EP2091929A1

EP2091929A1 - Agents that disrupt cellular replication and their use in inhibiting pathological conditions

Info

Publication number: EP2091929A1
Application number: EP07723461A
Authority: EP
Inventors: George Reid; Frank Gannon; Maria Polycarpou-Schwarz
Original assignee: Europaisches Laboratorium fuer Molekularbiologie EMBL
Current assignee: Europaisches Laboratorium fuer Molekularbiologie EMBL
Priority date: 2006-03-21
Filing date: 2007-03-21
Publication date: 2009-08-26

Abstract

The present invention provides novel compounds that inhibit cell proliferation, in particular through the disruption of chromosome segregation and uses of these compounds for treating, ameliorating or preventing diseases, conditions or disorders benefiting from the antiproliferative consequences of the disruption of chromosome segregation, in particular hyperproliferative diseases.

Description

AGENTS THAT DISRUPT CELLULAR REPLICATION AND THEIR USE IN INHIBITING

PATHOLOGICAL CONDITIONS

The present invention provides novel compounds that inhibit cell proliferation, in particular by disrupting normal chromatin segregation, and uses of these compounds for treating, ameliorating or preventing diseases, conditions or disorders benefiting from the inhibition of cellular replication, in particular hyperproliferative diseases.

BACKGROUND OF THE INVENTION

Estrogens are commonly recognized as pivotal in female reproductive physiology (Nilsson et α/.(2001), Physiol Rev 81: 1535-1565), however, they are also involved in male reproductive development and physiology (Lombardi et al, (2001), MoI Cell Endocrinol. 178: 51-55), in bone and lipid metabolism (Denger et al, (2001) MoI. Endocrinol. 15: 2064-2077; (2001) HMW. Reprod. Update 7: 303-313) and in the maintenance of the cardiovascular (Rosano and Fini, (2001) Int. J. Fertil. Womens Med. 46: 248-256) and neuronal systems (Green and Simpkins (2000) Ann. N. Y. Acad. Sci. 924: 93-98). The physiological effects of estrogens are transduced through specific nuclear receptors, the estrogen receptors (ERa and ERβ), which are dimeric, intranuclear, ligand dependent transcription factors. ERs recognize defined palindromic target sequences in the promoter of estrogen responsive target genes (Klinge (2001) Nucleic Acids Res. 29: 2905-2919). Upon binding ligand, ERa undergoes a major conformational change that generates surfaces that associate with intermediate transcription factors, which, in turn, activate transcription by recruiting polymerase II to the target promoter (Brzozowski et al., (1997) Nature 389: 753-758; Reid et al., (2003) MoI. Cell 11: 695-707; Metivier et al, (2003) Ce// 115: 751-763).

Estradiol (E2) has an obligate role in the development of the majority of breast neoplasia. E2 induces cellular proliferation in the endometrium and in breast, through modulating the expression and activity of key regulatory components of the cell cycle, in particular cyclin dependant kinases, cyclin Dl, c-myc and pRb, (Cariou et al, (2000) Proc. Natl. Acad. Sci. USA 97: 9042-9046; Carroll et al, (2000) J Biol Chem. 275: 38221-38229; Watts et al, (1995) MoI Endocrinol. 9: 1804-1813). Epidemiological evidence is also consistent with E2 having a key role in the aetiology of breast neoplasia. Prolonged exposure to estrogens, such as early menarche (MacMahon et ah, (1973 J. Natl. Cancer Inst. 50: 21-42), late menopause (Trichopoulos et ah, (1972) J. Natl. Cancer Inst. 48: 605-613), nulliparity and late age at first pregnancy (MacMahon et ah, (1973 J Natl. Cancer Inst. 50: 21-42) are associated with an increased risk of developing breast cancer. Moreover, high levels of exogenous estrogen are directly associated with an increase in the frequency of breast cancer incidence (London et a , (1992) JAMA 267: 941-944).

Cells expressing ERa are rare in normal breast and generally do not concomitantly express markers of cellular proliferation, such as Ki67. Dysregulation of the inverse relationship between proliferation and ERa expression is one of the earliest events that occurs in the progression of normal breast epithelia to neoplasia and is seen in proliferative conditions such as hyperplasia of the usual type (HUT), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and lobular in situ neoplasia (LIN). There is strong epidemiological evidence that these hyperplastic situations are precursors of manifest breast cancer (Bodian et ah, (1993) Cancer 71: 3896-3907; (London et ah, (1992) JAMA 267: 941-944). Concordant with the role that ERa has in the aetiology of breast cancer, tamoxifen and raloxifen, steroid mimetics that block the proliferative activity of the estrogen receptor in breast, are effective in the treatment (Anon. (1998) Lancet 351: 1451-1467) and in the prevention (Anon. (2002) Lancet 360: 817-824) of breast cancer. Tamoxifen in particular has limitations in therapy, with resistance to treatment being a frequent outcome (Kurebayashi, J. (2003) Breast Cancer 10: 112-119) and moreover, tamoxifen induces uterine proliferation (Shang and Brown (2002) Science 295: 2465-2468). Consequently, a need remains for alternative approaches that achieve profound anti-estrogenic effects that are mechanistically different from analogues of E2 or inhibitors of aromatase.

While characterising the class of compounds presented herein, which act as inhibitors of estrogen signaling, it was found that they are potent inhibitors of the normal process of cellular replication. These compounds induce arrests in the G₂/M phase of the cell cycle and provoke abnormal chromatin structures in treated cells, characterized as aster and micronuclei. Moreover, they induce abnormal aster-like structures of tubulin. These compounds induce clearance of ERa protein from ERa positive cells. The compounds of the present invention represent a novel class of inhibitors that also act to abrogate estrogen signaling within cells and which can be used for the treatment, prevention or amelioration of hyperproliferative diseases, in particular those where estrogen receptor signaling contributes to the disease. SUMMARY OF THE INVENTION

The present invention provides compounds capable of disrupting chromosome segregation, which are suitable in particular in antagonizing estrogen receptor signalling. Data presented herein establishes that compounds of formula (I) and formulas (LXVII) and in particular of formulas (VII) to (LXVI) and (LXXI) to (LXXIII) can inhibit estrogen signalling in a cell based assay format and that these compounds induce a profound arrest in the G₂/M phase of the cell cycle.

In a first aspect the present invention relates to a compound of formula (I)

(I) wherein

X is O or S; R¹ is aryl, heteroaryl, aralkyl, cycloalkyl, or heteroaralkyl, optionally substituted;

R² is H, alkyl, cycloalkyl, or aryl, optionally substituted;

R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, or linear or branched alkyl, optionally substituted and/or interrupted one or more times by O, N or S; and

R⁴ is H, alkyl, alkenyl, or alkynyl, optionally substituted; or R³ and R⁴ together form a heterocycloalkyl ring or an alicyclic system, optionally substituted and pharmaceutically acceptable salts thereof.

In a further aspect the present invention relates to compounds according to formula

(LXVII)

(LXVII) wherein

R²¹ is aralkyl or heteroaralkyl, optionally substituted R²² is aryl or heteroaryl, optionally substituted; and X is O or S and pharmaceutically acceptable salts thereof.

In a preferred embodiment the compound of the present invention has a structure according to formula (LXXI), (LXXII) or (LXXIII)

(LXXII)

(LXXIII)

In a further aspect the present invention is directed at pharmaceutical composition comprising an effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient.

In a further aspect the present invention is directed at the use of a compound of the invention for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced cellular replication.

DETAILED DESCRIPTION Definitions

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H. G. W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

In the following definitions of the terms: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alicyclic system, alkenyl, cycloalkenyl, and alkynyl are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings. Nevertheless in some instances of their use throughout the specification preferred meanings of these terms are indicated.

The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tørt-butyl, pentyl, hexyl, heptyl, octyl. Alkyl groups are optionally substituted.

The term "heteroalkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, sec-butyl, fer/-butyl, pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. CH₂-O-CH₃, CH₂-O-C₂H₅, C₂H₄- 0-CH₃, C₂H₄-O-C₂H₅ etc. Heteroalkyl groups are optionally substituted.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If bicyclic, tricyclic or polycyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e. they form a spiro ring system or they form "bridged" ring systems. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of heterocycloalkyl include 1 -(1,2, 5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza- spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.

The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond. However, an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs. Thus, the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus, the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system. Alicyclic systems are optionally substituted. The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthalenyl or anthracenyl. The aryl group is optionally substituted. The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl, zso-propyl, butyl, wo-butyl, sec-butenyl, tert-bxxtyl, pentyl, hexyl, heptyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group. Preferably the aryl attached to the alkyl has the meaning phenyl, naphthalenyl or anthracenyl.

The term "heteroaryl" preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1 , 2, or 3 (for the five membered ring) or 1 , 2, 3, or 4, (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2- benzo furanyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3- benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl.

The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the (2- pyridinyl) ethyl, (3 -pyridinyl) ethyl, or (2-pyridinyl) methyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, sec-butenyl, tert-buty\, pentyl, hexyl, heptyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group. Preferably the heteroaryl attached to the alkyl has the meaning oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofiiranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 2,3-benzodiazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl.

The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1 -propenyl, 2-propenyl, wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. Preferably the cycloalkenyl ring comprises from 3 to 8 carbon atoms, i.e. 3, 4, 5, 6, 7, or 8, e.g. 1 -cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cylcobutenyl, 1-cyclopentenyl, 2- cyclopentenyl, 3-cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl.

The term "alkynyl" refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.

In one embodiment, carbon atoms or hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, and N or with groups containing one ore more elements selected from the group consisting of O, S, and N.

Embodiments include alkoxy, cycloalkoxy, aryloxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.

Other embodiments include hydroxyalkyl, hydroxycycloalkyl, hydroxyaryl, hydroxyaralkyl, hydroxyalkenyl, hydroxycycloalkenyl, hydroxyalinyl, mercaptoalkyl, mercaptocycloalkyl, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl, mercaptocycloalkenyl, mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoaralkyl, aminoalkenyl, aminocycloalkenyl, aminoalkynyl radicals.

In another embodiment, hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one ore more halogen atoms. One radical is the trifluoromethyl radical. If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I). A prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 11 , 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

Compounds and also the starting materials for their preparation according to the invention can be synthesized by methods and standard procedures known to those skilled in the art, i. e. as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known to those skilled in the art and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.

If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the present invention. On the other hand, it is possible to carry out the reaction stepwise. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry at a sterogenic center is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.

Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention. Accordingly, the compounds of this invention include mixtures of stereoisomers, especially mixtures of enantiomers, as well as purified stereoisomers, especially purified enantiomers, or stereoisomerically enriched mixtures, especially enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formulas (I) to (LXXIII) below as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas below as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the compounds of formulae formulas (I) to (LXXIII) are included within the scope of the compounds of formulae formulas (I) to (LXXIII) and preferably the formulae and subformulae corresponding thereto.

Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent.

Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as -camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture. The diastereomer resolution can also be carried out by Standard purification processes, such as, for example, chromatography or fractional crystallization.

It is also possible to obtain optically active compounds of formulas (I) to (LXXIII) by the methods described above by using starting materials which are already optically active. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

General

The present invention provides compositions, compounds and uses of compounds for antagonizing estrogen receptor (ER) function in a cell. The compositions which are useful as antagonist will typically be those which contain an effective amount of an ER-modulating compound. In general, an effective amount of an ER-modulating compound is a concentration of the compound that will produce at least 50 percent decrease in ER activity in a cell-based reporter gene assay as described in the examples below.

Embodiments of the Invention

In a first aspect the present invention relates to a compound of formula (I)

(I) wherein X is O or S;

R¹ is aryl, heteroaryl, aralkyl, cycloalkyl, or heteroaralkyl, optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular C_rC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tørt-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-zso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ aikoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-C]-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl; or heteroaralkyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl; in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of substituents of R¹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; optionally the alkyl moiety of R¹, including the alkyl moiety of the aralkyl and the heteroaralkyl moiety, respectively is interrupted 1, 2, 3, 4 or more times by O, N, and/or S; it is further preferred that the substituents of R¹ are substituents of the aryl and heteroaryl moiety, respectively;

R² is H, alkyl, cycloalkyl, or aryl, optionally substituted; R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, or linear or branched alkyl, optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-buty\, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂,

C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably C]-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Cj-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, terf-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COOR'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,

1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g.

Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl,

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of substituents of R³ are taken together to form a cycloalkyl; heterocycloalkyl; alicyclic ring system; aryl or heteroaryl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-

R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazoiyi, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted, wherein

Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazoiyi, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; optionally the alkyl moiety of R³, including the alkyl moiety of the aralkyl and the heteroaralkyl moiety, respectively is interrupted 1, 2, 3, 4 or more times by O, N, and/or

S; it is further preferred that the substituents of R³ are substituents of the aryl and heteroaryl moiety, respectively;

R⁴ is H, alkyl, alkenyl, or alkynyl, optionally substituted; or R³ and R⁴ together form a heterocycloalkyl ring or an alicyclic system, optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-Zso-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxy methyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COOR'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g.

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl,

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and pharmaceutically acceptable salts thereof.

The compounds of the general formula (I) according to the present invention may be prepared according to the following scheme I: FVU

Providing agent

(1) (2)

(3) (5)

(7) wherein R¹, R², R³, R⁴ and X are as defined above, or have the particularly preferred meanings as defined below, Lie is a conventional leaving group such as halogen, sulfonyl or the like. If in the final compound R⁴ has the meaning H it is preferred that R⁴ in compounds (3), (5) or (7) is a protecting group, which is cleaved at the end of the synthesis process, accordingly, R⁴ may have the meaning protecting group for intermediates of the compounds according to formual (I). The above process comprise reacting a compound of the genera formula (1) with a -C(=X)-group providing agent in an organic solvent to obtain a compound of the general formula (2) and successively reacting the compound of formula (2) with a compound of the general formula (3) to give the compound of the general formula (5). Then the compound of the general formual (5) may be reacted with an alkylating or arylating agent in the presence of a base to give a compound of the general formula (6), wherein the nitrogen residue is substituted with R² wherein R² does not mean hydrogen.

The -C(=X)-group-providing agent used in the above reaction may include 1,1- carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide and phenylchloroformate, and it may be used in an amount of 1-1.5 equivalent, preferably 1-1.1 equivalent to the starting compound (1). The reaction may be carried out in a conventional organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.

The reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base. Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.

The reaction may be carried out at a temperature between 3°C and boiling point of the solvent used, preferably at 50°C- 100°C and for 5-48 hours, preferably for 10-24 hours.

The reaction of the compound (2) with the compound (3) to give the compound (5) may be carried out in the presence of a conventional organic solvent at the temperature of 50-100°C for 5-48 hours. The compound (3) may be used by 1-1.5 equivalent.

The reaction is preferably carried out in the presence of a conventional inorganic or organic base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.

Then, the compound of the formula (5) may be reacted with an alkylating agent (including agents that are capable of transferring a cycloalkyl) or an arylating agent in the presence of a conventional organic or inorganic base to give a compound of the general formula (6).

The alkylating agent and arylating agent used in the above step may include alkylhalide, preferably (Ci_-8)-alkylhalide; alkylsulfonate, preferably (C_1-g)-alkylsulfonate; cycloalkyl halide, preferably (C_3-i₀)-cycloalkyl halide; cycloalkyl sulfonate, preferably (C₃.i₀)-cycloalkyl sulfonate; or arylhalide which all may or may not be substituted as indicated in more detail below.

Substituted or unsubstituted (Ci_-8)-alkylhalide preferably means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, bromo ehtylacetate or the like. Substituted or unsubstituted (Ci_-8)-alkylsulfonate preferably means methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the like.

Substituted or unsubstituted (C_3-i₀)-cycloalkyl halid preferably means cyclopropyl chloride, cyclopropyl bromide, cyclopropyl iodide, cyclobutyl chloride, cyclobutyl bromide, cyclobutyl iodide, cyclopentyl chloride, cyclopentyl bromide, cyclopentyl iodide, cyclohexyl chloride, cyclohexyl bromide, cyclohexyl iodide, cyclopropyl methyl chloride, cyclopropyl methyl bromide, cyclopropyl methyl iodide, cyclobutyl methyl chloride, cyclobutyl methyl bromide, cyclobutyl methyl iodide, cyclopentyl methyl chloride, cyclopentyl methyl bromide, cyclopentyl methyl iodide, cyclohexyl methyl chloride, cyclohexyl methyl bromide, cyclohexyl methyl iodide, or the like.

Substituted or unsubstituted aryl halide preferably means benzyl chloride, benzyl bromide, benzyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, toluyl chloride, toluyl bromide and toluyl iodide.

Substituted or unsubstituted (C₃.i₀)-cycloalkyl sulfonate preferably means cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, cyclopropyl methyl sulfonate, cyclobutyl methyl sulfonate, cyclopentyl methyl sulfonate and cyclohexyl methyl sulfonate.

Aryl sulfonate preferably means benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, or the like. The reaction may be carried out in a conventional organic solvent as such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile and dimethylformamide.

The conventional inorganic or organic base used in above step may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.

In the above reaction process, if any acid material is formed, a basic material may be added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, and organic amines.

R⁴ or any substituent of R¹, R², R³, and/or R⁴, which would undergo unwanted reactions when carrying out a synthesis according to scheme I may be protected by a conventional protecting group, which is not cleaved during the reactions according to schema I but is cleavable under known conditions. The skilled person is aware of a large variety of protection groups, which can be employed in organic synthesis. Protecting groups are reviewed in, for example, Wuts, P. G. M. and Greene, T. W., Protective Groups in Organic Chemistry, 3^rd Ed., 1999; Wily & Sons Inc. and in Kocienski, P.J., Protecting groups. 2^nd Ed., 2000, Thieme Medical Publishing. Protecting groups are organized in these reference books according to the functionalities that are protected as well as according to the conditions which remove the respective protecting groups selectively. Particularly preferred protective groups, which can be used are: (i) protective group removed at acidic conditions, preferably at a pH between 4 and 6, which is selected from the group consisting of Boc or Trityl protecting groups;

(ii) a protecting group removed by a nucleophile, which is selected from the group consisting of Fmoc or Dde protecting groups;

(iii) a protecting group removed by hydrogenolysis consisting of the allyl type, the tert-butyl type, the benzyl type or Dmab (4,4-dimethyl-2,6-dicyclohexylidene)-3-methylbutyl]- amino} benzyl ester ;

(iv) a protecting group removed by radiation, which is selected from the group consisting of nitroveratryloxy carbonyl, nitrobenzyloxy carbonyl, dimethyl dimethoxybenzyloxy carbonyl, 5-bromo-7-nitroindolinyl, o-hydroxy-α-methyl cinnamoyl, and 2-oxymethylene anthraquinone.

In a preferred embodiment of the compounds of the invention

R¹ is aryl, heteroaryl, aralkyl, or heteroaralkyl optionally substituted preferably as outlined above and/or interrupted 1 , 2, 3, 4 or more times by O, N and/or S;

R² is H, or Ci to C₄ alkyl, optionally substituted; R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, linear or branched Ci to C₂₀ alkyl, optionally substituted as outlined above and/or interrupted 1, 2, 3, 4 or more times by O, N and/or S; and R⁴ is H, or Ci to C₄ alkyl, optionally substituted; or R³ and R⁴ together form a heterocycloalkyl ring, optionally substituted, preferably as outlined above.

In a further preferred embodiment R¹ is C_3-I₀ cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, or adamantyl.

In a further preferred embodiment of the compound of the present invention is Ci-C₄ aralkyl, or C1-C₄ heteroaralkyl, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl,

1-propenyl, 2-propenyl, l-wo-propenyl, 2-/5O-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, /so-butoxy, ter/-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Cj-C₆ alkyl, e.g.

Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzo thiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; and

R³ and R⁴ together form a heterocycloalkyl ring, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl,

1-propenyl, 2-propenyl, l-zso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular

C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, zso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted.

In a preferred embodiment of the compound of the present invention is aryl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propy\, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1- /so-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Cj-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso- butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,

1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄,

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; and

R³ and R⁴ together form a heterocycloalkyl ring, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C,, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, /sø-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl,

1-propenyl, 2-propenyl, 1 -/so-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ alkyl; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted.

In a preferred embodiment of the compound of the present invention

R² is H or Cj to C₄ alkyl, e.g. Cj, C₂, C₃, or C₄ alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, /sσ-butyl, or tert-butyl. R² has this preferred meaning in particular in the context of the preferred meanings of R¹, R³, and/or R⁴ as outlined above.

In a preferred embodiment of the compound of the present invention the terms aralkyl and heteroaralkyl, in particular if used to indicate the meaning of R¹ and/or R³ or of a substituent thereof, have the following preferred meanings: aralkyl preferably is benzyl, (1-napthyl) methyl, (2-napthyl) methyl, phenyl ethyl, (1- napthyl) ethyl, (2-napthyl) ethyl, phenyl propyl, (1-napthyl) propyl, (2-napthyl) propyl optionally substituted at the alkyl and/or aryl moiety, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci- C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-pvopoxy, butoxy, wo-butoxy, ter/-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl,

1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; and the heteroaralkyl preferably is (2-furanyl) methyl, (3-furanyl) methyl, (2-furanyl) ethyl, (3-furanyl) ethyl, (2-oxazolyl) methyl, (4-oxazolyl) methyl, (5-oxazolyl) methyl, (2-oxazolyl) ethyl, (4-oxazolyl) ethyl, (5-oxazolyl) ethyl, (2-isoxazolyl) methyl, (3-isoxazolyl) methyl, (4- isoxazolyl) methyl, (2-isoxazolyl) ethyl, ethyl (3-isoxazolyl), ethyl (4-isoxazolyl), (3- (1,2,5-oxadiazolyl)) methyl, (4-(l,2,5-oxadiazolyl)) methyl, (3-(l,2,5-oxadiazolyl)) ethyl, (4-(l,2,5-oxadiazolyl)) ethyl, (4-(l,2,3-oxadiazolyl)) methyl, (5-(l,2,3-oxadiazolyl)) methyl, (4-(l ,2,3-oxadiazolyl)) ethyl, (5-(l,2,3-oxadiazolyl)) ethyl, (2-pyrrolyl) methyl, (3-pyrrolyl) methyl, (2-pyrrolyl) ethyl, (3-pyrrolyl) ethyl, (2-imidazolyl) methyl, (4- imidazolyl) methyl, (2-imidazolyl) ethyl, (4-imidazolyl) ethyl, (3-pyrazolyl) methyl, (4- pyrazolyl) methyl, (3-pyrazolyl) ethyl, (4-pyrazolyl) ethyl, (4-(l,2,3-triazolyl) methyl, (4- (1,2,3-triazolyl) ethyl, (3-(l,2,4-triazolyl) methyl, (3-(l,2,4-triazolyl) ethyl, (2- thiophenyl) methyl, (3-thiophenyl) methyl, (2-thiophenyl) ethyl, (3-thiophenyl) ethyl, (2- thiazolyl) methyl, (4-thiazolyl) methyl, (5-thiazolyl) methyl, (2-thiazolyl) ethyl, (4- thiazolyl) ethyl, (5-thiazolyl) ethyl, (3-isothiazolyl) methyl, (4-isothiazolyl) methyl, (5- isothiazolyl) methyl, (3-isothiazolyl) ethyl, (4-isothiazolyl) ethyl, (5-isothiazolyl) ethyl, (4-(l,2,3,-thiadiazolyl)) methyl, (5-(l,2,3,-thiadiazolyl)) methyl, (4-(l,2,3,-thiadiazolyl)) ethyl, (5-0,2,3,-thiadiazolyl)) ethyl, (3-(l,2,5-thiadiazolyl)), (3-(l,2,5-thiadiazolyl)) ethyl, (2-pyridinyl) methyl, (3-pyridinyl) methyl, (4-pyridinyl) methyl, (2-pyridinyl) ethyl, (3-pyridinyl) ethyl, (4-pyridinyl) ethyl, (2-pyrimidinyl) methyl, (4-pyrimidinyl) methyl, (5-pyrimidinyl) methyl, (2-pyrimidinyl) ethyl, (4-pyrimidinyl) ethyl, (5- pyrimidinyl) ethyl, (2-pyrazinyl) methyl, (3-pyrazinyl) methyl, (2-pyrazinyl) ethyl, (3- pyrazinyl) ethyl, (4-(l,2,3-triazinyl) methyl, (5-(l,2,3-triazinyl)) methyl, (4-(l,2,3- triazinyl)) ethyl, (5-(l,2,3-triazinyl)) ethyl, (3-(l,2,4-triazinyl)) methyl, (5-(l,2,4- triazinyl)) methyl, (6-(l,2,4-triazinyl)) methyl, (3-(l,2,4-triazinyl)) ethyl, (5-(l,2,4- triazinyl)) ethyl, (6-(l,2,4-triazinyl)) ethyl, (2-(l,3,5-triazinyl) methyl, (2-(l,3,5-triazinyl) ethyl, (2-(l-benzofuranyl)) methyl, (3-(l-benzofϊιranyl)) methyl, (4-(l-benzofuranyl)) methyl, (ό-(l-benzofiiranyl)) methyl, (7-(l-benzofiιranyl)) methyl, (2-(l-benzofuranyl)) ethyl, (3-(l-benzofuranyl)) ethyl, (4-(l-benzofuranyl)) ethyl, (ό-(l-benzofuranyl)) ethyl, (7-(l-benzofiiranyl)) methyl, (4-(l-benzofiiranyl)) ethyl, (l-(2-benzofuranyl)) methyl, (4- (2-benzofuranyl)) methyl, (5-(2-benzofuranyl)) methyl, (l-(2-benzofϊιranyl)) ethyl, (4-(2- benzofuranyl)) ethyl, (5-(2-benzofiiranyl)) ethyl, (2-indolyl) methyl, (3-indolyl) methyl, (4-indolyl) methyl, (5-indolyl) methyl, (6-indolyl) methyl, (7-indolyl) methyl, (2-indolyl) ethyl, (3-indolyl) ethyl, ethyl (4-indolyl), ethyl (5-indolyl), ethyl (6-indolyl), ethyl (7- indolyl), methyl (1-isoindolyl), (4-isoindolyl) methyl, (5-isoindolyl) methyl, (1- isoindolyl) ethyl, (4-isoindolyl) ethyl, (5-isoindolyl) ethyl, (2-(l-benzothiophenyl)) methyl, (3-(l-benzothiophenyl)) methyl, (4-(l-benzothiophenyl)) methyl, (6-(l- benzothiophenyl)) methyl, (7-(l-benzothiophenyl)) methyl, (2-(l-benzothiophenyl)) ethyl, (3-(l-benzothiophenyl)) ethyl, (4-(l-benzothiophenyl)) ethyl, (6-(l- benzothiophenyl)) ethyl, (7-(l-benzothiophenyl)) methyl, (l-(2-benzothiophenyl)) methyl, (4-(2-benzothiophenyl)) methyl, (5-(2-benzothiophenyl)) methyl, (l-(2- benzothiophenyl)) ethyl, (4-(2-benzothiophenyl)) ethyl, (5-(2-benzothiophenyl)) ethyl, (1-indazolyl) methyl, (4-(lH-indazolyl)) methyl, (5-(lH-indazolyl)) methyl, (6-(1H- indazolyl)) methyl, (7-(lH-indazolyl)) methyl, (1-indazolyl) ethyl, (4-(lH-indazolyl)) ethyl, (5-(lH-indazolyl)) ethyl, (6-(lH-indazolyl)) ethyl, (7-(lH-indazolyl)) ethyl, (2- benzimidazolyl) methyl, (4-benzimidazolyl) methyl, (5-benzimidazolyl) methyl, (2- benzimidazolyl) ethyl, (4-benzimidazolyl) ethyl, (5-benzimidazolyl) ethyl, (2- benzoxazolyl) methyl, (4-benzoxazolyl) methyl, (5-benzoxazolyl) methyl, (6- benzoxazolyl) methyl, (7-benzoxazolyl) methyl, (2-benzoxazolyl) ethyl, (4-benzoxazolyl) ethyl, (5-benzoxazolyl) ethyl, (6-benzoxazolyl) ethyl, (7-benzoxazolyl) ethyl, (3- indoxazinyl) methyl, (4-indoxazinyl) methyl, (5-indoxazinyl) methyl, (6-indoxazinyl) methyl, (7-indoxazinyl) methyl, (3 -indoxazinyl) ethyl, (4-indoxazinyl) ethyl, (5- indoxazinyl) ethyl, (6-indoxazinyl) ethyl, (7-indoxazinyl) ethyl, (3-(2,l-benzoxazolyl)) methyl, (4-(2,l-benzoxazolyl)) methyl, (5-(2,l-benzoxazolyl)) methyl, (6-(2,l- benzoxazolyl)) methyl, (7-(2,l-benzoxazolyl)) methyl, (3-(2,l-benzoxazolyl)) ethyl, (4- (2,1-benzoxazolyl)) ethyl, (5-(2,l-benzoxazolyl)) ethyl, (6-(2,l-benzoxazolyl)) ethyl, (7-

(2,1-benzoxazolyl)) ethyl, (2-benzothiazolyl) methyl, (4-benzothiazolyl) methyl, (5- benzothiazolyl) methyl, (6-benzothiazolyl) methyl, (7-benzothiazolyl) methyl, (2- benzothiazolyl) ethyl, (4-benzothiazolyl) ethyl, (5-benzothiazolyl) ethyl, (6- benzothiazolyl) ethyl, (7-benzothiazolyl) ethyl, (3-(l,2-benzisothiazolyl)) methyl, (4-(l,2- benzisothiazolyl)) methyl, (5-(l,2-benzisothiazolyl)) methyl, (6-(l,2-benzisothiazolyl)) methyl, (7-(l,2-benzisothiazolyl)) methyl, (3-(l,2-benzisothiazolyl)) ethyl, (4-(l,2- benzisothiazolyl)) ethyl, (5-(l,2-benzisothiazolyl)) ethyl, (6-(l,2-benzisothiazolyl)) ethyl, (7-(l,2-benzisoihiazoiyl)) ethyl, (3-(2,l -benzisothiazolyl)) methyl, (4-(2,l- benzisothiazolyl)) methyl, (5-(2,l -benzisothiazolyl)) methyl, (6-(2,l -benzisothiazolyl)) methyl, (7-(2,l -benzisothiazolyl)) methyl, (3 -(2,1 -benzisothiazolyl)) ethyl, (4-(2,l- benzisothiazolyl)) ethyl, (5-(2,l -benzisothiazolyl)) ethyl, (6-(2,l -benzisothiazolyl)) ethyl, (7-(2,l -benzisothiazolyl)) ethyl, (4-benzotriazolyl) methyl, (5-benzotriazolyl) methyl, (4- benzotriazolyl) ethyl, (5-benzotriazolyl) ethyl, (2-quinolinyl) methyl, (3-quinolinyl) methyl, (4-quinolinyl) methyl, (5-quinolinyl) methyl, (7-quinolinyl) methyl, (8- quinolinyl) methyl, (2-quinolinyl) ethyl, (3-quinolinyl) ethyl, (4-quinolinyl) ethyl, (5- quinolinyl) ethyl, (7-quinolinyl) ethyl, (8-quinolinyl) ethyl, (1-isoquinolinyl) methyl, (3- isoquinolinyl) methyl, (4-isoquinolinyl) methyl, (5-isoquinolinyl) methyl, (6- isoquinolinyl) methyl, (7-isoquinolinyl) methyl, (8-isoquinolinyl) methyl, (1- isoquinolinyl) ethyl, (3-isoquinolinyl) ethyl, (4-isoquinolinyl) ethyl, (5-isoquinolinyl) ethyl, (6-isoquinolinyl) ethyl, (7-isoquinolinyl) ethyl, (8-isoquinolinyl) ethyl, (l-(2,3- benzodiazinyl)) methyl, (4-(2,3-benzodiazinyl)) methyl, (5-(2,3-benzodiazinyl)) methyl, (6-(2,3-benzodiazinyl)) methyl, (7-(2,3-benzodiazinyl)) methyl, (8-(2,3-benzodiazinyl)) methyl, (l-(2,3-benzodiazinyl)) ethyl, (4-(2,3-benzodiazinyl)) ethyl, (5-(2,3- benzodiazinyl)) ethyl, (6-(2,3-benzodiazinyl)) ethyl, (7-(2,3-benzodiazinyl)) ethyl, (8-

(2,3-benzodiazinyl)) ethyl, (2-quinoxalinyl) methyl, (3-quinoxalinyl) methyl, (5- quinoxalinyl) methyl, (6-quinoxalinyl) methyl, (2-quinoxalinyl) ethyl, (3-quinoxalinyl) ethyl, (5-quinoxalinyl) ethyl, (6-quinoxalinyl) ethyl, (2-quinazolinyl) methyl, (4- quinazolinyl) methyl, (5-quinazolinyl) methyl, (6-quinazolinyl) methyl, (7-quinazolinyl) methyl, (8-quinazolinyl) methyl, (2-quinazolinyl) ethyl, (4-quinazolinyl) ethyl, (5- quinazolinyl) ethyl, (6-quinazolinyl) ethyl, (7-quinazolinyl) ethyl, (8-quinazolinyl) ethyl, (4-(l,2,3-benzotriazinyl)) methyl, (5-(l,2,3-benzotriazinyl)) methyl, (6-(l,2,3- benzotriazinyl)) methyl, (7-(l,2,3-benzotriazinyl)) methyl, (8-(l,2,3-benzotriazinyl)) methyl, (4-(l,2,3-benzotriazinyl)) ethyl, (5-(l,2,3-benzotriazinyl)) ethyl, (6-(l,2,3- benzotriazinyl)) ethyl, (7-(l,2,3-benzotriazinyl)) ethyl, (8-(l,2,3-benzotriazinyl)) ethyl,

(3-(l,2,4-benzotriazinyl)) methyl, (5-(l,2,4-benzotriazinyl)) methyl, (6-(l,2,4- benzotriazinyl)) methyl, (7-(l,2,4-benzotriazinyl)) methyl, (8-(l,2,4-benzotriazinyl)) methyl, (3-(l,2,4-benzotriazinyl)) ethyl, (5-(l,2,4-benzotriazinyl)) ethyl, (6-(l ,2,4- benzotriazinyl)) ethyl, (7-(l,2,4-benzotriazinyl)) ethyl, or (8-(l,2,4-benzotriazinyl)) ethyl, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci- C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyϊ, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, zsø-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COOR'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted.

In a preferred embodiment of the compound of formula (I) R¹ has one of the following structures:

wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, /sø-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /50-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted;

R^b and R^c are independent of each other hydrogen, alkyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/.so-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted; R^d and R^e are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂,

C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or

C₆ alkynyl; optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; s is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl; and

* marks the bond of R¹ to the compound of formula (I).

In a preferred aspect the heterocycloalkyl formed by R³ and R⁴ is selected from the group consisting of (1,2,5,6-tetrahydropyridyl), 1,4, diaza heptyl, 1,4 diaza octyl, 1,5 diaza octyl, piperidinyl, morpholinyl, morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1 ,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza- spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, 1 aza 7,11 dioxo-spiro[5,5] undecyl and piperazinyl optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-/sø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /sø-propoxy, butoxy, /sσ-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CpC₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1 ,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, bcnzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂,

C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,

1 ,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,

1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or

C₆ alkyl, optionally substituted;

In a further preferred embodiment the compound of the present invention has a structure according to formula (II)

(II) wherein R² has the meaning as outlined above, in particular the preferred meanings, and wherein R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C,, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ aikynyi, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably CpC₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci- C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, MO-propoxy, butoxy, zso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C₆ alkoxy-Cj-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl,

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R , R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wø-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -zsø-propenyl, 2-/5o-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably C]-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wø-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-

R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g.

Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofiiranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted. is H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoyl, alkynoyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Cj-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Cp C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, /sø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

1,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl,

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzo furanyl, indolyl, isoindolyl, benzothiophenyl, 2- benzo thiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted;

R^{1 1}, R¹², R¹³ and R¹⁴ are independent of each other are H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular C-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl,

2-propenyl, l-Zso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso- propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; optionally substituted; m is an integer of 0 to 4, i.e. 0, 1 , 2, 3, or 4, preferably 0, 1 , or 2; and x is 1 or 2, preferably 1.

In a preferred embodiment of the compound of formula (II) the left (C_0-4)alkylphenyl residue, i.e. R¹, has one of the following structures: wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-/so-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, wø-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Cj-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Cj-C₆ alkyl, e.g.

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzo thiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted;

R^b and R^c are independent of each other hydrogen, alkyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted;

R^d and R^e are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /rø-propyl, butyl, wø-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-/5O-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; m is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl; and

* marks the bond of R^! to the compound of formula (II). In this context it is particularly preferred that R¹⁰ has the preferred meanings indicated below.

In a further preferred embodiment of the compound according to formula (II) R¹⁰ has a structure according to formula (III)

(HI), wherein R⁵ , R⁶ , R⁷ , R⁸ and R⁹ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, zsø-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, i,2,3-triazolyi, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2. In this context it is particularly preferred that x is 1.

In a further preferred embodiment the compound has a structure according to formula (II), R¹⁰ has a structure according to formula (III), and at least R⁵ and/or R⁹ are substituted by halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, zso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -/so-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /sø-butoxy, rert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci- C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C$, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,

1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

In a further preferred embodiment of the compound according to formula (II) R¹⁰ has a structure according to formula

(R^a)_k wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C,,

C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, /so-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or

C₆ alkynyl; alkoxy, in particular Q-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazoiyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; optionally substituted; wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3, 5 -triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1 , or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the respective aryl or heteroaryl; A, B, D and E are each independently of each other selected from carbon, oxygen and nitrogen atoms, with the proviso that at least two of A, B, D and E are carbon atoms, more preferably A is an oxygen or nitrogen atom and B, D, and E are carbon atoms; and * marks the bond between R¹⁰ and the compound according to formual (II). In a further preferred embodiment the compound has a structure according to formula

(IV)

(IV) wherein R¹ and R² have the meaning as outlined above, in particular the preferred meanings outlined above and wherein

R", R¹², R¹³ and R¹⁴ are independent of each other are H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /jo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl,

2-propenyl, 1 -wo-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular CpC₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso- propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; and R¹⁵ is H; CN; -NR'R"; -SO₂-R"", alkyl, in particular C₁-C₆ alkyl, e.g. C,, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-WO-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular

C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CpC₆ alkoxy-C]-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, in particular aryl-Ci-C₆-alkyl, e.g. phenyl methyl, or phenyl ethyl; or heteroaralkyl, in particular hetero-Ci-C₆-alkyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular C₁-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted,

R"" is hydrogen, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, z^'sø-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -/so-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkynyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl,

1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazoiyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, heteroaralkyl, optionally substituted, and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; In a further preferred embodiment R¹ in the structure according to formula (I) or formula

(IV) has a structure according to formula (V)

(V) R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, zso-butyl, tør/-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso- propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl,

1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzo thiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2.

In a further preferred embodiment of the compound of the present invention R¹ is Ci-C₄ aralkyl, e.g. Ci, C₂, C₃, or C₄ aralkyl or Ci-C₄ heteroaralkyl, e.g. Ci, C₂, C₃, or

C₄ heteroaralkyl; and R³ is aryl, heteroaryl, C]-C₄ aralkyl, or Ci-C₄ heteroaralkyl, optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C,, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /5O-propyl, butyl, /jo-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/5o-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyi, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-

R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzo furanyl, 2-benzo furanyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzo triazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular CpC₆ alkyl, e.g.

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3, 5 -triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more substituents are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl. In a preferred embodiment of the compound of formula (V) the substituents R⁵, R⁶, R⁷, R⁸, and R⁹ of the left (C_0-4)alkylphenyl residue, i.e R¹, have a structure:

wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-buty\, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-/so-propenyl, 2-z.so-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /sø-propoxy, butoxy, zso-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; wherein

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. Cj, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted;

R^b and R^c are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted;

R^d and R^e are independent of each other hydrogen, alkyl, in particular Cj-C₆ alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -wo-propenyl, 2-/5o-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl; and

* marks the bond between the substituent according to formula (V) and the remaining compound according to formula (I) or (IV). In this context it is particularly preferred that R¹⁵ has the preferred meanings indicated below.

In a further preferred embodiment of the compound according to formula (IV) R¹⁵ has a structure according to formula

(R^a)_k

wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular C,-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyϊ, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-jso-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or

C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /.so-propoxy, butoxy, /_?o-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. rnethoxymethyl, ethoxymethyl, propoxymethyl, methoxy ethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-

R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3, 5 -triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzo triazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; R^b and R^c are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-zso-propenyl, 2-/sO-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular (C_3-i₀)-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular (C]- C₆)heteroalkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ heteroalkyl, cycloheteroalkyl, in particular (C_3-i₀)-cycloheteroalkyl; optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the respective aryl or heteroaryl;

For six-membered rings A, B, D, E and G are each independently of each other selected from carbon and nitrogen atoms, with the proviso that at least two, preferably three, four or five of A, B, D, E and G are carbon atoms, more preferably A is a nitrogen atom and B, D, E, and G are carbon atoms or D is nitrogen and A, B, E, and G are carbon atoms. For five-membered rings A, B, D, and E are each independently of each other selected from carbon, oxygen, sulphur and nitrogen atoms, with the proviso that at least two of A, B, D, and E are carbon atoms, more preferably A is an oxygen or sulphur atom and B, D, and E are carbon atoms or D is oxygen or nitrogen and A, B, and E are carbon atoms. If R¹⁵ has the preferred meanings indicated above, it is particularly preferred that R¹ has a structure according to formula (V), wherein the substituents R⁵, R⁶, R⁷, R⁸ and R⁹ have the indicated preferred meanings.

In a further preferred embodiment the compound of the present invention has a structure according to formula (VI)

(VI) wherein

R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. d, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso- propoxy, butoxy, wø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g.

C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and

R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, are independent of each other H, halogen, e.g. F, Cl, Br or I;

CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. C,, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-pvopyl, butyl, wø-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl,

1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R' and R" are independent of each other hydrogen; alkyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyi, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; o is 1 to 4, e.g. 1, 2, 3, or 4, preferably 1 or 2; and p is 0 to 4, e.g. 0, 1, 2, 3, or 4, preferably 0, 1, or 2.

In above preferred embodiment, wherein the compound has a structure according to formula (VI) it is particularly preferred that R² is H, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and

R⁴ is H, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

In a further preferred embodiment of the compound of the present invention R¹ is Ci to C₄ aralkyl or Ci or C₄ heteroaralkyl, optionally substituted; and

R³ is branched or linear Ci to Ci₀ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and Ci₀ alkyl, optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci- C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃,

C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1 -/.so-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Cj-C₆ alkoxy, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, zso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazoiyl, pyrazoiyi, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazoiyl, pyrazoiyi, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; optionally the alkyl moiety is interrupted 1, 2, 3, 4, or more times by N, S, and/or O moiety(ies).

It is preferred that in the context of foregoing embodiment that R² and R⁴ have the preferred and particularly preferred meanings as outlined above, preferably R² is H, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R⁴ is H, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

In a further preferred embodiment of the compound according to formula (VI) the right (Ci_-4)alkylphenyl residue, i.e. R³, has one of the following meanings: wherein

R^a is halogen, e.g. F, Cl, Br or I; CN; NO₂; -NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wø-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-/5o-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R""^*; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; or two adjacent R^a together form an aryl or heteroaryl residue, preferably resulting in a two or three membered aryl or heteroaryl; wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl.

In a particular preferred embodiment the compound of the present invention is selected from the group of compounds indicated in Table 1 below or a pharmaceutically acceptable salt of such a compound.

Table 1

(VII) (VIII) (IX)

(X) (XI) (XII)

(XVI) (XVII) (XVIII)

(XIX) (XX)

(XXII) (XXIII) (XXIV)

(XXV) (XXVI) (XXVII)

(XXVIII) (XXIX) (XXX)

(XXXIV) (XXXV) (XXXVI)

(XXXVII) (XXXVIII) (XXXIX)

(XL) (XLI) (XLII)

(XLIII) (XLIV) (XLV)

(XLVI) (XLVII) (XLVIII)

(XLIX) (L) (LI)

(LV) (LVI) (LVII)

(LVIII) (LIX) (LX)

(LXIV) (LXV) (LXVI)

In a further aspect the present invention relates to compounds according to formula (LXVII)

(LXVII) wherein R 21 is aralkyl, preferably Ci to C₄ aralkyl; or heteroaralkyl, preferably Ci to C₄ heteroaralkyl; wherein the alkyl and/or the aryl or heteroaryl moiety are optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular C_rC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-iso-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, iso-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; is aryl, in particular phenyl, naphthalenyl or anthracenyl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazυiyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; wherein the aryl or heteroaryl are optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-zso-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂,

C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /sO-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COOR'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,

1,2,3-benzotriazinyl, or 1, 2, 4-benzo triazinyl; optionally substituted, wherein

1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzo thiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. C], C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; and

X is O or S, preferably O.

In a preferred embodiment of the compound according to formula (LXVII) R²¹ has a structure according to formula (LXVIII)

(LXVIII)

R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR' R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-Λsø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably CpC₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci- C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzo thiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and is an integer of 1 to 4, i.e. 1, 2, 3, or 4, preferably 1 or 2.

In a preferred embodiment R²¹ has a structure according to wherein

R^a is H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular C_rC₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Cj-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /,ϊø-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO- R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzo furanyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular C]-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzo thiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular C₁-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted;

R^b and R^c are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-zso-propenyl, 2-/5O-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or

C₆ alkynyl; cycloalkyl, in particular (C_3-i₀)-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular (Ci-

C₆)heteroalkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ heteroalkyl, cycloheteroalkyl, in particular

(C_3-i₀)-cycloheteroalkyl; optionally substituted;

R^d and R^e are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wø-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted; Hal is F, Cl, Br or I, preferably F, Cl or Br; q is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, most preferably 1; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl residue.

In a further preferred embodiment of the compound according to formula (LXVII) R²¹ has a structure according to formula (LXIX)

(LXIX)

R²⁸, R²⁹, and R³⁰ are independent of each other H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular

C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1 -wo-propenyl, 2-/5o-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular C)-

C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy,

/5O-propoxy, butoxy, iso-butoxy, tert-bxitoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein

R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyi, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular C₁-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; or two or more of R²⁸, R²⁹, and R³⁰ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and r is an integer of 1 to 4, i.e. 1, 2, 3, or 4, preferably 1 or 2.

In a preferred embodiment of the compound according to formula (LXVII) R²² has a structure according to formula (LXX)

(LXX)

R³¹, R³², R³³, R³⁴ and R³⁵ are independent of each other H, H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-bυty\, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl,

1-propenyl, 2-propenyl, l-wo-propenyl, 2-/5O-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, /sø-propoxy, butoxy, wo-butoxy, tert-butoxy, cyclobutoxy, pentoxy, cyclopentoxy, cyclohexoxy or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-

R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzoflιranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄,

C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzo thiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

C₅, or C₆ alkyl, optionally substituted; or two or more of R³¹, R³², R³³, R³⁴ and R³⁵ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted. It is particularly preferred that R²² has this preferred meaning, if R²¹ either has a structure according to formula (LXVIII) or (LXIX). It this context is particular preferred that q and r, respectively, have the meaning 1. In a preferred embodiment of the compound of formula (LXVII) the substituent R²² according to formula (LXX) has a structure as follows: wherein

R^a H, H, halogen, e.g. F, Cl, Br or I; CN; NO₂; NR'R"; alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso- butyl, tert-bvΛy\, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; alkanoyl, preferably Ci-C₆ alkanoyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkanoyl; alkenoyl, in particular C₃-C₆ alkenoyl, e.g. C₃, C₄, C₅, or C₆ alkenoyl, preferably propenoyl; alkynoyl, in particular C₃-C₆ alkynoyl, e.g. C₃, C₄, C₅, or C₆ alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /so-butoxy, tert- butoxy, cyclobutoxy, pentoxy, cyclopentoxy, cyclohexoxy or hexoxy; alkoxyalkyl, in particular Ci-C₆ alkoxy-Ci-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R'"; -COO-R'""; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C₆ alkyl, e.g.

Ci, C₂, C₃, C₄, C₅, or C_O alkyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two adjacent R^a are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl; optionally substituted;

R^b and R^c are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wø-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular (C_3-] ₀)-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular (Cj-

C₆)heteroalkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ heteroalkyl, cycloheteroalkyl, in particular (C_3-io)-cycloheteroalkyl; optionally substituted;

R^d and R^e are independent of each other hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wσ-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-zso-propenyl, 2-Λrø-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; optionally substituted;

Hal is F, Cl, Br or I, preferably F, Cl or Br; n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e. up to the maximum number of substituents on the phenyl. In this context it is particularly preferred that R²¹ has a structure according to formula (LXVIII) or (LXIX) indicated above.

In a particular preferred embodiment the compound of the present invention has a structure according to formula (LXXI), (LXXII) or (LXXIII)

(LXXII)

(LXXIII) or is a pharmaceutically acceptable salt thereof.

A further aspect of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

In a further aspect the present invention concerns the use of compounds of the invention in the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from disruption of cellular replication. These agents have the potential to be used in the treatment of a large number of different diseases, in particular acute lymphoblastic leukemia (in particular childhood), acute myeloid leukemia/other myeloid malignancies, B-cell lymphoma, brain tumors (in particular childhood), ependymoma (in particular childhood),Ewing's Sarcoma, extracranial germ cell tumors (in particular childhood), extragonadal germ cell tumors, gastric cancer (WiIs J and Bleiber H (1989) Eur. J. Cancer Clin. Oncol. 25:3-8), gastrointestinal carcinoid tumors, gestational trophoblastic tumors, Hodgkin's lymphoma, Kaposi's sarcoma, medulloblastoma (childhood), liver cancer (in particular childhood), Merkel cell carcinoma, myelodysplastic/myeloproliferative diseases, neuroblastoma, non-Hodgkin's lymphoma (childhood), non-small cell lung cancer (Klastersky (1986) Semin. Oncol. 13: 104-14), osteosarcoma/malignant fibrous histiocytoma of bone, ovarian germ cell tumors, ovarian epithelial cancer, retinoblastoma, rhabdomyosarcoma (in particular childhood), small cell lung cancer (Comis RL (1986) Semin Oncol. 13:75-8), supratentorial primitive neuroectodermal tumors and pineoblastoma (childhood), testicular cancer (Einhorn LH (1988) Semin. Oncol. 3:9-15), thymoma and thymic carcinoma, unusual cancers of childhood, visual pathway and hypothalamic glioma, Wilms' tumor (Green DM (1987) Cancer 60:602-11), other childhood kidney tumors and bone marrow transplantation (Stadtmauer et al. (1989) 13(8):639- 50).

It is further preferred that the hyperproliferative diseases are selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, fϊbromas, histiocytosis, chronic inflammatory proliferative diseases, vascular proliferative diseases and virus-induced proliferative diseases, skin diseases characterized by hyperproliferation of keratinocytes and/or T cells.

In a further aspect the present invention concerns the use of compounds of the invention in the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced cellular replication. There are a large number of different diseases that may be treated by the compounds disclosed in this invention and include, in particular acute lymphoblastic leukemia (in particular childhood), acute myeloid leukemia/other myeloid malignancies, B-cell lymphoma, brain tumors (in particular childhood), ependymoma (in particular childhood), Ewing's Sarcoma, extracranial germ cell tumors (in particular childhood), extragonadal germ cell tumors, gastric cancer, gastrointestinal carcinoid tumors, gestational trophoblastic tumors, Hodgkin's lymphoma, Kaposi's sarcoma, medulloblastoma (childhood), liver cancer (in particular childhood), merkel cell carcinoma, myelodysplastic/myeloproliferative diseases, neuroblastoma, non-Hodgkin's lymphoma (childhood), non-small cell lung cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian germ cell tumors, ovarian epithelial cancer, retinoblastoma, rhabdomyosarcoma (in particular childhood), small cell lung cancer, supratentorial primitive neuroectodermal tumors and pineoblastoma (childhood), testicular cancer, thymoma and thymic carcinoma, unusual cancers of childhood, visual pathway and hypothalamic glioma, Wilms¹ tumor, other childhood kidney tumors and bone marrow transplantation.

The precancerosis treatable with the compounds of the present invention are preferably selected from the group consisting of precancerosis of the skin, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray keratosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gynaecological precancerosis, in particular carcinoma ductale in situ (CDIS), cervical intraepithelial neoplasia (CIN), leukoplakia, endometrial hyperplasia (grade III), vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), hydatidiform mole; urologic precancerosis, in particular bladder papillomatosis, Queyrat's erythroplasia, testicular intraepithelial neoplasia (TIN), leukoplakia; carcinoma in situ (CIS); precancerosis caused by chronic inflammation, in particular pyoderma, osteomyelitis, acne conglobata, lupus vulgaris, and fistula.

Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exist chronic irritation or inflammation. Dysplastic disorders which can be treated with the compounds of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphysalis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysical dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.

Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplastic disorders, which are treatable are preferably selected from the group consisting of agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, symptomatic myeloid metaplasia and regenerative metaplasia.

Many skin diseases are characterized by hyperproliferation of keratinocytes and/or T cells. Examples of such diseases which are treatable with the compounds of the present invention comprise without limitations psoriasis in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic skin reaction; and periorale dermatitis.

In a further preferred embodiment the hyperproliferative disorders are those which benefit from a reduced estrogen receptor signalling, i.e. disorders associated with an increased estrogen receptor signalling, if compared to healthy tissue. This particular suitability of the compounds of the present invention is based on the fact, that the compounds of the present invention potentially through inhibiting cellular replication but possibly also through an additional activity of the compounds of the present invention exert a strong inhibition of estrogen receptor signalling. Thus preferred diseases, conditions and/or disorders which can be treated are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus. Whether a disease is associated an increased estrogen receptor activity can be measured by a variety of art known methods including determination of ER expression level in the diseased tissue by, e.g. immunological methods, which determine the amount of expressed protein, by methods determining the amount of transcribed ER encoding nucleic acids, e.g. RT- PCR, Northern-blots, nuclear run-ons etc., and determining the activity of a nucleic acid construct comprising an ER-receptor recognition element, which drives expression of a detectable reporter, e.g. CAT, luciferase, GFP etc as described in more detail in the Experimental Section below. Preferably, the disorders which benefit from a reduced estrogen receptor signalling are those, which show in the diseased tisse an increase in estrogen receptor signalling by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, if compared to healthy tissue. Preferably this increase is measured on the basis of a nucleic acid comprising an ER- receptor recognition element and the increase of the expression of a reporter driven by this element.

The quantity of active component in a unit dose preparation administered in the use of the present invention may be varied or adjusted from about 1 mg to about 1000 mg per m², preferably about 5 mg to about 150 mg/m² according to the particular application and the potency of the active component. The pharmaceutical composition can, if desired, also contain other compatible therapeutic agents (e.g., cytotoxic or cytostatic compounds, including, but not limited to, pure or mixed anti-estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling such as herceptin; any compound that interchelates DNA, such as doxorubicin. Particularly preferred cytostatic or cytotoxic drugs, which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-01, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their respective derivatives or analogs thereof. Several of the above indicated drugs are now administered simultaneously for cancer therapy and, consequently, it is also envisioned that more than one cytostatic and/or cytotoxic drug is comprised in compositions of the present invention.

In therapeutic use as an antagonist of estrogen receptor signaling, acting through inhibition of cellular replication, the compounds utilized in the use of the invention are administered at the initial dosage of about 0.05 mg/kg to about 20 mg/kg daily. A daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 1 mg/kg being most preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. BRIEF DESCRIPTION OF THE FIGURES

Fig. 1: Depicts the elements of the plasmid ERE-TK-luc used to transfect MCF-7 cells to provide a cell based quantitative estimate of estrogen signalling. Fig.2: Depicts the complete DNA sequence of reporter plasmid ERE-TK-luc.

Fig. 3: Summarizes the results of various assays performed with the particular preferred compounds of the present invention depicted in Table 1 and indicated in formula

(LXXI), (LXXII) or (LXXIII). Depicted are from left to right for each compound the

IC₅₀ of MCF-7 cells transfected, with ERE-TK-luc, which uses an ER element to drive expression of luciferase; the cytotoxicity on MCF-7 cells.

Fig. 4: Depicts cell cycle phase distribution of cells of MCF-7 cells, the cell cycle analysis and 4'-6-Diamidino-2-phenylindole (DAPI) staining of MCF-7 cells treated with selected preferred compounds of the invention.

Fig. 5: Depicts the IC₅₀ of selected compounds on either an ER signalling luc or a beta actin promoter luc construct, the toxicity on various cell lines, i.e. MCF-7 (human breast cancer cells), HL-60 (human promyelocy e leukemia cell line), OVCAR-3 (human ovary adenocarcinoma cell) and HFF (human forskin fibroblast cell line) and the results of RT-PCR for ERa, cyclin Dl, cyclin Bl, cdc2 and control with or without the compound.

EXPERIMENTAL SECTION

Cellular assay for the identification of compounds A cell-based screen designed to detect compounds that activate or inhibit estrogen signalling was constructed by transfecting a reporter construct into MCF-7 cells, an ER positive cell line. The reporter construct consists of an estrogen response element that controls expression of a luciferase reporter gene.

In essence, the ERa positive breast adenocarcinoma cell line MCF-7, arrayed in 96 well format with 5000 cells per well, was transfected with 0.05 μg of ERE-TK-luc (map is shown in Fig. 1 ; the full DNA sequence of the plasmid is shown in Fig. 2; SEQ ID No. 1) using 0.2 μg of polyethylimine (mol.wt. ca 25,000) as a transfection reagent. Cells were co-incubated with substances under test at a final concentration of 3 μM for 24 hours. Responses to test substances were scored against control replicates containing either no compound (no inhibition) or containing faslodex at a final concentration of 5xlO^'8M (100% inhibition).

This assay was screened against a chemical library provide by a commercial supplier under a confidentiality agreement. This library was generated by standard combinatorial chemistry using well known procedures. A series of nitrofurans were identified in this initial screen. These hits were then confirmed by determination of the IC₅₀ of the effect these compounds had in inhibiting estrogen signalling. Then the common structure within the series identified in this initial screen was used to perform a sub-structure search on a larger library to obtain further candidate molecules. The respective responses of exemplary compounds identified in the screen on estrogen receptor signalling are indicated below in Fig. 3.

Determination of distribution in cell cycle

This was performed essentially as described in "Current protocols in cytometry" John Willey and Sons, inc. New York, section 7.5.1 - 7.5.24. Sub-confluent, exponentially growing MCF-7 cells were treated for 24 hours. The cell cycle distribution of a total of 10,000 cells was then determined by flow cytometry following fixation and permeabilization of cells in alcohol and treatment with propidium iodide. Cells were gated to exclude cell debris and aggregates consisting of 2 or more cells (see Fig. 3 and Fig. 4).

Cytotoxicity assay

The cytotoxicity of compounds was estimated by co-incubating 2000 cells in 96 well plate format for three days with varying concentrations of the respective compound. Relative cell number was then estimated by determining the level of cellular ATP using ATPlite 1 step reagent supplied by Perkin Elmer, Germany.

Western blotting

An estimation of the expression level of ERa, cyclin Dl, cyclin Bl and cdc2 was obtained by western blot analysis of cells treated for 16 hours with the compound under evaluation at a concentration of 10 μM. All results are compared to untreated control samples. Western blotting was performed using 2x10⁵ cells per well as described in "Antibodies, A laboratory manual." Harlow and Lane, 1988, Cold Spring Harbor, chapter 12, p471-p504. Proteins resolved by SDS-PAGE were transferred onto PVDF membranes, blocked with low fat milk powder and then stained with the following primary antibodies: anti-ERα: sc-543; Santa Cruz Biotechnology; cycling Dl : sc-8396; Santa Cruz Biotechnology; cyclin Bl : sc-753; Santa Cruz Biotechnology; cdc2: sc-954; Santa Cruz Biotechnology. Primary antibodies were detected with horse radish peroxidase conjugated anti-rabbit IgG and visualized on photographic film using the Amersham ECL detection system (Amersham biosciences, Buckinghamshire, UK).

Visualization of DNA in cells

Cells were grown on glass coverslips, treated with compound under test at 10 μM for 16 hours, washed twice with phosphate buffered saline (PBS) and then fixed with methanol at -

20°C. Cells were then rehydrated in PBS, stained for 10 minutes with 10 mM diamino propidium iodide (DAPI; Sigma, Germany) then washed twice with PBS. Cells were visualised and recorded using an Olympus Fluoview 1000 laser scanning confocal microscope.

Claims

1. Compound of formula (I)

(I) wherein X is O or S;

R¹ is aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted; R² is H, alkyl, cycloalkyl, or aryl, optionally substituted; R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, or linear or branched alkyl, optionally substituted and/or interrupted one or more times by O, N and/or S; and

2. Compound according to claim 1, wherein

R¹ is aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted; R² is H, or Ci to C₄ alkyl, optionally substituted;

R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, linear or branched Ci to C₂₀ alkyl, optionally substituted and/or interrupted one or more times by O, N or S; and

R⁴ is H, or Ci to C₄ alkyl, optionally substituted; or R³ and R⁴ together form or heterocycloalkyl ring, optionally substituted.

3. Compound according to claims 1 or 2, wherein

R¹ is Ci-C₄ aralkyl, or Ci-C₄ heteroaralkyl, optionally substituted; and R³ and R⁴ together form a heterocycloalkyl ring, optionally substituted.

4. Compound according to any of claims 1 to 2, wherein R¹ is aryl or substituted aryl; and R³ and R⁴ together form a heterocycloalkyl ring, optionally substituted.

5. Compound according to any of claims 1 to 4, wherein R² is H or Ci to C₄ alkyl.

6. Compound according to any of claims 1 to 3 and 5, wherein the

(i) aralkyl is selected from the group consisting of benzyl, (1-napthyl) methyl, (2- napthyl) methyl, phenyl ethyl, (1-napthyl) ethyl, (2-napthyl) ethyl, phenyl propyl, (1-napthyl) propyl, (2-napthyl) propyl, optionally substituted at the alkyl and/or aryl moiety, preferably with one or more halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R"'; -COO-

R'"", aryl, heteroaryl or two or more substituents are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, wherein R' and R' ' are independent of each other hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C₆ alkyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; and the (ii) heteroaralkyl is selected from the group consisting of (2-furanyl) methyl, (3- furanyl) methyl, (2-furanyl) ethyl, (3-furanyl) ethyl, (2-oxazolyl) methyl, (4- oxazolyl) methyl, (5-oxazolyl) methyl, (2-oxazolyl) ethyl, (4-oxazolyl) ethyl, (5-oxazolyl) ethyl, (2-isoxazolyl) methyl, (3-isoxazolyl) methyl, (4- isoxazolyl) methyl, (2-isoxazolyl) ethyl, ethyl (3-isoxazolyl), ethyl (4- isoxazolyl), (3-(l,2,5-oxadiazolyl)) methyl, (4-(l,2,5-oxadiazolyl)) methyl,

(3-(l,2,5-oxadiazolyl)) ethyl, (4-(l,2,5-oxadiazolyl)) ethyl, (4-(l,2,3- oxadiazolyl)) methyl, (5-(l,2,3-oxadiazolyl)) methyl, (4-(l,2,3-oxadiazolyl)) ethyl, (5-(l,2,3-oxadiazolyl)) ethyl, (2-pyrrolyl) methyl, (3-pyrrolyl) methyl, (2-pyrrolyl) ethyl, (3-pyrrolyl) ethyl, (2-imidazolyl) methyl, (4-imidazolyl) methyl, (2-imidazolyl) ethyl, (4-imidazolyl) ethyl, (3-pyrazolyl) methyl, (4- pyrazolyl) methyl, (3-pyrazolyl) ethyl, (4-pyrazolyl) ethyl, (4-(l,2,3-triazolyl) methyl, (4-(l,2,3-triazolyl) ethyl, (3-(l,2,4-triazolyl) methyl, (3-(l,2,4- triazolyl) ethyl, (2-thiophenyl) methyl, (3-thiophenyl) methyl, (2-thiophenyl) ethyl, (3-thiophenyl) ethyl, (2-thiazolyl) methyl, (4-thiazolyl) methyl, (5- thiazolyl) methyl, (2-thiazolyl) ethyl, (4-thiazolyl) ethyl, (5-thiazolyl) ethyl, (3-isothiazolyl) methyl, (4-isothiazolyl) methyl, (5-isothiazolyl) methyl, (3- isothiazolyl) ethyl, (4-isothiazolyl) ethyl, (5-isothiazolyl) ethyl, (4-(l,2,3,- thiadiazolyl)) methyl, (5-(l,2,3,-thiadiazolyl)) methyl, (4-(l,2,3,-thiadiazolyl)) ethyl, (5-(l,2,3,-thiadiazolyl)) ethyl, (3-(l,2,5-thiadiazolyl)), (3-(l,2,5- thiadiazolyl)) ethyl, (2-pyridinyl) methyl, (3-pyridinyl) methyl, (4-pyridinyl) methyl, (2-pyridinyl) ethyl, (3-pyridinyl) ethyl, (4-pyridinyl) ethyl, (2- pyrimidinyl) methyl, (4-pyrimidinyl) methyl, (5-pyrimidinyl) methyl, (2- pyrimidinyl) ethyl, (4-pyrimidinyl) ethyl, (5-pyrimidinyl) ethyl, (2-pyrazinyl) methyl, (3-pyrazinyl) methyl, (2-pyrazinyl) ethyl, (3-pyrazinyl) ethyl, (4-

(1,2,3-triazinyl) methyl, (5-(l,2,3-triazinyl)) methyl, (4-(l,2,3-triazinyl)) ethyl, (5-(l,2,3-triazinyl)) ethyl, (3-(l,2,4-triazinyl)) methyl, (5-(l,2,4- triazinyl)) methyl, (6-(l,2,4-triazinyl)) methyl, (3-(l,2,4-triazinyl)) ethyl, (5- (1,2,4-triazinyl)) ethyl, (6-(l,2,4-triazinyl)) ethyl, (2-(l,3,5-triazinyl) methyl, (2-(l,3,5-triazinyl) ethyl, (2-(l-benzofuranyl)) methyl, (3-(l-benzofuranyl)) methyl, (4-(l-benzofurany I)) methyl, (6-(l-benzofuranyl)) methyl, (7-(l- benzofuranyl)) methyl, (2-(l-benzofuranyl)) ethyl, (3-(l-benzofuranyl)) ethyl, (4-(l-benzofuranyl)) ethyl, (ό-(l-benzofuranyl)) ethyl, (7-(l-benzofuranyl)) methyl, (4-(l-benzofuranyl)) ethyl, (l-(2-benzofuranyl)) methyl, (4-(2- benzofuranyl)) methyl, (5-(2-benzofuranyl)) methyl, (l-(2-benzofuranyl)) ethyl, (4-(2-benzofiiranyl)) ethyl, (5-(2-benzofuranyl)) ethyl, (2-indolyl) methyl, (3-indolyl) methyl, (4-indolyl) methyl, (5-indolyl) methyl, (6-indolyl) methyl, (7-indolyl) methyl, (2-indolyl) ethyl, (3-indolyl) ethyl, ethyl (4- indolyl), ethyl (5-indolyl), ethyl (6-indolyl), ethyl (7-indolyl), methyl (1- isoindolyl), (4-isoindolyl) methyl, (5-isoindolyl) methyl, (1-isoindolyl) ethyl,

(4-isoindolyl) ethyl, (5-isoindolyl) ethyl, (2-(l-benzothiophenyl)) methyl, (3- (1-benzothiophenyl)) methyl, (4-(l-benzothiophenyl)) methyl, (6-(l- benzothiophenyl)) methyl, (7-(l-benzothiophenyl)) methyl, (2-0- benzothiophenyl)) ethyl, (3-(l -benzothiophenyl)) ethyl, (4-0- b beennzzootthhiioopphheennyyll)))) eetthhyyll,, (6-(l -benzothiophenyl)) ethyl, (7-0- benzothiophenyl)) methyl, (1 -(2 -benzothiophenyl)) methyl, (4-(2- benzothiophenyl)) methyl, (5-(2 -benzothiophenyl)) methyl, (l-(2- benzothiophenyl)) ethyl, (4-(2-benzothiophenyl)) ethyl, (5-(2- benzothiophenyl)) ethyl, (1-indazolyl) methyl, (4-(lH-indazolyl)) methyl, (5- (lH-indazolyl)) methyl, (ό-(lH-indazolyl)) methyl, (7-(lH-indazolyl)) methyl, (1-indazolyl) ethyl, (4-(lH-indazolyl)) ethyl, (5-(lH-indazolyl)) ethyl, (ό-(lH-indazolyl)) ethyl, (7-(lH-indazolyl)) ethyl, (2-benzimidazolyl) methyl, (4-benzimidazolyl) methyl, (5-benzimidazolyl) methyl, (2-benzimidazolyl) ethyl, (4-benzimidazolyl) ethyl, (5-benzimidazolyl) ethyl, (2-benzoxazolyl) methyl, (4-benzoxazolyl) methyl, (5-benzoxazolyl) methyl, (6-benzoxazolyl) methyl, (7-benzoxazolyl) methyl, (2-benzoxazolyl) ethyl, (4-benzoxazolyl) ethyl, (5-benzoxazolyl) ethyl, (6-benzoxazolyl) ethyl, (7-benzoxazolyl) ethyl, (3-indoxazinyl) methyl, (4-indoxazinyl) methyl, (5-indoxazinyl) methyl, (6- indoxazinyl) methyl, (7-indoxazinyl) methyl, (3-indoxazinyl) ethyl, (4- indoxazinyl) ethyl, (5-indoxazinyl) ethyl, (6-indoxazinyl) ethyl, (7- indoxazinyl) ethyl, (3-(2,l-benzoxazolyl)) methyl, (4-(2,l-benzoxazolyl)) methyl, (5-(2,l-benzoxazolyl)) methyl, (6-(2,l-benzoxazolyl)) methyl, (7- (2,1-benzoxazolyl)) methyl, (3-(2,l-benzoxazolyl)) ethyl, (4-(2,l- benzoxazolyl)) ethyl, (5-(2,l-benzoxazolyl)) ethyl, (6-(2,l-benzoxazolyl)) ethyl, (7-(2,l -benzoxazolyl)) ethyl, (2-benzothiazolyl) methyl, (4- benzothiazolyl) methyl, (5-benzothiazolyl) methyl, (6-benzothiazolyl) methyl, (7-benzothiazolyl) methyl, (2-benzothiazolyl) ethyl, (4-benzothiazolyl) ethyl, (5-benzothiazolyl) ethyl, (6-benzothiazolyl) ethyl, (7-benzothiazolyl) ethyl, (3-(l,2-benzisothiazolyl)) methyl, (4-(l,2-benzisothiazolyl)) methyl, (5-(l,2- benzisothiazolyl)) methyl, (6-(l,2-benzisothiazolyl)) methyl, (7-(l,2- benzisothiazolyl)) methyl, (3 -(1 ,2-benzisothiazolyl)) ethyl, (4-(l ,2- benzisothiazolyl)) ethyl, (5-( 1 ,2-benzisothiazolyl)) ethyl, (6-(l,2- benzisothiazolyl)) ethyl, (7-( 1 ,2-benzisothiazolyl)) ethyl, (3-(2,l- bbeennzziissootthhiiaazzoollyyll)))) mmeetthhyyll,, (4-(2,l-benzisothiazolyl)) methyl, (5-(2,l- benzisothiazolyl)) methyl, (6-(2, 1 -benzisothiazolyl)) methyl, (7-(2,l- benzisothiazolyl)) methyl, (3 -(2, 1 -benzisothiazolyl)) ethyl, (4-(2,l- benzisothiazolyl)) ethyl, (5-(2,l -benzisothiazolyl)) ethyl, (6-(2,l- benzisothiazolyl)) ethyl, (7-(2, 1 -benzisothiazolyl)) ethyl, (4-benzotriazolyl) methyl, (5-benzotriazolyl) methyl, (4-benzotriazolyl) ethyl, (5-benzotriazolyl) ethyl, (2-quinolinyl) methyl, (3-quinolinyl) methyl, (4-quinolinyl) methyl, (5- quinolinyl) methyl, (7-quinolinyl) methyl, (8-quinolinyl) methyl, (2- quinolinyl) ethyl, (3-quinolinyl) ethyl, (4-quinolinyl) ethyl, (5-quinolinyl) ethyl, (7-quinolinyl) ethyl, (8-quinolinyl) ethyl, (1-isoquinolinyl) methyl, (3- isoquinolinyl) methyl, (4-isoquinolinyl) methyl, (5-isoquinolinyl) methyl, (6- isoquinolinyl) methyl, (7-isoquinolinyl) methyl, (8-isoquinolinyl) methyl, (1- isoquinolinyl) ethyl, (3 -isoquinolinyl) ethyl, (4-isoquinolinyl) ethyl, (5- isoquinolinyl) ethyl, (6-isoquinolinyl) ethyl, (7-isoquinolinyl) ethyl, (8- isoquinolinyl) ethyl, (l-(2,3-benzodiazinyl)) methyl, (4-(2,3-benzodiazinyl)) methyl, (5-(2,3-benzodiazinyl)) methyl, (6-(2,3-benzodiazinyl)) methyl, (7- (2,3-benzodiazinyl)) methyl, (8-(2,3-benzodiazinyl)) methyl, (l-(2,3- benzodiazinyl)) ethyl, (4-(2,3-benzodiazinyl)) ethyl, (5-(2,3-benzodiazinyl)) ethyl, (6-(2,3-benzodiazinyl)) ethyl, (7-(2,3-benzodiazinyl)) ethyl, (8-(2,3- benzodiazinyl)) ethyl, (2-quinoxalinyl) methyl, (3-quinoxalinyl) methyl, (5- quinoxalinyl) methyl, (6-quinoxalinyl) methyl, (2-quinoxalinyl) ethyl, (3- quinoxalinyl) ethyl, (5-quinoxalinyl) ethyl, (6-quinoxalinyl) ethyl, (2- quinazolinyl) methyl, (4-quinazolinyl) methyl, (5-quinazolinyl) methyl, (6- quinazolinyl) methyl, (7-quinazolinyl) methyl, (8-quinazolinyl) methyl, (2- quinazolinyl) ethyl, (4-quinazolinyl) ethyl, (5-quinazolinyl) ethyl, (6- quinazolinyl) ethyl, (7-quinazolinyl) ethyl, (8-quinazolinyl) ethyl, (4-(l,2,3- benzotriazinyl)) methyl, (5-(l,2,3-benzotriazinyl)) methyl, (6-(l,2,3- benzotriazinyl)) methyl, (7-(l ,2,3-benzotriazinyl)) methyl, (8-(l,2,3- benzotriazinyl)) methyl, (4-(l ,2,3-benzotriazinyl)) ethyl, (5-(l,2,3- benzotriazinyl)) ethyl, (6-(l ,2,3-benzotriazinyl)) ethyl, (7-0,2,3- benzotriazinyl)) ethyl, (8-(l ,2,3-benzotriazinyl)) ethyl, (3-0,2,4- benzotriazinyl)) methyl, (5-(l ,2,4-benzotriazinyl)) methyl, (6-0,2,4- benzotriazinyl)) methyl, (7-(l ,2,4-benzotriazinyl)) methyl, (8-0,2,4- benzotriazinyl)) methyl, (3 -(1 ,2,4-benzotriazinyl)) ethyl, (5-0,2,4- benzotriazinyl)) ethyl, (6-( 1 ,2,4-benzotriazinyl)) ethyl, (7-0,2,4- benzotriazinyl)) ethyl, or (8-(l,2,4-benzotriazinyl)) ethyl, optionally substituted at the alkyl and/or aryl moiety, preferably with one or more halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO-R'"", aryl, heteroaryl or two or more substituents are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

7. Compound according to any of claims 1 to 5, wherein the heterocycloalkyl formed by R³ and R⁴ is selected from the group consisting of (1,2,5,6-tetrahydropyridyl), 1,4, diaza heptyl, 1,4 diaza octyl, 1,5 diaza octyl, piperidinyl, morpholinyl, morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro- [4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza- spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza- spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza- spiro[5,4] decyl, l,4-diazabicyclo[2.2.2]oct-2-yl, 1 aza 7,11 dioxo-spiro[5,5] undecyl and piperazinyl, optionally substituted, preferably with one or more halogen, CN, NO₂, NR' R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-

R'"; -COO-R'"", aryl, heteroaryl or two or more substituents are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or

C₆ alkyl, optionally substituted; and

8. Compound according to any of claims 1 to 7 , wherein the compound has a structure according to formula (IF )

(H) wherein

R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'", -COO-R'"", aryl, heteroaryl, optionally substituted, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; R¹⁰ is H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoyl, alkynoyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted; R¹¹, R¹², R¹³ and R¹⁴ are independent of each other are H, halogen, alkyl, alkenyl, alkynyl, or alkoxy, optionally substituted; m is an integer of 0 to 4; and x is 1 or 2.

Compound according to any of claims 1 to 7, wherein the compound has a structure according to formula (IV)

(IV) R^{1 1}, R¹², R¹³ and R¹⁴ are independent of each other are H, halogen, alkyl, alkenyl, alkynyl, or alkoxy and

R¹⁵ is H, -NR'R", -OOC-R'", -SO₂-R"", -COO-R'"", alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoyl, alkynoyl, aryl, heteroaryl, aralkyl, or heteroaralkyl wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, optionally substituted; R"" is alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, optionally substituted, and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

10. Compound according to claim 9, wherein R¹ has a structure according to formula (V)

(V) R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R"', -COO-R'"", aryl, heteroaryl, optionally substituted, wherein R' and R' ' are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and n is an integer of 0 to 4.

11. Compound according to claims 1 or 2, wherein

R¹ is Ci-C₄ aralkyl, or Ci-C₄ heteroaralkyl; and R³ is aryl, heteroaryl, Ci-C₄ aralkyl, or Ci-C₄ heteroaralkyl, optionally substituted, wherein the substituents are preferably selected from one or more halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO-R'"", aryl, heteroaryl or two or more substituents are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted.

12. Compound according to claim 11, wherein the compound has a structure according to formula (VI)

(VI) wherein R⁵, R⁶, R⁷, R⁸ and R⁹ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO-R'"", aryl, heteroaryl, optionally substituted, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R⁵, R⁶, R⁷, R⁸ and R⁹ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independent of each other H, halogen, CN, NO₂,

NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO-

R'"", aryl, heteroaryl, optionally substituted, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; o is 1 to 4; and p is 0 to 4.

13. Compound according to claim 12, wherein R² is H, alkyl, optionally substituted; and

R⁴ is H, alkyl, optionally substituted.

14. Compound according to any of claims 1, 2, 5 and 6, wherein

R¹ is Ci to C₄ aralkyl or Ci or C₄ heteroaralkyl, optionally substituted; and R³ is branched or linear Ci to Ci₀ alkyl, optionally substituted.

15. Compound according to claim 14, wherein R² is H, alkyl, optionally substituted; and R⁴ is H, alkyl, optionally substituted.

16. Compound according to claim 1, wherein the compound is selected from the group indicated in Table 1 or pharmaceutical 1 acceptable salts thereof.

17. Compound according to formula (LXVII)

(LXVII) wherein

R²¹ is aralkyl or heteroaralkyl, optionally substituted R²² is aryl or heteroaryl, optionally substituted; and

X is O or S and pharmaceutically acceptable salts thereof.

18. Compound according to claim 17, wherein R²¹ has a structure according to formula (LXVIII)

(LXVIII)

R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO- R'"", aryl, heteroaryl, optionally substituted, wherein R' and R' ' are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted;

R'" is alkyl, alkenyl, alkynyl, optionally substituted; and

R'"" is hydrogen, alkyl, alkenyl, alkynyl, in particular CpC₆ alkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆ alkyl, optionally substituted; or two or more of R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and q is an integer of 1 to 4.

19. Compound according to claim 17, wherein R²¹ has a structure according to formula (LXIX)

(LXIX)

R²⁸, R²⁹, and R³⁰ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO-R'"", aryl, heteroaryl, optionally substituted, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, optionally substituted; or two or more of R²⁸, R² , and R are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted; and r is an integer of 1 to 4.

20. Compound according to any of claims 17 to 19, wherein R²² has a structure according to formula (LXX)

wherein

R³¹, R³², R³³, R³⁴ and R³⁵ are independent of each other H, halogen, CN, NO₂, NR'R", alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, -OOC-R'"; -COO- R'"", aryl, heteroaryl, optionally substituted, wherein R' and R" are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, aryl or heteroaryl; optionally substituted; R'" is alkyl, alkenyl, alkynyl, optionally substituted; and R'"" is hydrogen, alkyl, alkenyl, alkynyl, optionally substituted; or two or more of R³¹, R³², R³³, R³⁴ and R³⁵ are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally substituted.

21. Compound according to claim 17, wherein the compound has a structure according to formula (LXXI), (LXXII) or (LXXIII)

(LXXII)

22. Pharmaceutical composition comprising an effective amount of at least one compound of claims 1 to 21 and a pharmaceutically acceptable carrier or excipient.

23. Use of a compound of any of claims 1 to 21 for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from reduced cellular replication.

24. Use of a compound of claim 23, wherein the diseases, conditions and/or disorders are hyperproliferative diseases.

25. Use of a compound of claim 24, wherein the hyperproliferative diseases are selected from the group consisting of hyperproliferative disease is selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, fibromas, histiocytosis, chronic inflammatory proliferative diseases, vascular proliferative diseases and virus-induced proliferative diseases, skin diseases characterized by hyperproliferation of keratinocytes and/or T cells.

26. Use of a compound of claim 25, wherein the hyperproliferative diseases are characterized by the hyperproliferation of T-cells and/or keratinocytes.

27. Use of of a compound of claim 26, wherein the diseases are selected from the group consisting of psoriasis in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic skin reaction; and periorale dermatitis.

28. Use of a compound of claim 27, wherein the hyperproliferative disorders are those which benefit from a reduced estrogen receptor signalling.

29. Use of a compound of claim 28, wherein the diseases, conditions and/or disorders are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus.