the treatment of the mentioned diseases and further diseases in which cathepsin A plays a role. The present invention satisfies this need by providing the oxygen-substituted 3-heteroaroylamino-propionic acid derivatives of the formula I defined below.

Certain compounds in which a 3-heteroaroylamino-propionic acid moiety can be present, have already been described. For example, in WO 2006/076202 amine derivatives, which modulate the activity of steroid nuclear receptors, are described which carry on the nitrogen atom of the amine function a heteroaroyl group and a further group which is defined very broadly. In US 2004/0072802 broadly-defined beta-amino acid derivatives are described which carry an acyl group on the beta-amino group and are inhibitors of matrix metalloproteases and/or tumor necrosis factor. In WO 2009/080226 and WO 2009/080227, which relate to antagonists of the platelet ADP receptor P2Y12 and inhibit platelet aggregation, pyrazoloylamino-substituted carboxylic acid derivatives are described which, however, additionally carry a carboxylic acid derivative group on the carbon atom carrying the pyrazoloylamino group. Other pyrazoloylamino-substituted compounds, in which the nitrogen atom of the amino group is connected to a ring system and which are inhibitors of the blood clotting enzymes factor Xa and/or factor VIIa, are described in WO 2004/056815.

A subject of the present invention is a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,

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wherein

A is chosen from the series consisting of C(R¹) and N;
D is chosen from the series consisting of N(R²), O and S;
E is chosen from the series consisting of C(R³) and N;
G is chosen from the series consisting of R⁷¹—O—C(O)—, R⁷²—N(R⁷³)—C(O)—, NC— and tetrazol-5-yl;
R¹is chosen from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, Ar, HO—, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m— and NC—;
R²is chosen from the series consisting of (C₁-C₇)-alkyl, (C₃-C₇)-cycloalkyl-C_sH_2s— and Ar—C_sH_2s—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3;
R³is chosen from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m— and NC—;
R¹⁰is chosen from the series consisting of R¹¹—O—, R¹²—N(R¹³)—C(O)—O— and Het²—C(O)—O—;
R¹¹is chosen from the series consisting of hydrogen, R¹⁴, (C₃-C₇)-cycloalkyl, Ar and Het³;
R¹²and R¹³are independently of each other chosen from the series consisting of hydrogen, R¹⁵and Ar;
R¹⁴is (C₁-C₁₀)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Ar, Het¹, Het³, NC—, H₂N—C(O)—, (C₁-C₄)-alkyl-NH—C(O)—, di((C₁-C₄)-alkyl)N—C(O)—, Het¹—C(O)—, (C₁-C₄)-alkyl-C(O)—NH— and (C₁-C₄)-alkyl-S(O)_m—;
R¹⁵is (C₁-C₆)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting halogen, HO— and (C₁-C₆)-alkyl-O—;
R¹⁶is (C₁-C₆)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO—, (C₁-C₄)-alkyl-O— and NC—;
R³⁰is chosen from the series consisting of R³¹, (C₃-C₇)-cycloalkyl, R³²—C_uH_2u— and Het³—C_uH_2u—, wherein u is an integer chosen from the series consisting of 0, 1, 2 and 3;
R³¹is (C₁-C₁₀)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₃-C₇)-cycloalkyl, HO—, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m— and NC—;
R³²is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, HO—, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂—, (C₁-C₄)-alkyl-NH—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂—, H₂N—, (C₁-C₆)-alkyl-NH—, di((C₁-C₆)-alkyl)N—, Het¹, (C₁-C₄)-alkyl-C(O)—NH—, Ar—C(O)—NH—, (C₁-C₄)-alkyl-S(O)₂—NH— and NC—;
R³³is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, HO—, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂—, (C₁-C₄)-alkyl-NH—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂— and NC—;
R⁴⁰is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl;
or R³⁰and R⁴⁰together are (CH₂)_xwhich is optionally substituted by one or more identical or different (C₁-C₄)-alkyl substituents, wherein x is an integer chosen from the series consisting of 2, 3, 4 and 5;
R⁵⁰is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, HO— and (C₁-C₆)-alkyl-O—;
R⁶⁰is chosen from the series consisting of hydrogen and (C₁-C₆)-alkyl;
or R⁵⁰and R⁶⁰together are (CH₂)_ywhich is optionally substituted by one or more identical or different (C₁-C₄)-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5;
R⁷¹is chosen from the series consisting of hydrogen and (C₁-C₈)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-C(O)—O—;
R⁷²is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, —CH₂—(CH₂)_b—(C₃-C₆)-cycloalkyl, Het⁴and —(CH₂)_b—Het⁴, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-C(O)—O—, NC—, N((C₁-C₄)-alkyl)₂and b is 0, 1 or 2;
R⁷³is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl;
or
R⁷²and R⁷³together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—;
Ar, independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂— and NC—;
Het¹, independently of each other group Het¹, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het¹is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O—, oxo and NC—;
Het²is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het²is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—;
Het³, independently of each other group Het³, is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (C₁-C₄)-alkyl and oxo;
Het⁴, independently of each other group Het⁴, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O—, oxo and NC—;
m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2;
wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (C₁-C₄)-alkyl;
wherein all alkyl, C_sH_2s, C_uH_2u, (CH₂)_xand (CH₂)_ygroups, independently of each other, and independently of any other substituents, are optionally substituted by one or more fluorine substituents.

If structural elements such as groups, substituents or numbers, for example, can occur several times in the compounds of the formula I, they are all independent of each other and can in each case have any of the indicated meanings, and they can in each case be identical to or different from any other such element. In a dialkylamino group, for example, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear (straight-chain) or branched. This also applies if these groups are substituted or are part of another group, for example an alkyl-O— group (alkyloxy group, alkoxy group) or an HO-substituted alkyl group (hydroxyalkyl group). Depending on the respective definition, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1, for example. In one embodiment of the invention, a (C₁-C₁₀)-alkyl group present in the compounds of the formula I is a (C₁-C₈)-alkyl group, in another embodiment a (C₁-C₆)-alkyl group, in another embodiment a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group. In one embodiment of the invention, a (C₁-C₈)-alkyl group present in any position of the compounds of the formula I is a (C₁-C₆)-alkyl group, in another embodiment a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group, where any (C₁-C₈)-alkyl group present in the compounds of the formula I can independently of each other (C₁-C₈)-alkyl group be a group of any of these embodiments. In one embodiment of the invention, a (C₁-C₆)-alkyl group present in any position of the compounds of the formula I is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group, where any (C₁-C₆)-alkyl group present in the compounds of the formula I can independently of each other (C₁-C₆)-alkyl group be a group of any of these embodiments. In one embodiment of the invention, a (C₁-C₄)-alkyl group present in any position of the compounds of the formula I is a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group, where any (C₁-C₄)-alkyl group present in the compounds of the formula I can independently of each other (C₁-C₄)-alkyl group be a group of any of these embodiments. Examples of alkyl groups are methyl, ethyl, propyl groups including propyl (i.e. n-propyl) and isopropyl, butyl groups including butyl (i.e. n-butyl), sec-butyl, isobutyl and tert-butyl, pentyl groups including pentyl (i.e. n-pentyl), 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl groups including hexyl (i.e. n-hexyl), 3,3-dimethylbutyl and isohexyl, heptyl groups including heptyl (i.e. n-heptyl), octyl groups including octyl (i.e. n-octyl), nonyl groups including nonyl (i.e. n-nonyl), and decyl groups including decyl (i.e. n-decyl). Examples of alkyl-O— groups are methoxy, ethoxy, propoxy (i.e. n-propoxy), isopropoxy, butoxy (i.e. n-butoxy), isobutoxy, tert-butoxy, pentoxy (i.e. n-pentoxy). Examples of alkyl-S(O)_m— are methylsulfanyl-(CH₃—S—), methanesulfinyl-(CH₃—S(O)—), methanesulfonyl (CH₃—S(O)₂—), ethylsulfanyl-(CH₃—CH₂—S—), ethanesulfinyl-(CH₃—CH₂—S(O)—), ethanesulfonyl (CH₃—CH₂—S(O)₂—), 1-methylethylsulfanyl-((CH₃)₂CH—S—), 1-methylethanesulfinyl-((CH₃)₂CH—S(O)—), 1-methylethanesulfonyl ((CH₃)₂CH—S(O)₂—). In one embodiment of the invention the number m is chosen from 0 and 2, wherein all numbers m are independent of each other and can be identical or different. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 0. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 2.

A substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound, applies in general with respect to the definitions of all groups in the compounds of the formula I. In one embodiment of the invention, an individual carbon atom in any alkyl group in the compounds of the formula I, as well as in other groups such as cycloalkyl groups and heterocyclic groups, for example, independently of any other carbon atom does not carry more than one substituent which is bonded via an oxygen atom, nitrogen atom or sulfur atom, such as HO—, (C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S(O)_m-substituents, for example. An alkyl group which is optionally substituted by one or more fluorine substituents can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five, six or seven fluorine substituents, or by one, two, three, four or five fluorine substituents, or by one, two or three fluorine substituents, which can be located in any positions. For example, in a fluoro-substituted alkyl group one or more methyl groups can carry three fluorine substituents each and be present as trifluoromethyl groups, and/or one or more methylene groups (CH₂) can carry two fluorine substituents each and be present as difluoromethylene groups. The explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group, for example of an alkyl-O— group. Examples of fluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl and heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O— groups are trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy. Examples of fluoro-substituted alkyl-S(O)_m— groups are trifluoromethylsulfanyl-(CF₃—S—), trifluoromethanesulfinyl-(CF₃—S(O)—) and trifluoromethanesulfonyl (CF₃—S(O)₂—).

The above explanations with respect to alkyl groups apply correspondingly to alkanediyl groups (divalent alkyl groups) including the divalent groups C_sH_2s, C_uH_2u, (CH₂)_xand (CH₂)_y. Also the alkyl part of a substituted alkyl group may be regarded as an alkanediyl group. Thus, alkanediyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be substituted by fluorine substituents. Examples of alkanediyl groups including the groups C_sH_2sand C_uH_2uand, as far they constitute polymethylene chains, the groups (CH₂)_xare —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—. Examples of fluoro-substituted alkanediyl groups, which can contain one, two, three, four, five or six fluorine substituents, or one, two, three or four fluorine substituents, or one or two fluorine substituents, for example, are —CHF—, —CF₂— —CF₂—CH₂—, —CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂—, —C(CH₃)₂—CF₂—, —CF₂—C(CH₃)₂—.

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3, 4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As regards the optional substitution of cycloalkyl groups by one or more (C₁-C₄)-alkyl substituents, they be unsubstituted, i.e. not carry alkyl substituents, or substituted, for example by one, two, three or four, or by one or two, identical or different (C₁-C₄)-alkyl substituents, for example by methyl groups, which substituents can be located in any positions. Examples of such alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl. As regards the optional substitution of cycloalkyl groups by one or more fluorine substituents, they can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five or six fluorine substituents, or by one, two, three or four fluorine substituents, or by one or two fluorine substituents. The fluorine substituents can be located in any positions of the cycloalkyl group and can also be located in an alkyl substituent on the cycloalkyl group. Examples of fluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl and 3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl. Examples of (C₃-C₇)-cycloalkyl-substituted alkyl groups, which can represent R¹¹or R³⁰, for example, are cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. The explanations with respect cycloalkyl groups apply correspondingly to divalent cycloalkyl groups (cycloalkanediyl groups), which can occur in case the two groups R³⁰and R⁴⁰together are (CH₂)_xor the two groups R⁵⁰and R⁶⁰together are (CH₂)_y. Also the cycloalkyl part of a substituted cycloalkyl group may be regarded as a cycloalkanediyl group. Thus, for example, the bonds through which a cycloalkanediyl group is connected to the adjacent groups, can be located in any positions and can start from the same ring carbon atom, as in the case of the cycloalkanediyl group which is present if R³⁰and R⁴⁰together are (CH₂)_xor the two groups R⁵⁰and R⁶⁰together are (CH₂)_y, or from different ring carbon atoms.

In substituted phenyl groups the substituents can be located in any positions. In the case a the divalent substituents —O—CH₂—O— (methylenedioxy) and —O—CF₂-β-(difluoromethylenedioxy) which can be present on phenyl groups and aromatic heterocycles, the two oxygen atoms are bonded to adjacent ring carbon atoms of the phenyl group or the aromatic heterocycle and replace two hydrogen atoms of the parent system. In monosubstituted phenyl groups, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl groups, the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl groups, the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. If a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in 2,3,4,5-position, 2,3,4,6-position or 2,3,5,6-position. If a polysubstituted phenyl group carries different substituents, each substituent can be located in any suitable position, and the present invention comprises all positional isomers. The number of substituents in an optionally substituted phenyl group can be one, two, three, four or five. In one embodiment of the invention, an optionally substituted phenyl group, independently of any other optionally substituted phenyl group in a compound of the formula I, carries one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, identical or different substituents, and in another embodiment it is unsubstituted.

Likewise, in substituted heterocyclic groups, including aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R³², R³³and Ar, saturated and unsaturated 4-membered to 8-membered monocyclic heterocycles which can represent Het¹, and saturated 4-membered to 7-membered monocyclic heterocycles which can represent Het²and Het³, the substituents can be located in any positions and can be present on ring carbon atoms and/or on suitable ring nitrogen atoms. The present invention comprises all positional isomers. The number of substituents which can be present on substituted heterocycles in the compounds of the formula I, depends on the ring size, the number and type of the ring heteroatoms and the degree of unsaturation. In one embodiment of the invention, the number of identical or different substituents on any of the heterocyclic groups in the compounds of the formula I, independently of the number of substituents in any other occurrence of this group and the number of substituents in any other heterocyclic group in the compounds of the formula I, is one, two, three, four or five, in another embodiment one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. Ring nitrogen atoms which optionally carry a substituent, include ring nitrogen atoms in saturated heterocyclic rings other than those via which such a ring is bonded, and the ring nitrogen atom in 5-membered aromatic heterocycles such as pyrrole, imidazole or triazole, which in the parent heterocycle carry a hydrogen atom. In one embodiment of the invention, the substituents on any such ring nitrogen atoms in heterocyclic groups are chosen from those of the substituents specified in the definition of the respective group which are bonded via a carbon atom, for example from the series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and R³³, in another embodiment from the series consisting of (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in the case of the aromatic heterocycle which can represent R³², from the series consisting of (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl in the case of the aromatic heterocycle which can represent R³³, and are (C₁-C₆)-alkyl in the case of the aromatic heterocycle which can represent Ar and (C₁-C₄)-alkyl in the case of Het¹, Het²and Het³. Generally, besides optionally carrying the substituents indicated in the definition of the respective group, suitable ring nitrogen atoms in heterocyclic groups in the compounds of the formula I, in particular aromatic heterocyclic groups such as the heterocyclic groups which can represent R³², R³³and Ar, for example the ring nitrogen atom in a pyridinyl group, can also carry an oxido substituent —O⁻ and be present as an N-oxide.

The ring heteroatoms specified in the definitions of heterocyclic groups in the compounds of the formula I, including the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R³², R³³and Ar and the heterocycles which represent Het¹, Het², Het³and Het⁴can generally be present in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound, as mentioned above. In one embodiment of the invention, two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions. In another embodiment, two ring heteroatoms in any non-aromatic heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions. In another embodiment, two ring heteroatoms chosen from the series consisting of N atoms which carry a hydrogen atom or a substituent and are bonded to the adjacent ring atoms by single bonds, O atoms and S atoms in a non-aromatic heterocycle cannot be present in adjacent ring positions. In an aromatic heterocycle the choice of ring heteroatoms and their positions is limited by the prerequisite that the ring is aromatic, i.e., it comprises a cyclic system of six delocalized pi electrons. Thus, for example, in an aromatic monocyclic 6-membered heterocycle only nitrogen atoms can occur as ring heteroatoms, and in an aromatic monocyclic 5-membered heterocycle only one ring heteroatom chosen from the series consisting of O atoms, S atoms and N atoms carrying a hydrogen atom or a substituent, can be present. An unsaturated heterocycle which can represent Het¹, can be aromatic, for example in the case of a pyrrolyl, imidazolyl or triazolyl group which is bonded via a ring nitrogen atom and can represent Het¹, or non-aromatic and comprise one or two double bonds within the ring which can be present in any positions. In one embodiment, a 4-membered heterocycle representing Het¹cannot be unsaturated. A heterocyclic group can be bonded via any ring carbon atom or via any suitable ring nitrogen atom, respectively, as indicated in the definition of the respective group. The group Het¹can be 4-membered, 5-membered, 6-membered or 7-membered or 8-membered. The groups Het²and Het³can be 4-membered, 5-membered, 6-membered or 7-membered.

Examples of aromatic heterocycles, from any one or more of which the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R³², R³³and Ar and, as far as applicable, the group Het¹are chosen in one embodiment of the invention, are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,3,4]oxadiazole, pyridine, pyridazine, pyrimidine and pyrazine, which can all be bonded via any ring carbon atom or via any suitable ring nitrogen atom, and which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. Examples of specific residues of aromatic heterocycles, from any one or more of which the aromatic, 5-membered or 6-membered monocyclic heterocyclic residue which can represent R³², R³³or Ar and, as far as applicable, the group Het¹, are chosen in one embodiment of the invention, are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl (2-thienyl), thiophen-3-yl (3-thienyl), imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, [1,2,3]triazol-1-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-1-yl, [1,2,4]triazol-3-yl, [1,2,4]triazol-4-yl, [1,3,4]oxadiazol-2-yl, pyridin-2-yl (2-pyridyl), pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.

Examples of saturated heterocycles and non-aromatic unsaturated heterocycles, from any one or more of which the groups Het¹, Het², Het³and Het⁴are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size and the degree of saturation, are azetidine, oxetane, thietane, pyrrolidine, 2,5-dihydro-1H-pyrrole, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, 4,5-dihydro-1H-imidazole, [1,3]dioxolane, oxazolidine, thiazolidine, piperidine, 1,2,3,6-tetrahydropyridine, tetrahydropyran, tetrahydrothiopyran, piperazine, [1,3]dioxane, [1,4]dioxane, morpholine, thiomorpholine, azepane, oxepane, thiepane, [1,3]diazepane, [1,4]diazepane, [1,4]oxazepane, [1,4]thiazepane and azocane, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. Examples of specific residues of saturated and non-aromatic unsaturated heterocycles, from any one or more of which the groups Het¹, Het², Het³and Het⁴are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size, the degree of saturation and the kind of the atom via which the residue is bonded are azetidin-1-yl, oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, pyrazolidin-1-yl, pyrazolidin-4-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, 4,5-dihydro-1H-imidazol-2-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, piperazin-1-yl, piperazin-2-yl, [1,3]dioxan-2-yl, [1,3]dioxan-4-yl, [1,3]dioxan-5-yl, [1,4]dioxan-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepan-2-yl, oxepan-3-yl, oxepan-4-yl, [1,3]diazepan-1-yl, [1,4]diazepan-1-yl, [1,4]oxazepan-1-yl and [1,4]thiazepan-1-yl, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention, halogen in any occurrence in the compounds of the formula I, independently of all other occurrences, is fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine.

An oxo substituent, i.e. an oxygen atom which is bonded via a double bond, when bonded to a carbon atom, replaces two hydrogen atoms on the carbon atom of the parent system to which it is bonded. Thus, if a CH₂group is substituted by oxo, it becomes a carbonyl group (C(O), C═O). An oxo substituent cannot be present on a carbon atom in an aromatic ring. Besides on carbon atoms, oxo substituents can also be present on a ring sulfur atom in the group Het¹, in particular if the group Het¹is saturated, and in the group Het³, to give the ring member S(O) (S═O, i.e. a sulfoxide group), if one oxo substituent is present on the sulfur atom, or the ring member S(O)₂(S(═O)₂, i.e. a sulfone group), if two oxo substituents are present on the sulfur atom. As examples of heterocycles which can represent Het¹and Het³and which carry oxo substituent a ring sulfur atom, 1,1-dioxo-tetrahydrothiophene, 1-oxo-thiomorpholine and 1,1-dioxo-thiomorpholine may be mentioned, which all are optionally substituted by further substituents such as (C₁-C₄)-alkyl substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.

The present invention comprises all stereoisomeric forms of the compounds of the formula I, for example all enantiomers and diastereomers including cis/trans isomers. The invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in all ratios. Asymmetric centers contained in the compounds of the formula I, for example in unsubstituted or substituted alkyl groups, can all independently of each other have the S configuration or the R configuration. The invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in enantiomerically pure form and essentially enantiomerically pure form, for example with a molar ratio of the two enantiomers of 99:1 or greater, and in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. The invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios. The invention also comprises all cis/trans isomers of the compounds of the formula I in pure form and essentially pure form, for example with a molar ratio of the cis/trans isomers of 99:1 or greater, and in the form of mixtures of the cis isomer and the trans isomer in all ratios. Cis/trans isomerism can occur in substituted rings. The preparation of individual stereoisomers, if desired, can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemically uniform starting compounds in the synthesis or by stereoselective reactions. Optionally, before a separation of stereoisomers a derivatization can be carried out. The separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course of the synthesis. The invention also comprises all tautomeric forms of the compounds of the formula I.

Physiologically acceptable salts, including pharmaceutically utilizable salts, of the compounds of the formula I generally comprise a nontoxic salt component. They can contain inorganic or organic salt components. Such salts can be formed, for example, from compounds of the formula I which contain an acidic group, for example a carboxylic acid group (hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organic bases. Suitable bases are, for example, alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quaternary ammonium hydroxides. Reactions of compounds of the formula I with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent. Examples of salts of acidic groups thus are sodium, potassium, magnesium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom. Compounds of the formula I which contain a basic, i.e. protonatable, group, for example an amino group or a basic heterocycle, can be present in the form of their acid addition salts with physiologically acceptable acids, for example as salt with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds of the formula I by reaction with an acid in a solvent or diluent according to customary procedures. If the compounds of the formula I simultaneously contain an acidic and a basic group in the molecule, the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange. The present invention also comprises all solvates of the compounds of the formula I and their salts, including physiologically acceptable solvates, such as hydrates, i.e. adducts with water, and adducts with alcohols like (C₁-C₄)-alkanols, as well as active metabolites of compounds of the formula I and prodrugs of the compounds of the formula I, i.e. compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds of the formula I, for example compounds which are converted by metabolic hydrolysis into a compound of the formula I, such as compounds in which a carboxylic acid group is present in esterified form or in the form of an amide.

In one embodiment of the invention, the group A is C(R¹), in another embodiment A is N. In one embodiment of the invention, the group D is chosen from the series consisting of N(R²) and O, in another embodiment from the series consisting of N(R²) and S, in another embodiment from the series consisting of O and S, in another embodiment D is N(R²), in another embodiment D is O, in another embodiment D is S. In one embodiment of the invention, the group E is C(R³), in another embodiment E is N. In one embodiment of the invention, one or more of the groups A, D and E have any one or some of their meanings and any remaining groups A, D and E have all their meanings. For example, in one embodiment A is chosen from the series consisting of C(R¹) and N, D is N(R²) and E is chosen from the series consisting of C(R³) and N, in another embodiment A is chosen from the series consisting of C(R¹) and N, D is N(R²) and E is N, in another embodiment A is C(R¹), D is N(R²) and E is chosen from the series consisting of C(R³) and N, in another embodiment A is C(R¹), D is N(R²) and E is N, in another embodiment A is C(R¹), D is chosen from the series consisting of N(R²) and O and D is N, in another embodiment A is N, D is chosen from the series consisting of from N(R²), O and S and E is C(R³), in another embodiment A is N, D is N(R²) and E is chosen from the series consisting of C(R³) and N. In one embodiment of the invention, one of the groups A and D is N and the other of the groups A and D is C(R¹) or C(R³), respectively, in another embodiment one or both of the groups A and D are N and any remaining group A or D is C(R¹) or C(R³), respectively, in another embodiment both of the groups A and D are N, and in another embodiment none of the groups A and D is N.

In terms of formulae resulting from formula I by incorporation of meanings of A, D or E, in one embodiment of the invention a compound of the formula I is a compound of any one or more of formulae I-1 to I-35, for example a compound of formula I-1, or a compound of formula I-2, or a compound of formula I-6, or a compound of formula I-9, or a compound of formula I-10, or a compound of formula I-14, or a compound of formula I-17, or a compound of formula I-19, or a compound of formula I-6 or formula I-14, or a compound of formula I-11 or formula I-12, or a compound of formula I-6 or formula I-10 or formula I-14, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein in the compounds of formulae I-1 to 1-35 the groups A, D, E, G, R¹, R², R³, R¹⁰, R³⁰, R⁴⁰, R⁵⁰and R⁶⁰are defined as in the compounds of formula I in general or in any embodiment specified above or below.

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In one embodiment of the invention, the group G is chosen from the series consisting of R⁷¹—O—C(O)—, R⁷²—N(R⁷³)—C(O)— and tetrazol-5-yl, in another embodiment from the series consisting of R⁷¹—O—C(O)— and R⁷²—N(R⁷³)—C(O)—, in another embodiment G is R⁷¹—O—C(O)—, and in another embodiment G is R⁷²—N(R⁷³)—C(O)—.

In one embodiment of the invention, the group R¹is chosen from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, HO—, (C₁-C₆)-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, HO— and (C₁-C₆)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen and (C₁-C₆)-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, fluorine and chlorine, and in another embodiment R¹is hydrogen. In one embodiment of the invention, a (C₁-C₆)-alkyl group occurring in R¹is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment it is methyl.

In one embodiment of the invention, the group R²is chosen from the series consisting of (C₁-C₇)-alkyl and (C₃-C₇)-cycloalkyl-C_sH_2s—, in another embodiment from the series consisting of (C₃-C₇)-cycloalkyl-C C_sH_2s— and Ar—C_sH_2s—, in another embodiment R²is (C₁-C₇)-alkyl, in another embodiment R²is (C₃-C₇)-cycloalkyl-C C_sH_2s—, and in another embodiment R²is Ar—C_sH_2s—. In one embodiment, s is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiments is 0, and in another embodiments is 1. In one embodiment of the invention, R²is Ar—C_sH_2s— and s is 0, i.e., R²is the group Ar and the group D thus is the group N(Ar). In one embodiment, the divalent alkanediyl group C_sH_2sis a linear group. In one embodiment, a (C₁-C₇)-alkyl group representing R²is a (C₃-C₇)-alkyl group, in another embodiment a (C₃-C₆)-alkyl group. In one embodiment, a (C₃-C₇)-cycloalkyl group occurring in R²is a (C₃-C₆)-cycloalkyl group, in another embodiment a (C₅-C₆)-cycloalkyl group, in another embodiment a cyclopropyl group. In one embodiment, a group Ar occurring in R²is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment from the series consisting of phenyl, thiophenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and pyridinyl, and in another embodiment a group Ar occurring in R²is phenyl, which groups all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Ar occurring in R²is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent, in another embodiment it is substituted by one, two or three identical or different substituents, in another embodiment it is substituted by one or two identical or different substituents, and in another embodiment it is substituted by one substituent. In one embodiment, the substituents which are optionally present on a group Ar occurring in R², are chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S(O)_m—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-S(O)_m—, in another embodiment from the series consisting of halogen and (C₁-C₆)-alkyl, in another embodiment from the series consisting of halogen, in another embodiment from the series consisting of fluorine and chlorine, in another embodiment from the series consisting of fluorine, chlorine and methyl. In one embodiment of the invention, a (C₁-C₆)-alkyl group occurring in R²is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment it is methyl.

Examples of groups Ar which can occur in R², and from any one or more of which a group Ar occurring in R²is chosen in one embodiment of the invention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 3-isopropyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethyl-phenyl, 5-chloro-3-trifluoromethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 3-propoxy-phenyl, 3-isopropoxy-phenyl, 4-tert-butoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl, 2,3-methylenedioxy-phenyl, 2,3-difluoromethylenedioxy-phenyl, 3,4-methylenedioxy-phenyl, 3,4-difluoromethylenedioxy-phenyl, 3-methylsulfanyl-phenyl, 3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl, 3-methanesulfonyl-phenyl, 3-ethanesulfonyl-phenyl, 3-sulfamoyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, thiophen-2-yl, thiophen-3-yl, 3-chloro-thiophen-2-yl, 4-chloro-thiophen-2-yl, 5-chloro-thiophen-2-yl, 4,5-dichloro-thiophen-2-yl, 5-chloro-thiophen-3-yl, 2,5-dichloro-thiophen-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-3-yl, 4,5-dimethyl-thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-3-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2,6-dichloro-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl.

In one embodiment of the invention, the group R³is chosen from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen and (C₁-C₆)-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen and (C₁-C₆)-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and chlorine, in another embodiment R³is hydrogen, and in another embodiment R³is (C₁-C₆)-alkyl. In one embodiment of the invention, a (C₁-C₆)-alkyl group occurring in R³is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment it is methyl.

In one embodiment of the invention, the group R¹⁰is chosen from the series consisting of R¹¹—O— and R¹²—N(R¹³)—C(O)—O—, in another embodiment from the series consisting of R¹²—N(R¹³)—C(O)—O— and Het²—C(O)—O—, and in another embodiment R¹⁰is R¹¹—O—. In one embodiment, the group Het²which can occur in the group R¹⁰, is a saturated 4-membered to 6-membered, in another embodiment a 5-membered or 6-membered, in another embodiment a 5-membered, monocyclic heterocycle which, besides the ring nitrogen via which Het²is bonded, optionally comprises one further ring heteroatom chosen from the series nitrogen, oxygen and sulfur. In one embodiment, the group Het²which can occur in the group R¹⁰, does not comprise a further ring heteroatom besides the ring nitrogen atom via which Het²is bonded. In one embodiment, the number of substituents which are optionally present on a group Het²which can occur in R¹⁰, is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het²is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het²which can occur in the group R¹⁰, are chosen from the series consisting of fluorine, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of (C₁-C₄)-alkyl and HO— and (C₁-C₄)-alkyl-O—, in another embodiment they are (C₁-C₄)-alkyl substituents, and in another embodiment they are HO— substituents.

In one embodiment of the invention, the group R¹¹is chosen from the series consisting of hydrogen, R¹⁴, (C₃-C₇)-cycloalkyl and Het³, in another embodiment from the series consisting of hydrogen and R¹⁴, in another embodiment from the series consisting of hydrogen, R¹⁴and (C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of (C₃-C₇)-cycloalkyl, Ar and Het³, in another embodiment from the series consisting of (C₃-C₇)-cycloalkyl and Het³, in another embodiment R¹¹is hydrogen, in another embodiment R¹¹is R¹⁴, and in another embodiment R¹¹is Ar. In one embodiment, a group Ar representing R¹¹is phenyl which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Ar representing R¹¹is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent. In one embodiment, the substituents which are optionally present on a group Ar representing R¹¹, are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₁-C₄)-alkyl. In one embodiment, a (C₃-C₇)-cycloalkyl group representing R¹¹is a (C₃-C₆)-cycloalkyl group. In one embodiment, a group Het³representing R¹¹is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, in another embodiment it comprises one ring heteroatom chosen from the series consisting of nitrogen and oxygen, in another embodiment one ring heteroatom chosen from the series consisting of oxygen and sulfur, and in another embodiment it comprises one oxygen atom as ring heteroatom, wherein the heterocycle is bonded via a ring carbon atom and is optionally substituted by one, two, three or four, in another embodiment by one or two, identical or different substituents chosen from the series consisting of fluorine, (C₁-C₄)-alkyl and oxo, in another embodiment from the series consisting of fluorine and (C₁-C₄)-alkyl.

In one embodiment of the invention, the groups R¹²and R¹³are independently of each other chosen from the series consisting of hydrogen and R¹⁵, in another embodiment from the series consisting of R¹⁵and Ar, and in another embodiment they are identical or different groups R¹⁵. In one embodiment, one of the groups R¹²and R¹³is chosen from the series consisting of R¹⁵and Ar, and the other is a group R¹⁵. In one embodiment, a group Ar representing R¹²or R¹³is phenyl which is optionally substituted by one or two, in another embodiment by one, identical or different substituents chosen from the series consisting of halogen and (C₁-C₄)-alkyl, and in another embodiment it is unsubstituted phenyl.

In one embodiment of the invention, the (C₁-C₁₀)-alkyl group representing the group R¹⁴is a (C₁-C₈)-alkyl group, in another embodiment a (C₁-C₇)-alkyl group, in another embodiment a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a methyl group, in another embodiment a (C₄-C₈)-alkyl group, in another embodiment a (C₄-C₇)-alkyl group, in another embodiment a (C₅-C₇)-alkyl group, in another embodiment a C₆-alkyl group, wherein all these alkyl groups are linear or branched as applies to alkyl groups in the compounds of the formula I in general, and are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R¹⁴is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, an alkyl group representing R¹⁴is unsubstituted, and in another embodiment it is substituted by one, two, three or four, in another embodiment by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated.

In one embodiment, a (C₃-C₇)-cycloalkyl group occurring as a substituent on an alkyl group representing R¹⁴is a (C₃-C₆)-cycloalkyl group, in another embodiment it is a cyclopropyl group. In one embodiment, a group Ar occurring as a substituent on an alkyl group representing R¹⁴is phenyl or an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment comprises one nitrogen atom as ring heteroatom and in the case of a 5-membered heterocycle one additional ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment a group Ar occurring as a substituent in an alkyl group representing R¹⁴is chosen from phenyl, pyrazolyl, isoxazolyl and thiazolyl, wherein all these groups Ar are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of optional substituents on a group Ar occurring as a substituent in an alkyl group representing R¹⁴is one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Ar occurring as a substituent in an alkyl group representing R¹⁴, are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₁-C₄)-alkyl, and in another embodiment they are (C₁-C₄)-alkyl groups.

In one embodiment, a group Het¹occurring as a substituent on an alkyl group representing R¹⁴is a saturated or unsaturated 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het¹is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het¹occurring as a substituent on an alkyl group representing R¹⁴does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het¹is bonded. In one embodiment, a group Het¹occurring as a substituent on an alkyl group representing R¹⁴is saturated, in another embodiment it is unsaturated. In one embodiment, the number of substituents which are optionally present on a group Het¹occurring as a substituent on an alkyl group representing R¹⁴is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het¹occurring as a substituent on an alkyl group representing R¹⁴are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl and oxo, in another embodiment from the series consisting of (C₁-C₄)-alkyl and oxo, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het¹occurring as a substituent on an alkyl group representing R¹⁴, is not greater than two, and in another embodiment it is not greater than one.

In one embodiment, a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴is a 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which is saturated or unsaturated and comprises a ring nitrogen atom via which Het¹is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het¹is bonded. In one embodiment, a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴is saturated or comprises one double bond within the ring, and in another embodiment it is saturated. In one embodiment, the number of substituents which are optionally present on a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl and oxo, in another embodiment from (C₁-C₄)-alkyl and oxo, in another embodiment they are oxo substituents, and in another embodiment they are (C₁-C₄)-alkyl substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het¹occurring in the substituent Het¹—C(O)— on an alkyl group representing R¹⁴, is not greater than two, and in another embodiment it is not greater than one, and in another embodiment no oxo substituents are present on such a group Het¹.

In one embodiment, a group Het³occurring as a substituent on an alkyl group representing R¹⁴is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in a group Het³occurring as a substituent on an alkyl group representing R¹⁴are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms. In one embodiment, the number of substituents which are optionally present on a group Het³occurring as a substituent on an alkyl group representing R¹⁴is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het³occurring as a substituent on an alkyl group representing R¹⁴are chosen from the series consisting of fluorine and (C₁-C₄)-alkyl, in another embodiment from the series consisting of (C₁-C₄)-alkyl and oxo, in another embodiment they are (C₁-C₄)-alkyl substituents, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het³occurring as a substituent on an alkyl group representing R¹⁴, is not greater than two, and in another embodiment it is not greater than one.

In one embodiment, the substituents which are optionally present on an alkyl group representing R¹⁴are chosen from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Ar, Het¹, Het³, H₂N—C(O)—, (C₁-C₄)-alkyl-NH—C(O)—, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Het¹, Het³, H₂N—C(O)—, (C₁-C₄)-alkyl-NH—C(O)—, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Het¹, Het³, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Het¹and Het³, in another embodiment from the series consisting of halogen, HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Ar, Het¹and Het³, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Ar, Het¹, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Ar, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl and Ar, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, di((C₁-C₄)-alkyl)N—C(O)— and Het¹—C(O)—, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl, Het¹and Het³, in another embodiment from the series consisting of HO—, R¹⁶—O—, oxo, (C₃-C₇)-cycloalkyl and Het³, in another embodiment from the series consisting of HO—, oxo, (C₃-C₇)-cycloalkyl and Het³, in another embodiment from the series consisting of HO—, oxo and (C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of HO—, oxo and Het³, in another embodiment from the series consisting of HO— and oxo, in another embodiment from the series consisting of HO—, R¹⁶—O—, (C₃-C₇)-cycloalkyl and Het³, in another embodiment from the series consisting of HO—, (C₃-C₇)-cycloalkyl and Het³, in another embodiment from the series consisting of HO— and (C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of HO— and Het³, in another embodiment they are HO— substituents, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on an alkyl group representing R¹⁴, is not greater than two, and in another embodiment it is not greater than one. In one embodiment, halogen atoms occurring as substituents on an alkyl group representing R¹⁴, are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R¹⁴is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general.

Examples of groups which can represent R¹⁴, and from any one or more of which R¹⁴is chosen in one embodiment of the invention, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, benzyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-hydroxy-butyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-3-methyl-butyl, 2-hydroxy-2,3-dimethyl-butyl, 2-hydroxy-3,3-dimethyl-butyl, 2-ethyl-2-hydroxy-butyl, 2-hydroxy-2,3,3-trimethyl-butyl, 2-ethyl-2-hydroxy-3-methyl-butyl, 2-ethyl-2-hydroxy-3,3-dimethyl-butyl, 2-cyclopropyl-2-hydroxy-ethyl, 2-cyclopropyl-2-hydroxy-propyl, 2-cyclopropyl-2-hydroxy-butyl, 2-oxo-propyl, 2-oxo-butyl, 3-methyl-2-oxo-butyl, 3,3-dimethyl-2-oxo-butyl, 2-cyclopropyl-2-oxo-ethyl.

In case the optionally substituted alkyl group representing R¹⁴, including the examples of groups listed afore which can represent R¹⁴, contains a chiral carbon atom, the compound of the formula I can be present with respect to this carbon atom in any of it stereoisomeric forms, i.e. in R configuration or in S configuration, or in the form of a mixture of the stereoisomeric forms in any ratio, for example as a mixture of the two stereoisomeric forms in a molar ratio of 1:1, as applies to all chiral carbon atoms in the compounds of the formula I. In one embodiment of the invention, the compound of the formula I has at a chiral carbon atom in R¹⁴pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.

In one embodiment of the invention, the (C₁-C₆)-alkyl group representing the group R¹⁵is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R¹⁵is one or two, in another embodiment one. In one embodiment, the alkyl group representing R¹⁵is unsubstituted. In one embodiment, the substituents which are optionally present on an alkyl group representing R¹⁵are chosen from the series consisting of HO— and (C₁-C₄)-alkyl-O—.

In one embodiment of the invention, the (C₁-C₆)-alkyl group representing the group R¹⁶is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment an ethyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R¹⁶is one or two, in another embodiment one. In one embodiment, an alkyl group representing R¹⁴is unsubstituted, in another embodiment it is substituted by one or two identical or different substituents, in another embodiment it is substituted by one substituent. In one embodiment, the substituents which are optionally present on an alkyl group representing R¹⁵are chosen from the series consisting of HO— and (C₁-C₄)-alkyl-O—, in another embodiment they are HO— substituents, in another embodiment they are (C₁-C₄)-alkyl-O— substituents, and in another embodiment they are (C₁-C₂)-alkyl-O— substituents.

In one embodiment of the invention, the group R³⁰is chosen from the series consisting of R³¹, (C₃-C₇)-cycloalkyl and Het³—C_uH_2u—, in another embodiment from the series consisting of (C₃-C₇)-cycloalkyl, R³²—C_uH_2u— and Het³—C_uH_2u—, in another embodiment from the series consisting of R³²—C_uH_2u— and Het³—C_uH_2u—, in another embodiment R³⁰is R³²—C_uH_2u—, and in another embodiment R³⁰is R³¹. In one embodiment, u is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiment u is 0, and in another embodiment u is 1. In one embodiment, R³⁰is R³²—C_uH_2u— and u is 0, i.e., in this embodiment R³⁰is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the divalent alkanediyl group C_uH_2uis a linear group.

In one embodiment, the (C₃-C₇)-cycloalkyl group representing R³⁰is a (C₃-C₆)-cycloalkyl group, in another embodiment a (C₅-C₆)-cycloalkyl group, in another embodiment a cyclopropyl group. In one embodiment, a group Het³occurring in R³⁰is a saturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a saturated 5-membered or 6-membered heterocycle, in another embodiment a saturated 6-membered heterocycle, which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in a group Het³occurring in R³⁰are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms. In one embodiment, the number of substituents which are optionally present on a group Het³occurring in R³⁰is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Het³occurring in R³⁰is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het³occurring in R³⁰are chosen from the series consisting of fluorine and (C₁-C₄)-alkyl, in another embodiment they are (C₁-C₄)-alkyl substituents.

In one embodiment of the invention, the (C₁-C₁₀-alkyl group representing R³¹is a (C₁-C₈)-alkyl group, in another embodiment a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a methyl group, in another embodiment a (C₄-C₈)-alkyl group, in another embodiment a (C₅-C₈)-alkyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R³¹is one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, an alkyl group representing R³¹is unsubstituted, and in another embodiment it is substituted by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated. In one embodiment, the optional substituents on an alkyl group representing R³¹are chosen from the series consisting of halogen, (C₃-C₇)-cycloalkyl, (C₁-C₈)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C₃-C₇)-cycloalkyl and (C₁-C₈)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₃-C₇)-cycloalkyl, and in another embodiment they are (C₃-C₇)-cycloalkyl substituents. In one embodiment, halogen atoms occurring as substituents on an alkyl group representing R³¹, are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R³¹is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general. In one embodiment, a (C₃-C₇)-cycloalkyl group occurring as a substituent on an alkyl group representing R³⁰is a (C₃-C₆)-cycloalkyl group, in another embodiment a (C₅-C₆)-cycloalkyl group, in another embodiment a cyclopropyl group.

In one embodiment of the invention, the group R³²is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in an aromatic heterocycle representing R³²are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms. In one embodiment, R³²is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment R³²is a 6-membered monocyclic heterocycle as defined, in another embodiment R³²is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R³²is phenyl, and in another embodiment R³²is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R³²is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.

In one embodiment, the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R³², in particular on a phenyl group, are chosen from the series the series consisting of from halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂—, (C₁-C₄)-alkyl-NH—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂—, (C₁-C₆)-alkyl-NH—, di((C₁-C₆)-alkyl)N—, Het¹, (C₁-C₄)-alkyl-C(O)—NH—, Ar—C(O)—NH—, (C₁-C₄)-alkyl-S(O)₂—NH— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂—, (C₁-C₄)-alkyl-NH—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂—, (C₁-C₆)-alkyl-NH—, di((C₁-C₆)-alkyl)N—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, (C₁-C₆)-alkyl-NH—, di((C₁-C₆)-alkyl)N—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, —O—CH₂—O—, —O—CF₂—O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, di((C₁-C₄)-alkyl)N—S(O)₂—, H₂N—, di((C₁-C₆)-alkyl)N—, Het¹, (C₁-C₄)-alkyl-C(O)—NH—, Ar—C(O)—NH— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, di((C₁-C₄)-alkyl)N—S(O)₂—, H₂N—, di((C₁-C₆)-alkyl)N—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m—, di((C₁-C₄)-alkyl)N—S(O)₂—, di((C₁-C₆)-alkyl)N—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, R³³, (C₁-C₆)-alkyl-O—, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m—, di((C₁-C₄)-alkyl)N—S(O)₂—, di((C₁-C₆)-alkyl)N—, Het¹and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, R³³, (C₁-C₆)-alkyl-O— and R³³—O—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, R³³and (C₁-C₆)-alkyl-O—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl and R³³, in another embodiment from the series consisting of halogen and (C₁-C₆)-alkyl. In one embodiment, in case that substituents from the series consisting of (C₃-C₇)-cycloalkyl, R³³, R³³—O—, R³³—(C₁-C₄)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, Het¹and Ar—C(O)—NH— are present on a phenyl group and an aromatic heterocycle representing R³², not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents.

In one embodiment, a (C₁-C₆)-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R³²is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a methyl group. In one embodiment, a (C₃-C₇)-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R³²is a (C₃-C₆)-cycloalkyl group, in another embodiment a (C₃-C₅)-cycloalkyl group, in another embodiment a (C₃-C₄)-cycloalkyl group, in another embodiment it is a cyclopropyl group. In one embodiment, a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R³²is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, and in another embodiment it is a phenyl group, which groups all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of optional substituents on a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R³²is one or two, in another embodiment one, and the optional substituents are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_m— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₁-C₄)-alkyl, and in another embodiment such a group Ar is unsubstituted.

In one embodiment, a group Het¹occurring as a substituent on a phenyl group or an aromatic heterocycle representing R³²is a saturated or unsaturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het¹is bonded and optionally one or two further ring heteroatoms, in another embodiment one further ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het¹occurring as a substituent on a phenyl group or an aromatic heterocycle representing R³²does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het¹is bonded. In one embodiment, a group Het¹occurring as a substituent on a phenyl group or an aromatic heterocycle representing R³²is saturated, in another embodiment it is unsaturated. In one embodiment, the number of substituents which are optionally present on a group Het¹occurring as a substituent on a phenyl group or an aromatic heterocycle representing R³²is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het¹is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het¹occurring as a substituent on a phenyl group or an aromatic heterocycle representing R³²are chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C₁-C₄)-alkyl and oxo, and in another embodiment they are (C₁-C₄)-alkyl substituents.

Examples of groups R³²from any one or more of which R³²is chosen in one embodiment of the invention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 3-isopropyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethyl-phenyl, 5-chloro-3-trifluoromethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 3-propoxy-phenyl, 3-isopropoxy-phenyl, 4-tert-butoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl, 2,3-methylenedioxy-phenyl, 2,3-difluoromethylenedioxy-phenyl, 3,4-methylenedioxy-phenyl, 3,4-difluoromethylenedioxy-phenyl, 3-methylsulfanyl-phenyl, 3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl, 3-methanesulfonyl-phenyl, 3-ethanesulfonyl-phenyl, 3-sulfamoyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, thiophen-2-yl, thiophen-3-yl, 3-chloro-thiophen-2-yl, 4-chloro-thiophen-2-yl, 5-chloro-thiophen-2-yl, 4,5-dichloro-thiophen-2-yl, 5-chloro-thiophen-3-yl, 2,5-dichloro-thiophen-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-3-yl, 4,5-dimethyl-thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-3-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2,6-dichloro-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl.

In one embodiment of the invention, the group R³³is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in an aromatic heterocycle representing R³³are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms. In one embodiment, R³³is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R³³is a 6-membered monocyclic heterocycle as defined, in another embodiment it is an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R³³is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R³³is phenyl, and in another embodiment R³³is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R³³is one, two or three, in another embodiment one or two, in another embodiment one.

In one embodiment, the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R³³, are chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, HO—, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m—, H₂N—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, HO—, (C₁-C₆)-alkyl-O—, H₂N—S(O)₂—, di((C₁-C₄)-alkyl)N—S(O)₂— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, HO—, (C₁-C₆)-alkyl-O— and NC—, are chosen from the series the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_m— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₁-C₄)-alkyl. In one embodiment, a (C₁-C₆)-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R³³is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, in another embodiment a methyl group. In one embodiment, a (C₃-C₇)-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R³²is a (C₃-C₆)-cycloalkyl group, in another embodiment a (C₃-C₅)-cycloalkyl group, in another embodiment a (C₃-C₄)-cycloalkyl group, in another embodiment it is a cyclopropyl group.

In one embodiment of the invention, the group R⁴⁰is chosen from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R⁴⁰is hydrogen. In case R³⁰and R⁴⁰are different and the carbon atom carrying R³⁰and R⁴⁰thus is chiral, in one embodiment of the invention the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater. In case R³⁰is R³²—C_uH_2u— and u is 0, i.e. R³⁰is phenyl or an aromatic heterocycle as defined, R⁴⁰is hydrogen and R⁵⁰is hydrogen, in one embodiment of the invention the compound of the formula I has at the carbon atom carrying R³⁰and R⁴⁰pure S configuration, or essentially pure S configuration, for example with a molar ratio of S configuration to R configuration of 99:1 or greater.

In case R³⁰and R⁴⁰together are a divalent group (CH₂)_x, the two groups R³⁰and R⁴⁰together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties —C(O)—NH and —C(R⁵⁰)(R⁶⁰)-G depicted in formula I on the same ring carbon atom. In one embodiment of the invention, the number of (C₁-C₄)-alkyl substituents which are optionally present on the group (CH₂)_x, is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH₂)_x. In one embodiment, a (C₁-C₄)-alkyl group occurring as a substituent on the group (CH₂)_xis a methyl group. In one embodiment, the integer x is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment x is 2, and in another embodiment x is 4. In one embodiment of the invention, R³⁰and R⁴⁰together cannot be (CH₂)_x, and in this embodiment R³⁰and R⁴⁰thus only have their other meanings as defined.

In one embodiment of the invention, the group R⁵⁰is chosen from the series consisting of hydrogen, (C₁-C₄)-alkyl and HO—, in another embodiment from the series consisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, in another embodiment from the series consisting of hydrogen and HO—, and in another embodiment R⁵⁰is hydrogen.

In one embodiment of the invention, the group R⁶⁰is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₃)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R⁶⁰is hydrogen. In one embodiment of the invention, R⁵⁰and R⁶⁰both are hydrogen. In case R⁵⁰and R⁶⁰are different and the carbon atom carrying R⁵⁰and R⁶⁰thus is chiral, in one embodiment of the invention the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.

In case R⁵⁰and R⁶⁰together are a divalent group (CH₂)_y, the two groups R⁵⁰and R⁶⁰together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties —C(R³⁰)(R⁴⁰)— and G depicted in formula I on the same ring carbon atom. In one embodiment of the invention, the number of (C₁-C₄)-alkyl substituents which are optionally present on the group (CH₂)_y, is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH₂)_y. In one embodiment, a (C₁-C₄)-alkyl group occurring as a substituent on the group (CH₂)_yis a methyl group. In one embodiment, the integer y is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment y is 2, and in another embodiment y is 4. In one embodiment of the invention, R⁵⁰and R⁶⁰together cannot be (CH₂)_y, and in this embodiment R⁵⁰and R⁶⁰thus only have their other meanings as defined. In one embodiment of the invention, R⁵⁰and R⁶⁰together cannot be (CH₂)_yif simultaneously R³⁰and R⁴⁰together are (CH₂)_x.

In one embodiment of the invention, the group R⁷¹is chosen from the series consisting of hydrogen and (C₁-C₆)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₃)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment R⁷¹is hydrogen, in another embodiment R⁷¹is (C₁-C₆)-alkyl, in another embodiment R⁷¹is (C₁-C₄)-alkyl, in another embodiment R⁷¹is (C₁-C₃)-alkyl, and in another embodiment R⁷¹is (C₁-C₂)-alkyl, wherein all these alkyl groups are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on an alkyl group representing R⁷¹is one or two, in another embodiment it is one, in another embodiment an alkyl group representing R⁷¹is unsubstituted. In one embodiment, substituents which are optionally present on an alkyl group representing R⁷¹are (C₁-C₆)-alkyl-O— substituents, in another embodiment (C₁-C₄)-alkyl-O— substituents, in another embodiment (C₁-C₃)-alkyl-O— substituents, in another embodiment (C₁-C₆)-alkyl-C(O)—O— substituents, in another embodiment (C₁-C₄)-alkyl-C(O)—O— substituents, in another embodiment (C₁-C₃)-alkyl-C(O)—O— substituents.

In one embodiment the group R⁷²is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl —CH₂—(CH₂)_b—(C₃-C₆)-cycloalkyl and —(CH₂)_b—Het⁴, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-C(O)—O—, NC—, N((C₁-C₄)-alkyl)₂and b is 0, 1 or 2 and the group R⁷³is chosen from the series consisting hydrogen, (C₁-C₆)-alkyl.

In another embodiment the groups R⁷²and R⁷³together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—.

In another embodiment the group R⁷²is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, Het⁴and —CH₂—Het⁴, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-C(O)—O—, NC—, N((C₁-C₄)-alkyl)₂and the group R⁷³is chosen from the series consisting hydrogen, (C₁-C₆)-alkyl.

In another embodiment the groups R⁷²and R⁷³together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—.

In one embodiment the group R⁷²is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and —CH₂—Het⁴, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-C(O)—O—, NC—, N((C₁-C₄)-alkyl)₂and the group R⁷³is chosen from the series consisting hydrogen and (C₁-C₆)-alkyl.

In another embodiment the groups R⁷²and R⁷³together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain no further ring heteroatoms, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—.

In one embodiment the group R⁷²is chosen from the series consisting of hydrogen, 2,2-dimethyl-butane-3yl, 2,2-dimethyl-propane-3yl, pentan-3yl, propane-2yl, 2-methyl-propane-2yl, butane-1yl, butane-2yl, 2-methyl-butane-3yl, 2-methyl-butane-2-yl, —CH₂CHF₂, —CHCF₃, CH₂CN, —CH₂CH₂OCH₃, —CH(CH₂OH)CH(CH₃)₂, —CH₂C(CH₃)₂—CH₂OH, CH(C₂H₅)CH₂OCH₃, CH₂CH₂CH₂N(CH₃)₂, cyclopropane, cyclobutane, cyclopentane, cyclohexane and —CH₂—Het⁴and the group R⁷³is hydrogen. In another embodiment the groups R⁷²and R⁷³together with the nitrogen atom to which they are bonded form pyrrolidine, which is optionally substituted by HO—. In another embodiment the group R⁷²is chosen from the series consisting of hydrogen, (C₁-C₆)-alkyl, where alkyl is substituted by one or more times by HO— and the group R⁷³is hydrogen.

In one embodiment of the invention, the groups R⁷²and R⁷³are independently of each other chosen from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from the series consisting of hydrogen and methyl. In one embodiment, one of the groups R⁷²and R⁷³is hydrogen and the other is chosen from the series consisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from the series consisting of hydrogen and (C₁-C₂)-alkyl, in another embodiment from the series consisting of hydrogen an methyl, and in another embodiment both groups R⁷²and R⁷³are hydrogen.

In one embodiment of the invention the group Het⁴, independently of each other group Het⁴, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O—, oxo and NC—;

In another embodiment the group Het⁴, independently of each other group Het⁴, is a saturated or unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O—, oxo and NC—;

In another embodiment the group Het⁴, independently of each other group Het⁴, is a unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— and NC—;

In another embodiment the group Het⁴, independently of each other group Het⁴, is selected from 1,2-oxadiazolyl, tetrazlolyl, pyrazolyl, furanyl, pyridinyl, pyrizinyl, which is optionally substituted by methyl.

In one embodiment of the invention, a group Ar in any occurrence in the compounds of the formula I, independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom, in another embodiment Ar is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment Ar is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment a group Ar is phenyl, and in another embodiment a group Ar is pyridinyl, wherein the phenyl and all heterocycles are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a group Ar, independently of each other group Ar, is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Ar is unsubstituted. In one embodiment, in case that substituents from the series consisting of —O—CH₂—O— and —O—CF₂—O— are present on a group Ar, not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents.

In one embodiment, the substituents which are optionally present on a group Ar, independently of each other group Ar, are chosen from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, —O—CH₂—O—, —O—CF₂—O—, (C₁-C₆)-alkyl-S(O)_m— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_m— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-O—, in another embodiment from the series consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from the series consisting of halogen and (C₁-C₄)-alkyl.

A subject of the invention are all compounds of the formula I wherein any one or more structural elements such as groups, substituents and numbers are defined as in any of the specified embodiments or definitions of the elements or have one or more of the specific meanings which are mentioned herein as examples of elements, wherein all combinations of one or more specified embodiments and/or definitions and/or specific meanings of the elements are a subject of the present invention. Also with respect to all such compounds of the formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratios, and their physiologically acceptable salts, and the physiologically acceptable solvates of any of them, are a subject of the present invention.

As an example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I may be mentioned wherein

A is chosen from the series consisting of C(R¹) and N;
D is chosen from the series consisting of N(R²), O and S;
E is N;
R¹is chosen from the series consisting of hydrogen, halogen and (C₁-C₄)-alkyl;
R²is chosen from the series consisting of (C₃-C₇)-cycloalkyl-C_sH_2s— and Ar—C_sH_2s—, wherein s is an integer chosen from the series consisting of 0, 1 and 2;
and all other groups and numbers are defined as in the general definition of the compounds of the formula I or in any specified embodiments of the invention or definitions of structural elements, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts, and the physiologically acceptable solvates of any of them.