This invention relates to substituted bicyclic dihydropyrimidinones of formula 1

[Image Omitted]

and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergic disorders, allograft rejection, and oncological diseases.

BACKGROUND INFORMATION

- The following references describe neutrophil elastase inhibitors with a monocyclic dihydropyrimidinone core: GB2392910, WO04024700, WO05082864, WO05082863, DE102006031314, US100010024, WO10115548, WO09080199, DE102007061766, WO06136857, WO06082412, WO12002502.
- The following references describe neutrophil elastase inhibitors with a bicyclic tetrahydropyrrolopyrimidinedione core: WO07129060, WO08135537, US090093477, WO09013444, WO09060206, WO09060203, WO09060158, US110034433.
- The following references describe neutrophil elastase inhibitors with core structures other than those herein before mentioned: WO04020412, WO04020410, WO03053930, WO10078953, WO09135599, DE102009004197, WO11110858, WO11110859, WO09060158, WO09037413, WO04024701, WO13018804, US130065913, WO13018804, WO12002502.
- For a review on various inhibitors of neutrophil elastase see: P. SjÃ¶ (Future Med. Chem. 2012, 4, 651-660).

BRIEF SUMMARY OF THE INVENTION

Neutrophil elastase is a 29 kDa serine protease. It is expressed in bone marrow precursor cells, stored in the granula of peripheral blood granulocytes at high concentrations and it is released upon cellular activation. To the substrates of NE belong major elements of the extracellular matrix: elastin, fibronectin, laminin, collagen and proteoglycans. Neutrophil elastase activity leads to ECM degradation, increases migration and chemotaxis of mono-cytes and vascular smooth muscle cells and directly affects components of the coagulation and fibrinolytic pathways (PAI-1 and TFPI). Increased activity of neutrophil elastase is associated with chronic inflammatory and fibrotic diseases of several organs Inhibitors of neutrophil elastase will therefore have an important role for the treatment of different diseases like COPD, idiopathic pulmonary fibrosis and other fibrotic diseases, cancer, acute lung injury, acute respiratory distress syndrome, bronchiectasis, cystic fibrosis, alpha1-antitrypsin deficiency and others.

The compounds according to the present invention, including the physiologically acceptable salts, are effective as inhibitors of neutrophil elastase and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC₅₀), in an enzymatic inhibition assay.

Some compounds according to the present invention, including the physiologically acceptable salts, are additionally effective as inhibitors of neutrophil serin protease proteinase 3 and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC₅₀), in an enzymatic inhibition assay. This inhibitory activity on a second neutrophil serin protease may be benificial for pharmacological efficacy.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable inhibitory potency, as determined by the half maximal effective concentration (EC₅₀), in a plasma or whole-blood assay, for instance as described in T. Stevens et al. (J. Pharm. Exp. Ther. 2011, 339, 313-320).

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (EDO, in models of human neutrophil elastase-induced lung injury in mice, rat or hamster, for instance as described in Tremblay et al. (Chest 2002, 121, 582-588) or T. Stevens et al. (J. Pharm. Exp. Ther. 2011, 339, 313-320).

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (EDO, in a model of LPS/FMLP-induced lung injury in hamster, for instance as described in Mitsuhashi et al. (Br. J. Pharmacol. 1999, 126, 1147-1152).

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable metabolic stability in an in vitro microsomal assay for metabolic stability as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 29 and references therein.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable metabolic stability in an in vitro hepatocytes assay for metabolic stability as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 29 and references therein.

An improved metabolic stability in an in vitro test system is expected to translate into a reduced in vivo clearance (CL), because the metabolic conversion in the liver is reduced. Based on the pharmacokinetic equation CL/F_oral=Dose/AUC (F_oral: oral bioavailability, AUC: area under the curve), a reduced in vivo clearance is expected to lead to higher dose-normalized systemic exposure (AUC) of the drug.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable permeability in an in vitro Caco-2 cell layer method for permeability as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 26 and references therein. For an oral drug, improved permeability is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemic exposure (AUC).

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit a favourable, that is low efflux ratio (permeability in the efflux direction divided by the permeability in the influx direction) in an in vitro Caco-2 or MDCK cell layer method as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 26 and 27 and references therein. For an oral drug, an improved, that is reduced efflux ratio is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemic exposure (AUC).

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable aqueous solubility in a kinetic or thermodynamic solubility method as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 25 and references therein. For an oral drug, improved aqueous solubility is expected to translate into a higher fraction of the drug absorbed in the intestinal tract resulting in higher dose-normalized systemic exposure (AUC).

Comparatively higher dose-normalized systemic exposure (AUC) can be advantageous in several ways: (1) If a certain systemic exposure (AUC) needs to be achieved for efficacy, the drug can be dosed in a lower amount. Lower dosages have the advantages of lower drug load (parent drug and metabolites thereof) for the patient causing potentially less side effects, and lower production costs for the drug product. (2) Comparatively higher duration of action of the drug when the same dose is applied.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable metabolic stability, favourable permeability, favourable efflux ratio and favourable aqueous solubility. Accordingly, some compounds of the present invention are expected to exhibit favourable pharmacokinetic (PK) properties after oral dosing, in particular favourable systemic exposure (area under the curve, AUC), thus, leading to favourable efficacy in vivo.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable pharmacokinetic (PK) properties. The PK properties can be determined in pre-clinical animal species, for example mouse, rat, hamster, dog, guinea pig, mini pig, cynomolgus monkey, rhesus monkey. The PK properties of a compound can be described, for example, by the following parameters: Mean residence time (MRT), elimination half-live (t_1/2), volume-of-distribution (V_D), area under the curve (AUC), clearance (CL) and bioavailability after oral administration (F_oral).

The compounds of the invention and metabolites thereof are devoid of the hydrazine sub-structure that causes structural alerts for mutagenicity and carcinogenicity as described in Benigni et al. (Chem. Rev. 2011, 11, 2507-2536). Thus, compounds of the invention may bear the advantage of reduced genotoxic potential and reduced risk of failure during development because of genotoxic parent compound, metabolites and/or impurities.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable inhibition of cytochrome P450 (CYP) isozymes in corresponding in vitro assays for CYP isozyme inhibition as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 32 and references therein. Reduced inhibition of CYP isozymes is expected to translate into a reduced risk for undesirable drug-drug interactions which is the interference of one drug with the normal metabolic or pharmacokinetic behaviour of a co-administered drug.

Some compounds according to the present invention, including the physiologically acceptable salts, exhibit favourable, i.e. low inhibition of the hERG channel in a patch clamp assay as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1^sted, 2008), chapter 34 and references cited therein.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula 1

[Image Omitted]

wherein

R¹is phenyl or a five- or six-membered heteroaryl, wherein one, two or three elements are replaced by an element independently selected from the group consisting of N, O and S; preferably phenyl or pyridinyl; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, O₂Nâ€”, NCâ€”, H₂Nâ€”, HOâ€”, R^1.1, R^1.1Oâ€”, R^1.2. R^1.3Sâ€”, R^1.3(O)Sâ€” and R^1.3(O)₂Sâ€”;
- R^1.1is independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl- and C_3-6-halocycloalkyl;
- R^1.2is HOâ€”C_1-6-alkyl- or R^1.1â€”Oâ€”C_1-6-alkyl-;
- R^1.3is independently selected from the group consisting of H, HOâ€”, R^1.1and R^1.2; preferably R^1.1;
R²is phenyl or a five- or six-membered heteroaryl, wherein one or two elements are replaced by an element independently selected from the group consisting of N, O and S; preferably phenyl or pyridinyl; each ring optionally substituted with one or two substituents independently selected from the group consisting of halogen, C_1-4-alkyl-, C_1-4-haloalkyl- and C_1-4-alkyl-Oâ€”;
R³is a residue independently selected from the group consisting of
- R^3.1â€”;
- R^3.2(O)Câ€”;
- R^3.2O(O)Câ€”;
- R^3.2O(O)C-A-; preferably R^3.2O(O)Câ€”CH₂â€”;
- R^3.2Sâ€”; R^3.2(O)Sâ€”; R^3.2(O)₂Sâ€”; preferably R^3.2(O)₂Sâ€”;
- (R^3.2)₂N(O)Câ€”; and
- (R^3.2)₂N(O)C-A-; preferably (R^3.2)₂N(O)Câ€”CH₂â€”;
- R^3.1is independently selected from the group consisting of H, R^3.3, R^3.4, C_1-6-alkyl-C_3-6-cycloalkyl- and C_3-6-cycloalkyl-C_1-6-alkyl-, each optionally substituted with one or two substituents independently selected from among
  - R^3.1.1â€”;
  - R^3.1.1is selected from the group consisting of HOâ€”, halogen, NCâ€”, R^3.3Oâ€”, R^3.5, R^3.6and R^3.7or
  - R^3.1.1denotes a ring independently selected from phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)₂or
  - R^3.1.1denotes a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O)₂;
    - each of the rings optionally substituted with one or two substituents independently selected from among HOâ€”, Oâ• , halogen, NCâ€”, R^3.3, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7or two substituents are together R^3.8;
- R^3.2is independently selected from among R^3.1, phenyl, a four-membered heterocyclic ring containing one element independently selected from the group consisting of N, O, S, S(O) and S(O)₂; or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from the group consisting of HOâ€”, Oâ• , NCâ€”, halogen, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6, R^3.7or two substituents are together R^3.8;
  - or two R^3.2are together a three-, four-, five- or six-membered monocyclic or a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from the group consisting of HOâ€”, F, Oâ• , NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6, R^3.7, phenyl, a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; or two substituents are together R^3.8;
- R^3.3is independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl- and C_3-6-halocycloalkyl-;
- R^3.4is HOâ€”C_1-6-alkyl- or R^3.3â€”Oâ€”C_1-6-alkyl-;
- R^3.5is independently selected from the group consisting of H₂Nâ€”, R^3.3â€”HNâ€”, (R^3.3)₂Nâ€”, R^3.3â€”(O)Câ€”HNâ€” and R^3.3â€”(O)Câ€”(R^3.3)Nâ€”;
- R^3.6is independently selected from the group consisting of R^3.3â€”(O)Sâ€”, R^3.3â€”(O)₂Sâ€”, R^3.3(HN)Sâ€”, R^3.3(HN)(O)Sâ€”, R^3.3(R^3.3N)Sâ€”, R^3.3(R^3.3N)(O)Sâ€”, R^3.3(R^3.4N)Sâ€”, R^3.3(R^3.4N)(O)Sâ€”; R^3.3(NCâ€”N)Sâ€” and R^3.3(NCâ€”N)(O)Sâ€”;
- R^3.7is independently selected from the group consisting of HO(O)Câ€”, H₂N(O)Câ€”, R^3.3â€”Oâ€”(O)Câ€”, R^3.3â€”NHâ€”(O)Câ€” and (R^3.3)₂Nâ€”(O)Câ€”;
- R^3.8is independently C_1-6-alkylene or C_1-6-haloalkylene, wherein optionally one or two CH₂-groups independently from each other are replaced by â€”HNâ€”, â€”(R^3.3)Nâ€”, â€”(R^3.4)Nâ€”, â€”(R^3.3(O)Câ€”)Nâ€”, â€”(R^3.4(O)Câ€”)Nâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€” and â€”S(O)₂â€”;
- A is â€”CH₂â€”, â€”CH₂â€”CH₂â€” or â€”CH₂â€”CH₂â€”CH₂â€”; preferably â€”CH₂â€”; optionally substituted with one or two substituents independently selected from the it) group consisting of halogen, R^3.3, R^3.3Oâ€” and R^3.4or two substituents together are R^3.8;
R⁴is independently selected from the group consisting of halogen, C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl-, C_3-6-halocycloalkyl-, HOâ€”C_1-6-alkyl- and C_1-6-alkyl-Oâ€”C_1-6-alkyl-; preferably methyl
- or two R⁴are together C_1-6-alkylene or C_1-6-haloalkylene, wherein optionally one CH₂-group can be replaced by â€”Oâ€”, â€”Sâ€”, â€”S(O)â€” or â€”S(O)₂â€”;
X is 0, 1 or 2, preferably 0;
R⁵is independently selected from the group consisting of
- halogen, NCâ€”, R^5.1;
- HO(O)Câ€”, H₂N(O)Câ€”, R^5.1â€”Oâ€”(O)Câ€”, R^5.1â€”NHâ€”(O)Câ€”, (R^5.1)₂Nâ€”(O)Câ€”;
- phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, HOâ€”, Oâ• , NCâ€”, O₂Nâ€”, H₂Nâ€”, R^5.1, R^5.1Oâ€”, R^5.1â€”HNâ€”, (R^5.1)₂Nâ€”, R^5.1â€”(O)Câ€”HNâ€”, R^5.1â€”(O)Câ€”(R^5.1)Nâ€”, R^5.1â€”(O)Sâ€”, R^5.1â€”(O)₂Sâ€”, R^5.1â€”(HN)Sâ€”, R^5.1â€”(HN)(O)Sâ€”, R^5.1â€”(R^5.1N)Sâ€”, R^5.1â€”(R^5.1N)(O)Sâ€”, R^5.1â€”(NCâ€”N)Sâ€”, R^5.1â€”(NCâ€”N)(O)Sâ€”, HO(O)Câ€”, H₂N(O)Câ€”, R^5.1â€”Oâ€”(O)Câ€”, R^5.1â€”NHâ€”(O)Câ€” and (R^5.1)₂Nâ€”(O)Câ€”;
- R^5.1is independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-alkyl-C_3-6-cycloalkyl-, C_3-6-cycloalkyl-C_1-6-alkyl-, C_1-6-haloalkyl-, C_3-6-halocycloalkyl, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-Oâ€”C_1-6-alkyl-, C_3-6-cycloalkyl-Oâ€”C_1-6-alkyl-, C_1-6-haloalkyl-Oâ€”C_1-6-alkyl- and C_3-6-halocycloalkyl-Oâ€”C_1-6-alkyl-, or two R^5.1are together C_1-6-alkylene or C_1-6-haloalkylene, wherein optionally one or two CH₂-groups are replaced by â€”HNâ€”, â€”(C_1-6-alkyl-)Nâ€”, â€”(C_3-6-cycloalkyl-)Nâ€”, â€”(C_1-6-haloalkyl-)Nâ€”, â€”(C_3-6-halocycloalkyl-)Nâ€”, â€”(HOâ€”C_1-6-alkyl-)Nâ€”, â€”(C_1-6-alkyl-Oâ€”C_1-6-alkyl-)Nâ€”, â€”(C_3-6-cycloalkyl-Oâ€”C_1-6-alkyl-)Nâ€”, â€”(C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”(C_3-6-cycloalkyl-(O)Câ€”)Nâ€”, â€”(C_1-6-haloalkyl-(O)Câ€”)Nâ€”, â€”(HOâ€”C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”(C_1-6-alkyl-Oâ€”C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”(C_3-6-cycloalkyl-Oâ€”C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€” and â€”S(O)₂â€”;
y is 0, 1 or 2, preferably 0;
or a salt thereof.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C_1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, S(O), S(O)₂, NC (cyano), HOOC, F₃C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent â€œaryl-C_1-3-alkyl-â€ means an aryl group which is bound to a C_1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

For example, the term â€œ3-carboxypropyl-groupâ€ represents the following substituent:

[Image Omitted]

wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms â€œ1-methylpropyl-â€ , â€œ2,2-dimethylpropyl-â€ or â€œcyclopropylmethyl-â€ group represent the following groups:

[Image Omitted]

The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

The term â€œsubstitutedâ€ as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.

The expressions â€œpreventionâ€ , â€œprophylaxisâ€ , â€œprophylactic treatmentâ€ or â€œpreventive treatmentâ€ used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein. Thus the expression â€œprevention of a diseaseâ€ as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.

The expression â€œtreatmentâ€ or â€œtherapyâ€ means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression â€œtreatment of a diseaseâ€ as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.

All isomeric forms (especially all stereoisomeric forms, e.g. all chiral, enantiomeric, diastereomeric and racemic forms, all tautomeric and all geometric isomeric forms) of a compound of the present invention are intended with this invention, unless the specific isomer is specifically indicated. Obviously, the isomer which is pharmacologically more potent and/or more efficacious is preferred.

It will be appreciated that the compounds of the present invention contain at least one asymmetrically substituted carbon atom, and may therefore be isolated as pure enantiomers or as a racemic or non-racemic mixture of both enantiomers. It will be appreciated that some of the compounds of the present invention contain more than one stereogenic center, i.e. more than one asymmetrically substituted carbon or sulfur atom, and may therefore be isolated as pure diastereomers or as diastereomeric mixtures, both in optically active or racemic forms.

The invention contemplates all conceivable stereoisomers, particularly the diastereomers and enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or all other undesired enantiomers and/or diastereomers and/or in any mixing ratio, including the racemic forms, as well as the salts thereof.

In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.

Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantio-selective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

The term halogen generally denotes fluorine, chlorine, bromine and iodine.

As used herein the term â€œprodrugâ€ refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).

The terms â€œprodrugâ€ or â€œprodrug derivativeâ€ mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: â€œDesign and Applications of Prodrugsâ€ ; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.

The term â€œpharmaceutically acceptable prodrugâ€ as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.

The phrase â€œpharmaceutically acceptableâ€ is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, â€œpharmaceutically acceptable saltsâ€ refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, 2,2â€²-iminobis(ethanol), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2â€²,2â€³-nitrilotris-(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-c amphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethane-sulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (âˆ’)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (âˆ’)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

The term â€œC_1-n-alkylâ€ , wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C_1-5-alkyl embraces the radicals H₃Câ€”, H₃Câ€”CH₂â€”, H₃Câ€”CH₂â€”CH₂â€”, H₃Câ€”CH(CH₃)â€”, H₃Câ€”CH₂â€”CH₂â€”CH₂â€”, H₃Câ€”CH₂â€”CH(CH₃)â€”, H₃Câ€”CH(CH₃)â€”CH₂â€”, H₃Câ€”C(CH₃)₂â€”, H₃Câ€”CH₂â€”CH₂â€”CH₂â€”CH₂â€”, H₃Câ€”CH₂â€”CH₂â€”CH(CH₃)â€”, H₃Câ€”CH₂â€”CH(CH₃)â€”CH₂â€”, H₃Câ€”CH(CH₃)â€”CH₂â€”CH₂â€”, H₃Câ€”CH₂â€”C(CH₃)₂â€”, H₃Câ€”C(CH₃)₂â€”CH₂â€”, H₃Câ€”CH(CH₃)â€”CH(CH₃)â€” and H₃Câ€”CH₂â€”CH(CH₂CH₃)â€”.

The term â€œC_1-n-alkyleneâ€ wherein n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C_1-4-alkylene includes â€”CH₂â€”, â€”CH₂â€”CH₂â€”, â€”CH(CH₃)â€”, â€”CH₂â€”CH₂â€”CH₂â€”, â€”C(CH₃)₂â€”, â€”CH(CH₂CH₃)â€”, â€”CH(CH₃)â€”CH₂â€”, â€”CH₂â€”CH(CH₃)â€”, â€”CH₂â€”CH₂â€”CH₂â€”CH₂â€”, â€”CH₂â€”CH₂â€”CH(CH₃)â€”, â€”CH(CH₃)â€”CH₂â€”CH₂â€”, â€”CH₂â€”CH(CH₃)â€”CH₂â€”, â€”CH₂â€”C(CH₃)₂â€”, â€”C(CH₃)₂â€”CH₂â€”, â€”CH(CH₃)â€”CH(CH₃)â€”, â€”CH₂â€”CH(CH₂CH₃)â€”, â€”CH(CH₂CH₃)â€”CH₂â€”, â€”CH(CH₂CH₂CH₃)â€”, â€”CH(CH(CH₃))₂â€” and â€”C(CH₃)(CH₂CH₃)â€”.

The term â€œC_3-n-cycloalkylâ€ , wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C_3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

By the term â€œhaloâ€ added to a â€œalkylâ€ , â€œalkyleneâ€ or â€œcycloalkylâ€ group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H₂FCâ€”, HF₂Câ€”, F₃Câ€”.

The term â€œarylâ€ as used herein, either alone or in combination with another radical, denotes is a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term â€œheterocyclylâ€ means a saturated or unsaturated mono- or polycyclic-ring system including aromatic ring system containing one or more elements selected from the group consisting of N, O, S, S(O) or S(O)₂, consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term â€œheterocyclylâ€ is intended to include all the possible isomeric forms; thus, the term â€œheterocyclylâ€ includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

[Image Omitted]

The term â€œheteroarylâ€ means a mono- or polycyclic-ring systems containing one or more elements selected from among N, O, S, S(O) and S(O)₂, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term â€œheteroarylâ€ is intended to include all the possible isomeric forms; Thus, the term â€œheteroarylâ€ includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

[Image Omitted]

PREFERRED EMBODIMENTS

Preferred are the above compounds of formula 1, wherein R¹is R^1.aand R^1.ais phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of halogen, O₂Nâ€”, NCâ€”, H₂Nâ€”, HOâ€”, R^1.1, R^1.1Oâ€”, R^1.2, R^1.3Sâ€”, R^1.3(O)Sâ€” and R^1.3(O)₂Sâ€”.

Particularly preferred are the above compounds of formula 1, wherein R¹is R^1.aand R^1.ais phenyl, optionally substituted by one, two or three residues independently selected from the group consisting of halogen, O₂Nâ€”, NCâ€”, H₂Nâ€”, HOâ€”, R^1.1R^1.1Oâ€”, R^1.2, R^1.3Sâ€”, R^1.3(O)Sâ€” and R^1.3(O)₂Sâ€”.

Particularly preferred are the above compounds of formula 1, wherein R¹is R^1.aand R^1.ais pyridinyl, optionally substituted by one, two or three residues independently selected from the group consisting of halogen, O₂Nâ€”, NCâ€”, H₂Nâ€”, HOâ€”, R^1.1, R^1.1Oâ€”, R^1.2, R^1.3Sâ€”, R^1.3(O)Sâ€” and R^1.3(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.band R^1.bis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of halogen, NCâ€”, R^1.1, R^1.3(O)Sâ€” and R^1.3(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.cand R^1.cis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of halogen, NCâ€”, R^1.1, R^1.1(O)Sâ€” and R^1.1(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.dand R^1.dis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, NCâ€”, R^1.1and R^1.3(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.eand R^1.eis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, NCâ€”, R^1.1, R^1.1Oâ€” and R^1.1(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.fand R^1.fis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, NCâ€”, Me, Et, i-Pr, t-Bu, cyclopropyl, Me(O)₂Sâ€”, Et(O)₂Sâ€”, i-Pr(O)₂Sâ€”, t-Bu(O)₂Sâ€” and cyclopropyl(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.gand R^1.gis phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, NCâ€”, Me, MeOâ€”, Me(O)₂Sâ€” and Et(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.hand R^1.his phenyl or pyridinyl; each ring optionally substituted by one or two residues independently selected from the group consisting of NCâ€”, Me(O)₂Sâ€” and Et(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.iand R^1.iis phenyl; optionally substituted by one or two residues independently selected from the group consisting of NCâ€”, Me(O)₂Sâ€” and Et(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.jand R^1.jis pyridinyl; optionally substituted by one or two residues independently selected from the group consisting of NCâ€” and Me(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R¹is R^1.kand R^1.kis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R¹is R^1.mand R^1.mis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R¹is R^1.nand R^1.nis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R¹is R^1.oand R^1.ois

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R²is R^2.aand R^2.ais phenyl or a six-membered heteroaryl; wherein one or two elements are replaced by an element independently selected from among N, O and S; each ring optionally substituted with one or two substituents independently selected from the group consisting of halogen, C_1-4-alkyl-, C_1-4-haloalkyl- and C_1-4-alkyl-Oâ€”.

Preferred are the above compounds of formula 1, wherein R²is R^2.band R^2.bis phenyl or a six-membered heteroaryl; wherein one or two elements are replaced by N; each ring optionally substituted with one or two substituents independently selected from the group consisting of halogen, C_1-4-alkyl- and C_1-4-haloalkyl-.

Preferred are the above compounds of formula 1, wherein R²is R^2.cand R^2.cis phenyl or pyridinyl; each optionally substituted with one or two substituents independently selected from the group consisting of halogen, C_1-4-alkyl- and C_1-4-haloalkyl-.

Preferred are the above compounds of formula 1, wherein R²is R^2.dand R^2.dis phenyl or pyridinyl; each optionally substituted with one or two substituents independently selected from the group consisting of Fâ€”, F₃Câ€”, F₂HCâ€” and FH₂Câ€”.

Particularly preferred are the above compounds of formula 1, wherein R²is R^2.dand R^2.dis phenyl or pyridinyl; each optionally substituted with one or two substituents independently selected from the group consisting of Fâ€”, F₃Câ€” and F₂HCâ€”.

Preferred are the above compounds of formula 1, wherein R²is R^2.eand R^2.eis phenyl; optionally substituted with one or two substituents independently selected from the group consisting of Fâ€”, F₃Câ€” and F₂HCâ€”. Particularly preferred are the above compounds of formula 1, wherein R²is R^2.eand R^2.eis phenyl; optionally substituted with one or two substituents independently selected from the group consisting of Fâ€” and F₃Câ€”.

Preferred are the above compounds of formula 1, wherein R²is R^2.fand R^2.fis pyridinyl; optionally substituted with one or two substituents independently selected from the group consisting of Fâ€”, F₃Câ€” and F₂HCâ€”.

Particularly preferred are the above compounds of formula 1, wherein R²is R^2.fand R^2.fis pyridinyl; optionally substituted with one or two substituents substituents independently selected from the group consisting of Fâ€” and F₃Câ€”.

Preferred are the above compounds of formula 1, wherein R²is R²g and R²g is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of F₃Câ€”, F₂HCâ€” and FH₂Câ€”.

Particularly preferred are the above compounds of formula 1, wherein R²is R²g and R²g is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of F₃Câ€” and F₂HCâ€”.

Preferred are the above compounds of formula 1, wherein R²is R^2.hand R^2.his phenyl, optionally substituted with a substituent independently selected from the group consisting of F₃Câ€”, F₂HCâ€” and FH₂Câ€”.

Particularly preferred are the above compounds of formula 1, wherein R²is R^2.hand R^2.his phenyl, optionally substituted with a substituent independently selected from the group consisting of F₃Câ€” and F₂HC.

Preferred are the above compounds of formula 1, wherein R²is R^2.iand R^2.iis pyridinyl, optionally substituted with a substituent independently selected from the group consisting of F₃Câ€”, F₂HCâ€” and FH₂Câ€”.

Particularly preferred are the above compounds of formula 1, wherein R²is R^2.iand R^2.iis pyridinyl, optionally substituted with a substituent independently selected from the group consisting of F₃Câ€” and F₂HCâ€”.

In a preferred embodiment of the invention R²is one of the above mentioned rings carrying the above mentioned substituent in meta-position to the connection of R²with the compound of formula 1.

Preferred are the above compounds of formula 1, wherein R²is R^2.jand R^2.jis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R²is R^2.kand R^2.kis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R²is R^2.mand R^2.mis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R²is R^2.nand R^2.nis

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R²is R^2.oand R^2.ois

[Image Omitted]

Preferred are the above compounds of formula 1, wherein R³is R^3.aand R^3.ais

- R^3.1â€”;
- R^3.2O(O)Câ€”;
- R^3.2O(O)Câ€”CH₂â€”;
- R^3.2(O)₂Sâ€”;
- (R^3.2)₂N(O)Câ€”; and
- (R^3.2)₂N(O)Câ€”CH₂

Preferred are the above compounds of formula 1, wherein R³is R^3.band R^3.bis

- R^3.1â€”;
- R^3.2O(O)Câ€”;
- R^3.2(O)₂Sâ€”,
- (R^3.2)₂N(O)Câ€”; and
- (R^3.2)₂N(O)Câ€”CH₂â€”.

Preferred are the above compounds of formula 1, wherein R³is R^3.cand R^3.cis independently selected from the group consisting of HO(O)Câ€”H₂Câ€”, MeO(O)Câ€”H₂Câ€”, H₂N(O)Câ€”H₂Câ€”, MeHN(O)Câ€”H₂Câ€”, Me₂N(O)Câ€”H₂Câ€”, morpholinyl-(O)Câ€”H₂Câ€”, azetidinyl-(O)Câ€”H₂Câ€”, pyrrolidinyl-(O)Câ€”H₂Câ€”, MeHN(O)Câ€”, EtHN(O)Câ€”, HO(CH₂)₂HN(O)Câ€”, HO(CMe₂)(CH₂)HN(O)Câ€”, HO(CH₂)₃HN(O)Câ€”, Me(O)S(CH₂)₂HN(O)Câ€”, Me(O)₂S(CH₂)₂HN(O)Câ€”, Et(O)₂Sâ€” and Me(O)₂Sâ€”.

Preferred are the above compounds of formula 1, wherein R³is R^3.dand R^3.dis independently selected from the group consisting of HO(O)Câ€”H₂Câ€”, MeO(O)Câ€”H₂Câ€”, H₂N(O)Câ€”H₂Câ€”, MeHN(O)Câ€”H₂Câ€”, Me₂N(O)Câ€”H₂Câ€”, morpholinyl-(O)Câ€”H₂Câ€”, azetidinyl-(O)Câ€”H₂Câ€” and pyrrolidinyl-(O)Câ€”H₂Câ€”.

Preferred are the above compounds of formula 1, wherein R³is R^3.eand R^3.eis independently selected from the group consisting of MeHN(O)Câ€”, EtHN(O)Câ€”, HO(CH₂)₂HN(O)Câ€”, HO(CH₂)₃HN(O)Câ€”, HO(CMe₂)(CH₂)HN(O)Câ€”, Me(O)S(CH₂)₂HN(O)Câ€” and Me(O)₂S(CH₂)₂HN(O)Câ€”.

Preferred are the above compounds of formula 1, wherein R³is selected from the examples (E#) 1 to 54 of Table R³â€” Embodiments of the invention for R³, R^3.2, R^3.3, R^3.4, R^3.5, R^3.6, R^3.7, R^3.8(if present):

TABLE 1R³- Embodiments of the inventionsE#R³R^3.2R^3.3R^3.4R^3.5R^3.6R^3.7R^3.81.R^3.1.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.b2.R^3.1.bR^3.3.aR^3.4.b3.R^3.1.cR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b4.R^3.1.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.b5.H6.Me7.NCâ€”CH₂â€”8.R^3.2O(O)Câ€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b9.R^3.2O(O)Câ€”R^3.2.bR^3.3.aR^3.4.b10.R^3.2O(O)Câ€”R^3.2.c11.R^3.2O(O)Câ€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b12.R^3.2O(O)Câ€”R^3.2.h13.R^3.2O(O)Câ€”CH₂â€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b14.R^3.2O(O)Câ€”CH₂â€”R^3.2.bR^3.3.aR^3.4.b15.R^3.2O(O)Câ€”CH₂â€”R^3.2.c16.R^3.2O(O)Câ€”CH₂â€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b17.R^3.2O(O)Câ€”CH₂â€”R^3.2.h18.R^3.2(O)₂Sâ€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b19.R^3.2(O)₂Sâ€”R^3.2.bR^3.3.aR^3.4.b20.R^3.2(O)₂Sâ€”R^3.2.c21.R^3.2(O)₂Sâ€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b22.R^3.2(O)₂Sâ€”Me;23.R^3.2(O)₂Sâ€”R^3.2.h24.R^3.2HN(O)Câ€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b25.R^3.2HN(O)Câ€”R^3.2.bR^3.3.aR^3.4.b26.R^3.2HN(O)Câ€”R^3.2.c27.R^3.2HN(O)Câ€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b28.R^3.2HN(O)Câ€”R^3.2.h29.R^3.2HN(O)Câ€”H30.R^3.2HN(O)Câ€”Me31.R^3.2HN(O)Câ€”Et32.R^3.2HN(O)Câ€”cyclo-PR33.R^3.2HN(O)Câ€”iso-PR34.R^3.2HN(O)Câ€”HO(CH₂)₂â€”35.R^3.2HN(O)Câ€”HO(CMe₂)CH₂â€”36.R^3.2HN(O)Câ€”HO(CH₂)₃â€”37.R^3.2HN(O)Câ€”F₂CHâ€”CH₂â€”38.R^3.2HN(O)Câ€”CH₂â€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b39.R^3.2HN(O)Câ€”CH₂â€”R^3.2.bR^3.3.aR^3.4.b40.R^3.2HN(O)Câ€”CH₂â€”R^3.2.c41.R^3.2HN(O)Câ€”CH₂â€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b42.R^3.2HN(O)Câ€”CH₂â€”R^3.2.h43.(R^3.2)₂N(O)Câ€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b44.(R^3.2)₂N(O)Câ€”R^3.2.bR^3.3.aR^3.4.b45.(R^3.2)₂N(O)Câ€”R^3.2.eR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b46.(R^3.2)₂N(O)Câ€”R^3.2.fR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b47.(R^3.2)₂N(O)Câ€”R^3.2.gR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b48.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.aR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b49.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.bR^3.3.aR^3.4.b50.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.c51.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.dR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b52.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.eR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b53.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.fR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b54.(R^3.2)₂N(O)Câ€”CH₂â€”R^3.2.gR^3.3.aR^3.4.bR^3.5.bR^3.6.bR^3.7.bR^3.8.b

Preferred are the above compounds of formula 1, wherein R^3.1is R^3.1.aand R^3.1.ais selected from among H, R^3.3, R^3.4, C_1-6-alkyl-C_3-6-cycloalkyl- and C_3-6-cycloalkyl-C_1-6-alkyl-, each optionally substituted with one or two substituents independently selected from among R^3.1.1; and R^3.1.1is selected from among HOâ€”, halogen, NCâ€”, R^3.3Oâ€”, R^3.5, R^3.6and R^3.7.

Preferred are the above compounds of formula 1, wherein R^3.1is R^3.1.band R^3.1.bis selected from among H, R^3.3, R^3.4, C_1-6-alkyl-C_3-6-cycloalkyl- and C_3-6-cycloalkyl-C_1-6-alkyl-.

Preferred are the above compounds of formula 1, wherein R^3.1is R^3.1.cand R^3.1.cis selected from among H, R^3.4and C_1-6-alkyl-, optionally substituted with one or two substituents independently selected from among R^3.11; and

R^3.1.1is a ring independently selected from the group consisting of phenyl, a four-membered heterocyclic ring containing one element independently selected from the group consisting of N, O, S, S(O) and S(O)₂; or

R^3.1.1denotes a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O)₂; each of the rings optionally substituted with one or two substituents independently selected from among HOâ€”, Oâ• , halogen, NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7or two substituents are together R^3.8.

Preferred are the above compounds of formula 1, wherein R³is R^3.1.dand R^3.1.dis selected from among H, R^3.4and C_1-6-alkyl-, optionally substituted with one or two substituents independently selected from among R^3.1.1; and

R^3.1.1is a ring independently selected from among phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O)₂;
- each of the rings optionally substituted with one or two substituents independently selected from HOâ€”, Oâ• , halogen, NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.aand R^3.2.ais R^3.1.a.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.band R^3.2.bis R^3.1b.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.cand R^3.2.cis phenyl.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.dand R^3.2.dis a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from HOâ€”, Oâ• , NCâ€”, halogen, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7or two substituents are together R^3.8.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.eand two R^3.2.eare together a three-, four-, five- or six-membered monocyclic or a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heterocyclic ring optionally containing additional to the nitrogen one or two elements independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from among HOâ€”, F, Oâ• , NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.7and R^3.6or two substituents are together R^3.8.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.fand two R^3.2.fare together a three-, four-, five- or six-membered heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from among HOâ€”, F, Oâ• , NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.7and R^3.6or two substituents are together R^3.8.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.gand two R^3.2.gare together a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from among HOâ€”, F, Oâ• , NCâ€”, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.7and R^3.6or two substituents are together R^3.8.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.hand R^3.2.his selected from among H, Me, Et, n-Pr, i-Pr and cyclopropyl.

Preferred are the above compounds of formula 1, wherein R^3.2is R^3.2.iand R^3.2.iis selected from among H, Me, Et, i-Pr, cyclopropyl, HO(CH₂)₂â€”, HO(CMe₂)(CH₂)â€” and HO(CH₂)₃â€”.

Preferred are the above compounds of formula 1, wherein R^3.3is R^3.3.aand R^3.3.ais selected from among Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F₃Câ€”, F₂HCâ€”, F₃Câ€”CH₂â€”, F₂HCâ€”CH₂â€” and FH₂Câ€”CH₂â€”.

Preferred are the above compounds of formula 1, wherein R^3.4is R^3.4.aand R^3.4.ais selected from among HOâ€”CH₂â€”, HOâ€”CH₂â€”CH₂â€”, HOâ€”CH₂â€”CH₂â€”CH₂â€”, R^3.3.aOâ€”CH₂â€”, R^3.3.aOâ€”CH₂â€”CH₂â€” and R^3.3.aOâ€”CH₂â€”CH₂â€”CH₂â€”.

Preferred are the above compounds of formula 1, wherein R^3.4is R^3.4.band R^3.4.bis selected from among HOâ€”CH₂â€”, HOâ€”CH₂â€”CH₂â€”, HOâ€”CH₂â€”CH₂â€”CH₂â€”, MeO-CH₂â€”, MeO-CH₂â€”CH₂â€”, MeO-CH₂â€”CH₂â€”CH₂â€”, EtO-CH₂â€” EtO-CH₂â€”CH₂â€” and EtO-CH₂â€”CH₂â€”CH₂â€”.

Preferred are the above compounds of formula 1, wherein R^3.5is R^3.5.aand R^3.5.ais selected from among H₂Nâ€”, R^3.3.aHNâ€”, (R^3.3.a)₂Nâ€”, R^3.3.a(O)Câ€”HNâ€” and R^3.3.aâ€”(O)Câ€”(R^3.3.a)Nâ€”.

Preferred are the above compounds of formula 1, wherein R^3.5is R^3.5.band R^3.5.bis selected from among H₂Nâ€”, MeHNâ€”, (Me)₂Nâ€”, EtHNâ€”, (Et)₂Nâ€”, Et(Me)Nâ€”, i-PrHNâ€”, (i-Pr)(Me)Nâ€”, t-BuHNâ€”, (t-Bu)(Me)Nâ€”, Me(O)Câ€”HNâ€”, Et(O)Câ€”HNâ€”, n-Pr(O)Câ€”HNâ€”, i-Pr(O)Câ€”HNâ€”, t-Bu(O)Câ€”HNâ€”, Me(O)C-(Me)Nâ€”, Et(O)C-(Me)Nâ€”, n-Pr(O)C-(Me)Nâ€”, i-Pr(O)C-(Me)Nâ€” and t-Bu(O)C-(Me)Nâ€”.

Preferred are the above compounds of formula 1, wherein R^3.6is R^3.6.aand R^3.6.ais selected from among R^3.3.a(O)Sâ€”, R^3.3.a(O)₂Sâ€”, R^3.3.a(HN)Sâ€”, R^3.3.a(HN)(O)Sâ€”, R^3.3.a(R^3.3.aN)Sâ€”, R^3.3.a(R^3.3.aN)(O)Sâ€”, R^3.3.a(R^3.4.aN)Sâ€”, R^3.3.a(R^3.4.aN)(O)Sâ€”, R^3.3.a(NCâ€”N)Sâ€” and R^3.3.a(NCâ€”N)(O)Sâ€”.

Preferred are the above compounds of formula 1, wherein R^3.6is R^3.6.band R^3.6.bis selected from among Me(O)Sâ€”, Et(O)Sâ€”, i-Pr(O)Sâ€”, Me(O)₂Sâ€”, Et(O)₂Sâ€”, i-Pr(O)₂Sâ€”, Me(HN)Sâ€”, Et(HN)Sâ€”, i-Pr(HN)Sâ€”, Me(HN)(O)Sâ€”, Et(HN)(O)Sâ€”, i-Pr(HN)(O)Sâ€”, Me(MeN)Sâ€”, Et(MeN)Sâ€”, i-Pr(MeN)Sâ€”, Me(MeN)(O)Sâ€”, Et(MeN)(O)Sâ€”, i-Pr(MeN)(O)Sâ€”, Me(HOCH₂CH₂N)Sâ€”, Et(HOCH₂CH₂N)Sâ€”, i-Pr(HOCH₂CH₂N)Sâ€”, Me(HOCH₂CH₂N)(O)Sâ€”, Et(HOCH₂CH₂N)(O)Sâ€”, i-Pr(HOCH₂CH₂N)(O)Sâ€”, Me(MeOCH₂CH₂N)Sâ€”, Et(MeOCH₂CH₂N)Sâ€”, i-Pr(MeOCH₂CH₂N)Sâ€”, Me(MeOCH₂CH₂N)(O)Sâ€”, Et(MeOCH₂CH₂N)(O)Sâ€” and i-Pr(MeOCH₂CH₂N)(O)Sâ€”,

Preferred are the above compounds of formula 1, wherein R^3.7is R^3.7.aand R^3.7.ais selected from among HO(O)Câ€”, H₂N(O)Câ€”, R^3.3.a0(O)Câ€”, R^3.3.aNH(O)Câ€” and (R^3.3.a)₂N(O)Câ€”.

Preferred are the above compounds of formula 1, wherein R^3.7is R^3.7.band R^3.7.bis selected from among HO(O)Câ€”, H₂N(O)Câ€”, MeO(O)Câ€”, EtO(O)Câ€”, i-PrO(O)Câ€”, t-BuO(O)Câ€”, MeNH(O)Câ€”, EtNH(O)Câ€”, i-PrNH(O)Câ€”, t-BuNH(O)Câ€”, (Me)₂N(O)Câ€”, (Et)₂N(O)Câ€”, (i-Pr)(Me)N(O)Câ€”, (t-Bu)(Me)N(O)Câ€”, Et(Me)N(O)Câ€”, i-Pr(Me)N(O)Câ€” and t-Bu(Me)N(O)Câ€”.

Preferred are the above compounds of formula 1, wherein R^3.8is R^3.8.aand R^3.8.ais independently selected from the group consisting of â€”CH₂â€”, â€”CH₂CH₂â€”, â€”CH₂CH₂CH₂â€”, â€”CH₂CH₂CH₂CH₂â€”, â€”CH₂CH₂CH₂CH₂CH₂â€”, wherein optionally one or two CH₂-groups are replaced by â€”HNâ€”, -MeNâ€”, -EtNâ€”, -(Me(O)Câ€”)Nâ€”, -(Et(O)Câ€”)Nâ€”, -(MeO(O)Câ€”)Nâ€”, -(EtO(O)Câ€”)Nâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€”, â€”S(O)₂â€”.

Preferred are the above compounds of formula 1, wherein R^3.8is R^3.8.band R^3.8.bis selected from among â€”CH₂â€”, â€”CH₂CH₂â€”, â€”CH₂CH₂CH₂â€”, â€”CH₂CH₂CH₂CH₂â€” and â€”CH₂CH₂CH₂CH₂CH₂â€”, wherein optionally one or two CH₂-groups are replaced by â€”HNâ€”, -MeNâ€”, -EtNâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€”, â€”S(O)_2-.

Preferred are the above compounds of formula 1, wherein A is A^aand A^ais â€”CH₂â€”, optionally substituted with one or two substituents independently selected from the group consisting of halogen, R^3.3, R^3.3Oâ€” and R^3.4or two substituents together are â€”CH₂CH₂â€”.

Preferred are the above compounds of formula 1, wherein R³is a residue independently selected from the group consisting of

- R^3.1â€”;
- R^3.2O(O)Câ€” or R^3.2O(O)Câ€”CH₂â€”;
- R^3.2(O)₂Sâ€”; and
- (R^3.2)₂N(O)Câ€” or (R^3.2)₂N(O)Câ€”CH₂â€”;
R³is independently selected from the group consisting of H, R^3.3, R^3.4, C_1-6-alkyl-C_3-6-cycloalkyl- and C_3-6-cycloalkyl-C_1-6-alkyl-, each optionally substituted with one or two substituents independently selected from among R^3.11â€”;
- R^3.1.1is selected from the group consisting of HOâ€”, halogen, NCâ€”, R^3.3Oâ€”, R^3.5, R^3.6and R³⁷; or
- R^3.1.1denotes a ring independently selected from among phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)₂; or
- R^3.1.1denotes a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from among N, O, S, S(O) and S(O)₂;
  - each of the rings as defined for R^3.1.1is optionally substituted with one or two substituents independently selected from among HOâ€”, Oâ• , halogen, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7or two substituents are together R^3.8;
R^3.2is independently selected from the group consisting of R^3.1, phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three elements independently selected from the group consisting of N, O, S, S(O) or S(O)₂; each ring optionally substituted with one or two substituents independently selected from the group consisting of HOâ€”, Oâ• , NCâ€”, halogen, R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.6and R^3.7or two substituents are together R^3.8; or two R^3.2are together a five- or six-membered monocyclic or an eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from the group consisting of HOâ€”, F, Oâ• , R^3.3, R^3.3Oâ€”, R^3.3â€”(O)Câ€”, R^3.4, R^3.5, R^3.7and R^3.6or two substituents are together R^3.8;
R^3.3is independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl- and C_3-6-halocycloalkyl-;
R^3.4is HOâ€”C_1-6-alkyl- or R^3.3â€”Oâ€”C_1-6-alkyl-;
R^3.5is independently selected from the group consisting of H₂Nâ€”, R^3.3â€”HNâ€”, (R^3.3)₂Nâ€” and R^3.3â€”(O)Câ€”HNâ€”;
R^3.6is independently selected from the group consisting of R^3.3â€”(O)Sâ€”, R^3.3â€”(O)₂Sâ€”, R^3.3(HN)Sâ€”, R^3.3(HN)(O)Sâ€”, R^3.3(R^3.3N)Sâ€”, R^3.3(R^3.3N)(O)Sâ€”, R^3.3(R^3.4N)Sâ€” and R^3.3(R^3.4N)(O)Sâ€”;
R^3.7is independently selected from the group consisting of HO(O)Câ€”, H₂N(O)Câ€”, R^3.3â€”Oâ€”(O)Câ€”, R^3.3â€”NHâ€”(O)Câ€” and (R^3.3)₂Nâ€”(O)Câ€”;
R^3.8is independently selected from the group consisting of C_1-6-alkylene and C_1-6-haloalkylene, wherein optionally one or two CH₂-groups are replaced independently from each other by â€”HNâ€”, â€”(R^3.3)Nâ€”, â€”(R^3.4)Nâ€”, â€”(R^3.3(O)Câ€”)Nâ€”, â€”(R^3.4(O)Câ€”)Nâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€” or â€”S(O)₂â€”;
or a salt thereof.

Preferred are the above compounds of formula 1, wherein A is A^band A^bis â€”CH₂â€”, optionally substituted with one or two substituents independently selected from the group consisting of F, Me, Et, i-Pr, MeO, EtO, HOCH₂Oâ€” and MeOCH₂â€”.

Preferred are the above compounds of formula 1, wherein A is A^cand A^cis â€”CH₂â€”, optionally substituted with a substituent independently selected from among F and Me.

Preferred are the above compounds of formula 1, wherein A is A^dand A^dis â€”CH₂â€”.

Preferred are the above compounds of formula 1, wherein R⁴is R^4.aand R^4.ais independently selected from the group consisting of fluorine, C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl-, C_3-6-halocycloalkyl-, HOâ€”C_1-6-alkyl- and C_1-6-alkyl-Oâ€”C_1-6-alkyl-; or two R^4.aare together C_1-6-alkylene or C_1-6-haloalkylene, wherein optionally one CH₂-group can be replaced by â€”Oâ€”.

Preferred are the above compounds of formula 1, wherein R⁴is R^4.band R^4.bis independently selected from the group consisting of fluorine, C_1-4-alkyl-, C_3-4-cycloalkyl-, C_1-4-haloalkyl-, C_3-4-halocycloalkyl-, HOâ€”C_1-4-alkyl- and C_1-4-alkyl-Oâ€”C_1-4-alkyl-; or two R^4.bare together C_1-6-alkylene or C_1-6-haloalkylene.

Preferred are the above compounds of formula 1, wherein R⁴is R^4.cand R^4.cis independently selected from the group consisting of fluorine, C_1-4-alkyl-, C_3-4-cycloalkyl-, C_1-4-haloalkyl-, C_3-4-halocycloalkyl-, HOâ€”C_1-4-alkyl- and C_1-4-alkyl-Oâ€”C_1-4-alkyl-.

Preferred are the above compounds of formula 1, wherein R⁴is R^4.dand R^4.dis independently selected from the group consisting of fluorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, HOâ€”CH₂â€”, HOâ€”CH₂CH₂â€” and HOâ€”CH₂CH₂CH₂â€”.

Preferred are the above compounds of formula 1, wherein R⁴is R^4.eand R^4.eis fluorine or methyl.

Particularly preferred are the above compounds of formula 1, wherein R⁴is R^4.eand R^4.eis methyl.

Preferred are the above compounds of formula 1, wherein x is 2, and R⁴is R^4.f, wherein R^4.fdenotes independently from each other C_1-4-alkyl-.

Particularly preferred are the above compounds of formula 1, wherein x is 2, and R⁴is methyl.

Preferred are the above compounds of formula 1, wherein x is x^aand x^ais 0 or 1.

Preferred are the above compounds of formula 1, wherein x is x^band x^bis 0.

Preferred are the above compounds of formula 1, wherein R⁵is R^5.aand R^5.ais independently selected from the group consisting of

- fluorine, NCâ€”, R^5.1;
- HO(O)Câ€”, H₂N(O)Câ€”, R^5.1â€”Oâ€”(O)Câ€”, R^5.1â€”NHâ€”(O)Câ€”, (R^5.1)₂Nâ€”(O)Câ€”;
- phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one or two elements independently selected from the group consisting of N, O, S, S(O) and S(O)₂; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, HOâ€”, Oâ• , NCâ€”, O₂Nâ€”, H₂Nâ€”, R^5.1and R^5.1Oâ€”;

and R^5.1is R^5.1.aand R^5.1.ais independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-alkyl-C_3-6-cycloalkyl-, C_3-6-cycloalkyl-C_1-6-alkyl-, C_1-6-haloalkyl-, C_3-6-halocycloalkyl-, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-Oâ€”C_1-6-alkyl-, C_3-6-cycloalkyl-Oâ€”C_1-6-alkyl-, C_1-6-haloalkyl-Oâ€”C_1-6-alkyl- and C_3-6-halocycloalkyl-Oâ€”C_1-6-alkyl-; or two R^5.1.aare together C_1-6-alkylene or C_1-6-haloalkylene, wherein optionally one CH₂-group is replaced by â€”HNâ€”, â€”(C_1-6-alkyl-)Nâ€”, â€”(C_3-6-cycloalkyl-)Nâ€”, â€”(HOâ€”C_1-6-alkyl-)Nâ€”, â€”(C_1-6-alkyl-Oâ€”C_1-6-alkyl-)Nâ€”,

â€”(C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”(C_3-6-cycloalkyl-(O)Câ€”)Nâ€”, â€”(HOâ€”C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”(C_1-6-alkyl-Oâ€”C_1-6-alkyl-(O)Câ€”)Nâ€”, â€”Oâ€”, â€”Sâ€”, â€”S(O)â€” or â€”S(O)₂â€”;

Preferred are the above compounds of formula 1, wherein R⁵is R^5.band R^5.bis independently selected from the group consisting of fluorine, R^5.1, HO(O)Câ€”, H₂N(O)Câ€”, R^5.1â€”Oâ€”(O)Câ€”, R^5.1â€”NHâ€”(O)Câ€” and (R^5.1)₂Nâ€”(O)Câ€”; and R^5.1is R^5.1.band R^5.1.bis independently selected from the group consisting of C_1-6-alkyl-, C_3-6-cycloalkyl-, C_1-6-haloalkyl-, C_3-6-halocycloalkyl-, HOâ€”C_1-6-alkyl-, C_1-6-alkyl-Oâ€”C_1-6-alkyl-, C_3-6-cycloalkyl-Oâ€”C_1-6-alkyl-, C_1-6-haloalkyl-Oâ€”C_1-6-alkyl- and C_3-6-halocycloalkyl-Oâ€”C_1-6-alkyl-; or two R^5.1are together C_1-6-alkylene or C_1-6-haloalkylene; wherein optionally one CH₂-group is replaced by â€”Oâ€”;

Preferred are the above compounds of formula 1, wherein R⁵is R^5.cand R^5.cis independently selected from the group consisting of R^5.1, HO(O)Câ€” and H₂N(O)Câ€”; and R^5.1is R^5.1.cand R^5.1.cis independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, F₃Câ€”, HOâ€”CH₂â€”, HOâ€”CH₂CH₂â€”, HOâ€”CH₂CH₂CH₂â€”, CH₃â€”Oâ€”CH₂â€”, CH₃â€”Oâ€”CH₂CH₂â€” and CH₃â€”Oâ€”CH₂CH₂CH₂â€”.

Preferred are the above compounds of formula 1, wherein R⁵is R^5.cand R^5.cis independently selected from the group consisting of R^5.1, HO(O)Câ€” and H₂N(O)Câ€”; and R^5.1is R^5.1.dand R^5.1.dis independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl and F₃Câ€”.

Preferred are the above compounds of formula 1, wherein R⁵is R^5.aand R^5.dis independently selected from the group consisting of MeO(O)Câ€”, HO(O)Câ€”, H₂N(O)Câ€”, Ph, thiophene-2-yl, Me and F₃Câ€”.

Preferred are the above compounds of formula 1, wherein R⁵is R^5.eand R^5.eis independently selected from the group consisting of MeO(O)Câ€”, HO(O)Câ€”, H₂N(O)Câ€” and Me-.

Preferred are the above compounds of formula 1, wherein y is 2, and R⁵is R^5.f, wherein R^5.fdenotes independently from each other C_1-4-alkyl-.

Particularly preferred are the above compounds of formula 1, wherein y is 2, and R^5.fis methyl.

Preferred are the above compounds of formula 1, wherein y is y^aand y^ais 0 or 1.

Preferred are the above compounds of formula 1, wherein y is y^band y^bis 0.