ANTAGONISTS OF TOPOISQMERASE ACTIVITY AND THEIR USE IN INHIBITING

PATHOLOGICAL CONDITIONS

The present invention provides novel compounds that inhibit cell proliferation, in particular by inhibiting topoisomerase activity and uses of these compounds for treating, ameliorating or preventing diseases conditions or disorders benefiting from the inhibition of topoisomerase activity, 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; Juul (2001) Hum Reprod Update 7: 303-313) and in the maintenance of the cardiovascular (Rosano and Fini, (2001) lnt 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 recognise 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) Cell 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 US A 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 al, (1973 J Natl Cancer Inst 50: 21-42), late menopause (Trichopoulos

et al, (1972) J Natl Cancer Inst 48: 605-613), nulliparity and late age at first pregnancy (MacMahon et al, (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 al., (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 al, (1993) Cancer 71: 3896-3907; (London et al, (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: 1 12-1 19) 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 topoisomerase II activity and, to a lesser extent, of topoisomerase I activity. Many tumour cell types overexpress topoisomerase enzymes to resource enhanced cellular proliferation. Consequently, inhibitors of topoisomerase I, Ilα and Ilβ are among the most frequently used drugs in cancer chemotherapy and include drugs such as doxorubicin, camptothecan and etoposide. Despite such extensive use, inhibitors of topoisomerase in clinical practice have limitations, exemplified by cardiotoxicity, resistance and poor availability (reviewed by Denny, (2004) Expert Opin. Emerg. Drugs 9 105- 133). The compounds of the present invention represent a novel class of topoisomerase 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 inhibiting topoisomerase activity, which are suitable in particular in antagonizing estrogen receptor signaling. Data presented herein establishes that compounds of formula (I) and formulas (XXIX) to (XXXII) can inhibit estrogen signalling in a cell based assay format and that these compounds induce a profound arrest in the G ₀ /Gi phase of the cell cycle. Moreover, compounds of formula (I) are shown to inhibit topoisomerase II activity but that they do not result in the characteristic double stranded

DNA break that established topoisomerase II inhibitors elicit, such as etoposide. Moreover, we present data that demonstrates that the claimed compounds act in a mechanistic way that is distinct to the podophyllotoxin class of topoisomerase II inhibitors, such as etoposide. The claimed compounds, in contrast to etoposide, do not induce double stranded

DNA breaks in cells in vivo and induce cells to arrest in the G _o /G] stage of the cell cycle, whereas etoposide induces an M/G ₂ arrest. By implication, treatment with the claimed compounds is unlikely to result in treatment related leukaemia that arises from topoisomerase II inhibition using epiphodophyllotoxins (Rowley and Olney (2002) Genes Chromosomes Cancer

33 331-345).

The present invention in particular provides compounds of the formula (I):

(I), wherein

R ¹ is hydrogen or alkyl;

R ² is a five-membered or six-membered aryl or fused fϊve-membered or six-membered aryl; or R ¹ and R ² are taken together to form a five-membered or six-membered N-heterocycle

R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl;

R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN,

NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with

one or more heteroatoms selected independent of each other from the group consisting of O, S and N;

R ⁷ is NO ₂ , CN ₅ F, or Cl; or a pharmaceutically acceptable salt or solvate of such a salt, with the proviso that 2-propenamide, N-lH-indazol-5-yl-3-(5-nitro-2-furanyl-(2E)

(CAPlus Registry No. 353539-89-6), 2-furanacrylamide, N-(9-amino-7-ethoxy-3-acridinyl)-5- nitro-(7CI) (CAPlus Registry No. 95025-08-4), 2-furanacrylamide, N-(6-methoxy-8-quinolyl)-5- nitro-(7CI) (CAPlus Registry No. 93326-30-8) and 2-propenamide, N-l,3-benzodioxol-5-yl-3- (5-nitro-2-furanyl)-(9CI) (CAPlus Registry No. 37542-74-8) are excluded. In a preferred embodiment of the compounds of the present invention the fused five- membered or fused six-membered aryl is fused with a cycloalkyl, a heterocycloalkyl, or an alicyclic system or with an aryl or heteroaryl.

In a preferred embodiment of the compounds of present invention the fϊve-membered aryl is fused with a six-membered aryl or heteroaryl. In a preferred embodiment of the compounds of present invention the six-membered aryl is fused with a fϊve-membered or six-membered aryl or heteroaryl.

In a preferred embodiment of the compounds of present invention said a) fused five-membered aryl is fused to cyclopentadienyl; b) fused five-membered aryl is fused to benzyl, naphtyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl; c) fused six membered aryl is fused to furanyl, 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, or thiophenyl; c) fused six membered aryl is fused to pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl; 1,2,4-triazinyl.

In a preferred embodiment of the compounds of present invention the five or six- membered aryl and the fused five or six-membered aryl or heteroaryl form a radical selected from the group consisting of 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2, 1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl.

In a preferred embodiment of the compounds of present invention one or more of the hydrogens of the five-membered or six-membered aryl or fused five-membered or six-membered

aryl are substituted independent of each other by one or more radicals R ⁸ selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl, and X(CH ₂ ) _n R ⁹ , wherein R ⁹ is R ¹⁰ , Y-R ¹⁰ , Y-CO-R ¹⁰ , or Y-COO-R ¹⁰ ;

R ¹⁰ is alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl; and n is O to 5 or 1 to 5, if R ⁹ is Y-R ¹⁰ , Y-CO-R ¹⁰ , or Y-COO-R ¹⁰ ; X and Y are independently of each other selected from O, N and S.

In a preferred embodiment of the compounds of present invention the five-membered N- heterocycle is 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, or pyrolidinyl. In a preferred embodiment of the compounds of present invention the six-membered N- heterocycle is piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane.

In a preferred embodiment of the compounds of present invention one or more of the hydrogens of the five-membered or six-membered N-heterocycle are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen

(F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl.

In a preferred embodiment of the compounds of present invention radical R ¹ ' is selected from the group consisting of 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, 2-alklypyridinyl, 3-alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl.

In a preferred embodiment of the compounds of present invention one or more hydrogens of the one or more radicals R ¹ ' are substituted independent of each other by one or more radicals

R ¹² selected from the group of radicals consisting of halogen (F, Cl, Br, or I); OH; CN; NO ₂ ; alkyl; cycloalkyl; heterocycloalkyl; aryl; aralkyl; aralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N; heteroaryl; heteroaralkyl; heteroaralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N; alkenyl; cycloalkenyl; alkynyl; or -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl, and

R ¹⁴ is (CHi) _n -R ¹⁵ , wherein R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0 to 5.

In a preferred embodiment of the compounds of present invention the aryl or heteroaryl moiety comprised in radical R ¹² , if radical R ¹² has the meaning aryl, aralkyl, heteroaryl, or heteroaralkyl, is selected from the group of radicals consisting of benzyl, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and

1 ,2,4-benzotriazinyl.

In a preferred embodiment of the compounds of present invention radical R ¹⁵ is selected from the group of radicals consisting of phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl,

2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and

1 ,2,4-benzotriazinyl, which may be substituted with one or more halogen (F, Cl, Br, or I), OH,

CN, NO ₂ , alkyl, or alkoxy radicals.

In a preferred embodiment of the compounds of present invention the compound is selected from one of the compounds according to formulas (II) to (X)

10

(H) (III)

(IV) (V)

(VIII) (IX)

20

(X) (XI)

(XII) (XIII)

(XIV) (XV)

10 (XVI) (XVII)

(XVIII) (XIX)

(XX) (XXI)

(XXVI) (XXVII)

(XXVIII)

A further preferred compound of the present invention is selected from one of the compounds according to formulas (XXIX) to (XXXII)

(XXIX) (XXX)

(XXXI) (XXXII)

In a preferred embodiment of the compounds (XXIX) to (XXXII) one or more hydrogens are substituted independent of each other by one or more radicals selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, aralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, heteroaryl, heteroaralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom

independently selected form the group consisting of O and N, alkenyl, cycloalkenyl, alkynyl, or alkoxy.

A further aspect of the present invention is a compound of the present invention for the use as a medicament. 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.

A further aspect of the present invention is 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 reduced topoisomerase activity.

In a preferred embodiment the diseases, conditions and/or disorders are hyperproliferative diseases.

In a preferred embodiment 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. In a further preferred embodiment the hyperproliferative disorders are those which benefit from a reduced estrogen receptor signalling.

In a preferred embodiment the diseases, conditions and/or disorders are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus.

In a further aspect the present invention concerns methods of producing a compound of the invention, wherein R ¹ and R ² are taken together to form a five or six-membered N- heterocycle and the five or six-membered N-heterocycle is pyrolidinyl, piperidinyl, 1,2- diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1-oxa-

3-azacyclo-hexane, or l-oxa-4-azacyclohexane comprising the step according to (XV)

(XV) wherein R ¹⁶ is a protection group and

Z is a nucleophile, preferably Br, Cl, or O-Ts.

In a further aspect the present invention concerns methods of producing a compound of the invention, wherein the R ¹ is hydroxy 1 or alkyl and R ² is five or six-membered aryl or fused five or six-membered aryl comprising the step according to reaction scheme (XVII)

VII)

wherein R ¹⁶ is a protection group and

Z is a leaving group, preferably Cl, Br, SOPh, SO ₂ Ph or p-nitrophenoxy.

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 integer or step.

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, heteroalkyl, cycloalkyl, heterocycloalkyl, alicyclic system, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl 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.

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, /jo-butyl, tert-butyl, pentyl, hexyl, pentyl, or 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, iso-buty\, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, 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. -0-CH ₃ , -S-CH ₃ , -CH ₂ -O-CH ₃ , - CH ₂ -O-C ₂ H ₅ , -CH ₂ -S-CH ₃ , -CH ₂ -S-C ₂ H ₅ , -C ₂ H ₄ -O-CH ₃ , -C ₂ H ₄ -O-C ₂ H ₅ , -C ₂ H ₄ -S-CH ₃ , -C ₂ H ₄ -S- C ₂ H ₅ 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. The term "heterocycloalkyl" preferably refers to a saturated ring having five 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. 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 l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morρholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1 ,6 diazo-spiro-[4,5] decyl, 2,8 diazo-spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1 ,8 diazo-spiro-[5,4] decyl, 1,7 diazo-spiro- [5,4] decyl, 2,8 diazo-spiro-[5,4] decyl, 2,7 diazo-spiro[5,4] decyl, 3,8 diazo-spiro[5,4] decyl, 3,7 diazo-spiro[5,4] decyl, l-azo-7,l l-dioxo-spiro[5,5] undecyl, l,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, naphtyl 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 methyl, ethyl, propyl, wo-propyl, butyl, /jo-butyl, sec-butenyl, tert-buty\, pentyl, hexyl, pentyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.

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, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (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, 1 1 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 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 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- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl. 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, /50-propyl, butyl, wo-butyl, seobutenyl, tert-butyl, pentyl, hexyl, pentyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group. 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, i5o-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, pentenyl, 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, cyclopentenyl, 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, heteroalkyl, 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, N or with groups containing one ore more elements selected from the group consisting of O, S, N.

Embodiments include alkoxy, cycloalkoxy, arykoxy, 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, mercaptocycloalkyk, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl, mercaptocycloalkenyl, mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoaralkyl, aminoalkenyl, aminocycloalkenyl, aminoalkynyl radicals.

In another embodiment, hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one ore more halogen atoms. One radical is the trifluoro methyl 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 choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, rumaric 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 an 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)). Hydroxyl 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 according to the invention can be synthesized according to one or more of the following methods. 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 about a group 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, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.

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 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). 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 50 percent decrease in ER activity in a cell-based reporter gene assay as described in the examples below.

Embodiments of the Invention

The present invention provides compounds capable of antagonizing estrogen receptor, in particular compounds of the formula (I):

(I), wherein

R ¹ is hydrogen or alkyl;

R ² is a five-membered or six-membered aryl or fused five-membered or six-membered aryl; or R ¹ and R ² are taken together to form a five-membered or six-membered N-heterocycle R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl;

R ^D and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN,

NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N;

R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ ; or a pharmaceutically acceptable salt or solvate of such a salt, with the proviso that 2-propenamide, N-lH-indazol-5-yl-3-(5-nitro-2-furanyl-(2E) (CAPlus Registry No. 353539-89-6), 2-furanacrylamide, N-(9-amino-7-ethoxy-3-acridinyl)-5- nitro-(7CI) (CAPlus Registry No. 95025-08-4), 2-furanacrylamide, N-(6-methoxy-8-quinolyl)-5- nitro-(7CI) (CAPlus Registry No. 93326-30-8) and 2-propenamide, N-l,3-benzodioxol-5-yl-3- (5-nitro-2-furanyl)-(9CI) (CAPlus Registry No. 37542-74-8) are excluded. It is preferred that the double bond in the alkenyl chain in above formula (I) has a trans configuration. In a certain preferred embodiment R ¹ is hydrogen; R ² is a five-membered or six- membered aryl or fused five-membered or six-membered aryl; or R ¹ and R ² are taken together to

form a fϊve-membered or six-membered N-heterocycle; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ is hydrogen; R ² is a five-membered aryl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ is hydrogen; R ² is a six-membered aryl; or R ¹ and R ² are taken together to form a five-membered or six-membered N-heterocycle; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ³ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R is hydrogen; R is a fused five-membered aryl; R and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ is hydrogen; R ² is a fused six-membered aryl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R and R are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ . In a preferred embodiment of the compounds of present invention the fused five- membered or fused six-membered aryl is fused with a cycloalkyl, heterocycloalkyl, or alicyclic system or with an aryl or heteroaryl.

In a preferred embodiment of the compounds of present invention the five-membered aryl is fused with a six-membered aryl or heteroaryl. Alternatively, the six-membered aryl is fused with a five-membered or six-membered aryl or heteroaryl.

In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is a five-membered aryl fused with a six-membered aryl or heteroaryl, preferably heteroaryl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵

and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is a six-membered aryl fused with a six-membered aryl or heteroaryl, preferably heteroaryl; R and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ . In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is a six-membered aryl fused with a five-membered aryl or heteroaryl, preferably heteroaryl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ . In a preferred embodiment of the compounds of present invention said a) fused five-membered aryl is fused to cyclopentadienyl; b) fused five-membered aryl is fused to benzyl, naphtyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl; c) fused six-membered aryl is fused to furanyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, l,2,3-oxadiazolyl;pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1 ,2,5-thiadiazolyl, or thiophenyl; d) fused six-membered aryl is fused to pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl; 1,2,4-triazinyl.

In a preferred embodiment of the compound of present invention the five or six- membered aryl and the fused five or six-membered aryl or heteroaryl form a radical selected

from the group consisting of phenyl, naphtyl, 1 -benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl, in particular benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl, more preferably, R ² is selected from the group consisting of napht-1-yl, napht-2- yl, l-benzofuran-2-yl, l -benzofuran-3-yl, 1 -benzofuran-4-yl, 1 -benzofuran-5-yl, 1 -benzofuran-6- yl, l-benzofuran-7-yl, 2-benzofuran-l-yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl, l-indol-2-yl, 1- indol-3-yl, l-indol-4-yl, l-indol-5-yl, l-indol-6-yl, l-indol-7-yl, 2-indol-l-yl, 2-indol-4-yl, 2- indol-5-yl, l-benzothiophen-2-yl, l-benzothiophen-3-yl, 1 -benzothiophen-4-yl, 1- benzothiophen-5-yl, l-benzothiophen-6-yl, 1 -benzothiophen-7-yl, 2-benzothiophen-l-yl, 2- benzothiophen-4-yl, 2-benzothiophen-5-yl, lH-indazol-3-yl, lH-indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, lH-indazol-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, IH- indoxazin-3-yl, 1 H-indoxazin-4-yl, lH-indoxazin-5-yl, lH-indoxazin-6-yl, lH-indoxazin-7-yl, lH-2,l-benzisoxazol-3-yl, lH-2,l-benzisoxazol-4-yl, lH-2,l-benzisoxazol-5-yl, 1H-2,1- benzisoxazol-6-yl, lH-2,l-benzisoxazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, l,2-benzisothiazol-3-yl, 1,2- benzisothiazol-4-yl, l,2-benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl, 1 ,2-benzisothiazol-7-yl, 2, 1 -benzisothiazol-3-yl, 2, 1 -benzisothiazol-4-yl, 2,1 -benzisothiazol-5-yl, 2, 1 -benzisothiazol-6-yl, 2,l-benzisothiazol-7-yl, benzotriazol-4-yl, benzotriazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, 2,3-benzodiazin-l-yl, 2,3-benzodiazin-4-yl, 2,3-benzodiazin-5-yl, quinazolin-2- yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, 1,2,3- benzotriazin-4-yl, l,2,3-benzotriazin-5-yl, l,2,3-benzotriazin-6-yl, l,2,3-benzotriazin-7-yl, 1,2,3- benzotriazin-8-yl, l,2,4-benzotriazin-3-yl, 1 ,2,4-benzotriazin-5-yl, 1 ,2,4-benzotriazin-6-yl, 1,2,4- benzotriazin-7-yl, and 1 ,2,4-benzotriazin-8-yl, in particular benzothiazol-6-yl.

In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is selected from the group consisting of phenyl, naphtyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl, preferably

benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl, more preferably R ² is selected from the group consisting of napht-1 -yl, napht-2-yl, 1 -benzofuran-2-yl, l-benzofuran-3- yl, l-benzofuran-4-yl, l-benzofuran-5-yl, l-benzofuran-6-yl, 1 -benzofuran-7-yl, 2-benzofuran-l- yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl, l-indol-2-yl, l-indol-3-yl, 1 -indol-4-yl, l-indol-5-yl, l-indol-6-yl, l-indol-7-yl, 2-indol-l-yl, 2-indol-4-yl, 2-indol-5-yl, 1 -benzothiophen-2-yl, 1- benzothiophen-3-yl, l-benzothiophen-4-yl, 1 -benzothiophen-5-yl, 1 -benzothiophen-6-yl, 1- benzothiophen-7-yl, 2-benzothiophen-l-yl, 2-benzothiophen-4-yl, 2-benzothiophen-5-yl, IH- indazol-3-yl, lH-indazol-4-yl, l H-indazol-5-yl, 1 H-indazol-6-yl, lH-indazol-7-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, lH-indoxazin-3-yl, lH-indoxazin-4-yl, lH-indoxazin-5-yl, lH-indoxazin-6-yl, lH-indoxazin-7-yl, lH-2,l-benzisoxazol-3-yl, lH-2,l-benzisoxazol-4-yl, lH-2,l-benzisoxazol-5-yl, lH-2,l-benzisoxazol-6-yl, 1 H-2, 1 -benzisoxazol-7-yl, benzothiazol-2- yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, 1,2- benzisothiazol-3-yl, l,2-benzisothiazol-4-yl, 1 ,2-benzisothiazol-5-yl, l,2-benzisothiazol-6-yl, l,2-benzisothiazol-7-yl, 2,l-benzisothiazol-3-yl, 2,l-benzisothiazol-4-yl, 2,l-benzisothiazol-5-yl, 2,l-benzisothiazol-6-yl, 2,l-benzisothiazol-7-yl, benzotriazol-4-yl, benzotriazol-5-yl, quinolin- 2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, 2,3-benzodiazin-l -yl, 2,3-benzodiazin-4-yl, 2,3-benzodiazin- 5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, l,2,3-benzotriazin-4-yl, 1 ,2,3-benzotriazin-5-yl, l,2,3-benzotriazin-6-yl, 1,2,3- benzotriazin-7-yl, l,2,3-benzotriazin-8-yl, l,2,4-benzotriazin-3-yl, l,2,4-benzotriazin-5-yl, 1,2,4- benzotriazin-6-yl, l,2,4-benzotriazin-7-yl, and 1 ,2,4-benzotriazin-8-yl, in particular benzothiazol-6-yl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a preferred embodiment of the compound of present invention one or more of the hydrogens of the five-membered or six-membered aryl or the fused five-membered or six- membered aryl are substituted independent of each other by one or more radicals R ⁸ selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl;

heteroalkyl, in particular alkoxy, -OOC-R', -COO-R', wherein R' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, optionally substituted; cycloalkyl; heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl, and X(CH ₂ ) _n R ⁹ , wherein R ⁹ is R ¹⁰ , Y-R ¹⁰ , Y-CO-R ¹⁰ , or Y-COO-R ¹⁰ ;

R ¹⁰ is alkyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, rso-butyl, tert-butyl, pentyl, hexyl; heteroalkyl, cycloalkyl, aryl, in particular phenyl, aralkyl, in particular Ci _-6 - aralkyl; 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodoazinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; heteroaralkyl, in particular Ci- ₆ -heteroaralkyl; alkenyl; in particular C ₂ -C ₆ alkenyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1- /iO-propenyl, 2-z.yø-propenyl, 1-bιitenyl, 2-butenyl, 3-butenyl; cycloalkenyl, or alkynyl; and n is 0, 1, 2, 3, 4, or 5, preferably 2 or 3; or 1, 2, 3, 4, 5, preferably 2 or 3, if R ⁹ is Y-R ¹⁰ , Y-CO-R ¹⁰ , or Y-COO-R ¹⁰ ; X and Y are independently of each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N.

It is preferred that one or more of the hydrogens of the fϊve-membered or six-membered aryl or the fused five-membered or six-membered aryl are substituted by -X(CH ₂ ) _n R ⁹ , wherein R ⁹ has the meaning as outlined above. The substituent is preferably bound to the aryl via the X radical. Additionally, the five-membered or six-membered aryl or the fused five-membered or six-membered aryl can have one or more of the other substituents mentioned above. In this context it is particularly preferred that R ⁹ has the meaning Y-R ¹⁰ or Y-COO-R ¹⁰ , wherein R ¹⁰ has the meaning alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl,

cycloalkenyl, or alkynyl, preferably alkenyl, more preferably propenyl (1-propenyl or 2- propenyl).

In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is selected from the group consisting of phenyl and naphtyl; R ³ and R ⁴ are independent of each other hydrogen; cycloalkyl; aryl; aralkyl; alkenyl; cycloalkenyl; or alkynyl; preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein optionally one or more of the hydrogens of the phenyl or naphtyl residue are substituted independent of each other by one, two , three, four or more radicals R ⁸ selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, alkyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, /so-butyl, /er/-butyl, pentyl, hexyl, optionally substituted, e.g. CF ₃ ; heteroalkyl, in particular Ci-C ₆ alkoxy, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkoxy, preferably methoxy, ethoxy, propoxy, /sopropoxy, butoxy, /.so-butoxy, tørt-butoxy, pentoxy, or hexoxy, optionally substituted, preferably with one, two three or more substituents, e.g. trifluoromethoxy; alkoxyalkyl, in particular Ci-C ₆ -alkoxy-Ci-C ₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl, -OOC-R', -COO-R', wherein R' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, optionally substituted; cycloalkyl; heterocycloalkyl; aryl, in particular phenyl, naphtyl or anthracenyl; aralkyl; 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodoazinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3- benzotriazinyl, or 1 ,2,4-benzotriazinyl, optionally substituted, preferably with alkyl; heteroaralkyl; alkenyl, in particular C ₂ -C ₆ alkenyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkenyl,

preferably ethenyl, 1-propenyl, 2-propenyl, 1 -wo-propenyl, 2-/so-propenyl, 1-butenyl, 2- butenyl, 3-butenyl; cycloalkenyl; alkynyl, in particular C ₂ -C ₆ alkynyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkynyl; and -X(CH ₂ ) _n R ⁹ , wherein -R ⁹ is -R ¹⁰ , -Y-R ¹⁰ , -Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ; -R ¹⁰ is alkyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, λϊø-propyl, butyl, wø-butyl, tert-butyl, pentyl, hexyl; heteroalkyl, cycloalkyl, aryl, in particular phenyl, aralkyl, in particular C _1-6 - aralkyl; 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodoazinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; heteroaralkyl, in particular Ci _-6 -heteroaralkyl; alkenyl; in particular C ₂ -C ₆ alkenyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-

/5O-propenyl, 2-/iO-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; cycloalkenyl, or alkynyl; and n is 0, 1, 2, 3, 4, or 5, preferably 2 or 3; or 1, 2, 3, 4, 5, preferably 2 or 3, if R ⁹ is -Y-

R ¹⁰ , Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ;

X and Y are independently of each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N. In particular, if R ⁹ is Y-R ¹⁰ than Y has the preferred meaning O and if R ⁹ is -Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ than Y has the preferred meaning N or two substituents of the phenyl or naphtyl residue together form an alicyclic ring, e.g. cyclopentenyl, cyclohexenyl, 1,4-dioxocyclohexenyl, or 1,3-dioxocyclohexenyl. In a more preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is selected from the group consisting of phenyl; R ³ and R ⁴ are independent of each other hydrogen; cycloalkyl; aryl; aralkyl; alkenyl; cycloalkenyl; or alkynyl; preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I),

OH, CN ₅ NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,

heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein optionally the phenyl residue is substituted, preferably in meta and/or para with one, two or three substituents selected from the group consisting of -OH, -CN, alkyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, λrø-butyl, tert-buty\, pentyl, hexyl, optionally substituted, e.g. CF ₃ ; alkoxy, in particular CpC ₆ alkoxy, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkoxy, preferably methoxy, ethoxy, propoxy, wø-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy, optionally substituted, preferably with one, two three or more substituents, e.g. trifluoromethoxy; halogen, e.g. F, Cl, Br, or I, preferably Cl or Br; -COO-R', wherein R' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, optionally substituted; and heteroaryl, in particular benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl, optionally substituted, preferably with alkyl or halogen. In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is selected from the group consisting of phenyl, naphtyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1 -benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotiϊazinyl, or 1 ,2,4-benzotriazinyl, preferably benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl, more preferably R ² is selected from the group consisting of napht-1 -yl, napht-2-yl, 1 -benzofuran-2-yl, l-benzofuran-3- yl, 1 -benzofuran-4-yl, l-benzofuran-5-yl, 1 -benzofuran-6-yl, l-benzofuran-7-yl, 2-benzofuran-l- yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl, l-indol-2-yl, l-indol-3-yl, l-indol-4-yl, l-indol-5-yl, l-indol-6-yl, l-indol-7-yl, 2-indol-l-yl, 2-indol-4-yl, 2-indol-5-yl, l-benzothiophen-2-yl, 1- benzothiophen-3-yl, l-benzothiophen-4-yl, 1 -benzothiophen-5-yl, 1 -benzothiophen-6-yl, 1- benzothiophen-7-yl, 2-benzothiophen-l-yl, 2-benzothiophen-4-yl, 2-benzothiophen-5-yl, IH- indazol-3-yl, lH-indazol-4-yl, lH-indazol-5-yl, 1 H-indazol-6-yl, lH-indazol-7-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, lH-indoxazin-3-yl, 1 H-indoxazin-4-yl, lH-indoxazin-5-yl, lH-indoxazin-6-yl, lH-indoxazin-7-yl, lH-2,l-benzisoxazol-3-yl, lH-2,l-benzisoxazol-4-yl, lH-2,l-benzisoxazol-5-yl, lH-2,l-benzisoxazol-6-yl, lH-2,l-benzisoxazol-7-yl, benzothiazol-2- yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, 1,2- benzisothiazol-3-yl, l,2-benzisothiazol-4-yl, l,2-benzisothiazol-5-yl, l,2-benzisothiazol-6-yl,

1 ,2-benzisothiazol-7-yl, 2, 1 -benzisothiazol-3-yl, 2, 1 -benzisothiazol-4-yl, 2, 1 -benzisothiazol-5-yl, 2,l-benzisothiazol-6-yl, 2,l-benzisothiazol-7-yl, benzotriazol-4-yl, benzotriazol-5-yl, quinolin- 2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, 2,3-benzodiazin-l-yl, 2,3-benzodiazin-4-yl, 2,3-benzodiazin- 5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, l,2,3-benzotriazin-4-yl. l,2,3-bcnzotriazin-5-yl, l,2,3-benzotriazin-6-yl, 1,2,3- benzotriazin-7-yl, l,2,3-benzotriazin-8-yl, l ,2,4-bcnzotriazin-3-yl, l ,2,4-benzotriazin-5-yl, 1,2,4- benzotriazin-6-yl, l,2,4-benzotriazin-7-yl, and 1 ,2,4-benzotriazin-8-yl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one, two, three or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one, two, three or more of the hydrogens of naphtyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably benzothiazolyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl are substituted independent of each other by one or more radicals R selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl, and - X(CH ₂ ) _n R ⁹ , wherein

-R ⁹ is R ¹⁰ , -Y-R ¹⁰ , -Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ;

-R ¹⁰ is alkyl, in particular Ci-C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-buty\, tert-buty\, pentyl, hexyl; heteroalkyl, cycloalkyl, aryl, in particular phenyl, naphtyl, aralkyl, in particular Ci- ₆ -aralkyl; 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, indoyl, isoindoyl, benzothiophenyl, 2-

benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzosoxazoyl, benzothiazoly], 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodoazinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; heteroaralkyl, in particular Ci _-6 -heleroaralkyl; alkenyl; in particular C ₂ -C ₆ alkenyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1- zsø-propenyl, 2-z.so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; cycloalkenyl, or alkynyl; and n is 0, 1, 2, 3, 4, or 5, preferably 2 or 3; or 1, 2, 3, 4, 5, preferably 2 or 3, if R ⁹ is -Y-R ¹⁰ ,

Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ;

X and Y are independently of each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N. In particular, if R ⁹ is Y-R ¹⁰ than Y has the preferred meaning O and if R ⁹ is -Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ than Y has the preferred meaning N. In a certain preferred embodiment R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is selected from the group consisting of phenyl, naphtyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl, preferably benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl, more preferably R is selected from the group consisting of 1 -benzofuran-2-yl, l-benzofuran-3-yl, 1 -benzofuran-4-yl, l-benzofuran-5-yl, l-benzofuran-6-y!, 1 -benzofuran-7-yl, 2-bεnzofuran-l-yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl, l-indol-2-yl, l-indol-3-yl, l-indol-4-yl, l-indol-5-yl, 1 -indol-6-yl, l-indol-7- yl, 2-indol-l-yl, 2-indol-4-yl, 2-indol-5-yl, 1 -benzothiophen-2-yl, l-benzothiophen-3-yl, 1- benzothiophen-4-yl, l-benzothiophen-5-yl, 1 -benzothiophen-6-yl, 1 -benzothiophen-7-yl, 2- benzothiophen-1 -yl, 2-benzothiophen-4-yl, 2-benzothiophen-5-yl, lH-indazol-3-yl, lH-indazol- 4-yl, lH-indazol-5-yl, lH-indazol-6-yl, lH-indazol-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, lH-indoxazin-3-yl, lH-indoxazin-4-yl, lH-indoxazin-5-yl, lH-indoxazin-6-yl, lH-indoxazin-7-yl, lH-2,l-benzisoxazol-3-yl, lH-2,l -benzisoxazol-4-yl, lH-2,l-benzisoxazol- 5-yl, lH-2,l-benzisoxazol-6-yl, lH-2,l-benzisoxazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, l,2-benzisothiazol-3-yl, 1,2- benzisothiazol-4-yl, l ,2-benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl, 1 ,2-benzisothiazol-7-yl,

2,l-benzisothiazol-3-yl, 2,l-benzisothiazol-4-yl, 2,l-benzisothiazol-5-yl, 2,l-benzisothiazol-6-yl, 2,l-benzisothiazol-7-yl, benzotriazol-4-yl, benzotriazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, 2,3-benzodiazin-l-yl, 2,3-benzodiazin-4-yl, 2,3-benzodiazin-5-yl, quinazolin-2- yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, 1,2,3- benzotriazin-4-yl, l,2,3-benzotriazin-5-yl, l,2,3-benzotriazin-6-yl, l,2,3-benzotriazin-7-yl, 1,2,3- benzotriazin-8-yl, l,2,4-benzotriazin-3-yl, l,2,4-benzotriazin-5-yl, 1 ₅ 2,4-benzotriazin-6-yl, 1,2,4- benzotriazin-7-yl, and l ,2,4-benzotriazin-8-yl, in particular benzothiazol-6-yl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or 1), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of phenyl, naphtyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl are substituted by -X(CH ₂ ) _n R ⁹ , wherein R ⁹ has the meaning as outlined above. The substituent is preferably bound to the aryl via the X moiety. It is particularly preferred that this substituent is bound in benzothiazolyl at the position 2 of the heterocycle. Additionally, the 1-benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl, preferably benzothiophenyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl ore more preferably the particular preferred heterocyclces indicated for this embodiment may have one or more of the other substituents mentioned above under R ⁸ . In this context it is particularly preferred that R ⁹ has the meaning Y-R ¹⁰ or Y-COO-R ¹⁰ , wherein R ¹⁰ has the meaning alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably alkenyl, more preferably propenyl (1-propenyl or 2-propenyl) and X and Y are independently of

each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N.

In a certain preferred embodiment R is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R ² is benzimidazolyl, benzoxazolyl, benzothiazolyl, preferably benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of benzothiazolyl, are substituted by -X(CH ₂ ) _n R ⁹ , wherein R ⁹ has the meaning as outlined above. Preferably, this substituent is located at the 2, 4, or 5 position of the benzothiazolyl. The substituent is preferably bound to the benzothiazolyl via the X moiety. Additionally, the benzothiazolyl can have one or more of the other substituents mentioned above. In this context it is particularly preferred that R has the meaning Y-R ¹⁰ or Y- COO-R ¹⁰ , wherein R ¹⁰ has the meaning alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably alkenyl, more preferably propenyl (1- propenyl or 2-propenyl) and X and Y are independently of each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N.

In a certain preferred embodiment of the compounds of the formula (I) the compound has a structure as set out in formula (XXXIII)

(XXXIII)

R ¹ is hydrogen or alkyl, preferably hydrogen or methyl and more preferably hydrogen; R and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl,

alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one, two, three or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^s and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ ; R ⁸ is halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl, or -X(CH ₂ ) _n R ⁹ , wherein -R ⁹ is R ¹⁰ , -Y-R ¹⁰ , -Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ; -R ¹⁰ is alkyl, in particular Ci -C ₆ alkyl, e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; heteroalkyl, cycloalkyl, aryl, in particular phenyl, aralkyl, in particular Ci _-6 - aralkyl; heteroaryl, , in particular luranyl, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzosoxazoyl, benzothiazolyl. 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodoazinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; heteroaralkyl, in particular Ci- ₆ -heteroaralkyl; alkenyl; in particular C ₂ -C ₆ alkenyl, e.g. C ₂ , C ₃ , C ₄ , C ₅ , or C ₆ alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1- wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; cycloalkenyl, or alkynyl; optionally substituted and n is O, 1, 2, 3, 4, or 5, preferably 2 or 3; or 1, 2, 3, 4, 5, preferably 2 or 3, if R ⁹ is -Y-R ¹⁰ , Y-CO-R ¹⁰ , or -Y-COO-R ¹⁰ ;

X and Y are independently of each other selected from O, N and S, preferably X has the meaning S and Y has the meaning O or N

Xi and X ₂ are independently of each other selected from O, N and S and one OfX ₁ and X ₂ may be CH, preferably Xi is S and X ₂ is selected from O, N, S or CH, preferably N or O. In particular, if R ⁹ is Y-R ¹⁰ than Y has the preferred meaning O and if R ⁹ is -Y-CO-R ¹⁰ , or -Y- COO-R ¹⁰ than Y has the preferred meaning N

or a pharmaceutically acceptable salt or solvate of such a salt. Additionally, the benzothiazolyl can have one or more additional substituents selected from the group consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl and alkynyl. In cases, wherein R ¹ and R are taken together to form a five or six-membered N- heterocycle, the N-heterocycle can be fused with an cycloalkyl, cycloheteroalkyl, alicyclic, aromatic or heteroaromatic system, wherein the resulting system may be substituted with hydrogen and/or with other substituents, preferably those, which are defined below.

In one embodiment, the five-membered N-heterocycle is fused with an aromatic or heteroaromatic system. Preferably, said aromatic system is the benzo system and the heteroaromatic systems, with which five-membered N-heteroaryl can be fused, are for example pyridine, chinoline, or benzo thiazo Ie.

In another embodiment, the six-membered N-heterocycle is fused with an aromatic system. Preferably, said aromatic system is the benzo system. Resulting six-membered N- heteroaryl systems include chinolinyl and isochinolinyl. Other aromatic systems, with which five- and six membered N-heteroaryl can be fused, include the pyridine and pyrimidine systems. In a further preferred embodiment of the compounds of present invention the five- membered N-heterocycle is 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, or pyrolidinyl.

In a preferred embodiment of the compounds of present invention the six-membered N- heterocycle is piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane. In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered

N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group

consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ .

In a preferred embodiment of the compounds of present invention one or more of the hydrogens of the five-membered or six-membered N-heterocycle are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more radicals R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl.

In a certain preferred embodiment R ¹ and R are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl.

In a certain preferred embodiment of the compounds of the formula (I) the compound has a structure as set out in formula (XXXIV)

R1 1

(XXXIV)

R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl.

In a preferred embodiment of the compounds of present invention radical R ¹¹ is selected from the group consisting of 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, 2-alklypyridinyl, 3-alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl. In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered

N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or

alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ^{1 1} , wherein the radical is selected from 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, 2-alklypyridinyl, 3- alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2, 1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl. Additionally, one or more further hydrogen of the five-membered N-heterocycle, i.e. 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, or pyrolidinyl, preferably pyrolidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1 ,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably

hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I) ₃ OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical (s) R ^{1 1} , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl. Additionally, one or more further hydrogen of the six-membered N-heterocycle, i.e. piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2- diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexanε, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl,

Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl. Additionally, one or more further hydrogens of the pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexanε, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2-methylpyridinyl, imidazolyl or pyrrolyl. Additionally, one or more further hydrogens of the piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a preferred embodiment of the compounds of present invention one or more hydrogens of the one or more, preferably one radical(s) R ¹ ' is(aie) substituted independent of each other by

one or more, preferably one radical(s) R ¹² selected from the group of radicals consisting of halogen (F, Cl, Br, or I); OH; CN; NO ₂ ; alkyl; cycloalkyl; heterocycloalkyl; aryl; aralkyl; aralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N; heteroaryl; heteroaralkyl; heteroaralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N; alkenyl; cycloalkenyl; alkynyl; or -CO-NR ¹³ -R ¹⁴ , wherein R ¹³ is hydrogen or alkyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is O, 1 , 2, 3, 4, or 5.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R is(are) substituted independent of each other by one or more, preferably one radical(s) R , wherein R has the meaning aryl or aralkyl, wherein the alkyl group may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O.

In a certain preferred embodiment R ¹ and R are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹ , wherein R has the meaning aryl or aralkyl, wherein the alkyl group is preferably a Cj to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent

of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroar alkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ^M selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹ has the meaning heteroaryl; or heteroaralkyl. wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting

of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning heteroaryl or heteroaralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are)

substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ VR ¹⁵ , wherein R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN ₅ F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3 -azacyclohexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R' ⁵ , wherein

R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazoly!, 1.2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1 ,2,5-thiadiazolyl, or pyrolidinyl, preferably pyrolidinyl; R and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ^{! l} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered

N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-

diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R and R are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l -oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO?, alkyl. heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is aryl, substituted aryl, heteroaryl. or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkyny], preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or

heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ^{1 1} , wherein the radical is selected from 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, 2-alklypyridinyl, 3- alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably pyrrolyl. pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning aryl or aralkyl, wherein the alkyl group is preferably a Ci to Cm alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1 , 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having 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, or pyrolidinyl, preferably pyrolidinyl, may be substituted with one or more halogen (F, Cl, Br, or I) ₅ OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen,

alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1,2- diazacyclohexane, 1 ,3-diazacyclohexanc, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} , wherein the radical is selected from the group consisting of oxazolyl, isoxazolyl, 1 ,2,5-oxadiazoIyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, and 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein radical R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning aryl or aralkyl, wherein the alkyl group ay be interrupted one or more times with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 , 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these

compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ¹¹ , wherein the radical is selected from oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl. 1 ,2.3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, l ,2,3.-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, 2-alklypyridinyl, 3- alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, bεnzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3 -alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning heteroaryl; heteroaralkyl; or heteroaralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ¹ ' having 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, or pyrolidinyl, preferably

pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.-

In a certain preferred embodiment R ¹ and R ^" are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1, 2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning heteroaryl; heteroaralkyl; or heteroaralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl,

propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^? and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ^{1 1} , wherein the radical is selected from 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, 2-alklypyridinyl, 3- alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,

isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹ , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1 , 2, 3, 4, or 5. Additionally, one or more further hydrogen atoms of radical R ¹¹ having 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, or pyrolidinyl, preferably pyrolidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted

independent of each other by one or more, preferably one radical(s) R ¹¹ , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, and 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein R ¹³ is hydrogen or alkyl preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or 1), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group

consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ^{1 1} , wherein the radical is selected from 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, 2-alklypyridinyl, 3- alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzo triazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R is alkyl, preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein R ¹⁵ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having 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, or pyrolidinyl, preferably pyrolidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1 ,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably

hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l -oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, and 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein R ^lj is alkyl, preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein R ¹⁵ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably

these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^π having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning aryl or aralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1. 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1,3 -diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, 1-oxa-

3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹ , wherein R ¹² has the meaning aryl or aralkyl, wherein the alkyl group is preferably a Ci to Cio alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-buiyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1 , 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning heteroaryl; heteroaralkyl; or heteroaralkyl, wherein the alkyl group is preferably a Ci to Cio alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN,

NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^? and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} having the meaning 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² . wherein R ¹² has the meaning heteroaryl; heteroaralkyl; or heteroaralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-buty], tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1 , 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O. Additionally, one or more further hydrogen atoms of radical R ¹ ' having the meaning piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo- hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl,

Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ¹³ -R ¹⁴ , wherein R ¹³ is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1 , 2, 3, 4, or 5. Additiormlly, one or more further hydrogen atoms of radical R ¹¹ having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ³ and R ⁶ arc independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1 ,3 -diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ^I3 -R ¹⁴ , wherein

R is hydrogen or alkyl preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is 0, 1, 2, 3, 4, or 5. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXlV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered

N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl,

Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl. cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^? and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably

NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹¹ having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and R ¹⁴ is (CH ₂ )n-R ¹⁵ , wherein

R ¹⁵ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is O, 1, 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3-

diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ^""1 and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ V-R ¹⁵ , wherein

R ¹⁵ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is O, 1, 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l -oxa-2-azacyclohexane, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, hetεrocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a preferred embodiment of the compound of present invention the aryl or heteroaryl moiety comprised in radical R ¹² , if radical R ¹² has the meaning aryl, aralkyl, heteroaryl, or heteroaralkyl, is selected from the group of aryls and heteroaryls consisting of benzyl, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,

quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl, in particular 1,2,3-benzotriazinyl or pyrrolyl, wherein said aryls or heteroaryls can be further substituted by one or more radicals R ¹⁷ preferably selected from the group consisting of halogen (F, Cl, Br, or I); OH; CN; NO ₂ ; alkyl; cycloalkyl; heterocycloalkyl; aryl; aralkyl, wherein the alky] group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, wo-bulyl, tert-buty\, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1 , 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O, a particular preferred aralkyl group is benzyl; heteroaryl; heteroaralky], wherein the alkyl group is preferably a Ci to C] ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O; alkenyl; cycloalkenyl; or alkynyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ³ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl. heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning aralkyl; aralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O; heteroaralkyl; heteroaralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O; the aryl or heteroaryl moiety comprised in radical R ¹² , if radical R ¹² is selected from the group of aryls and heteroaryls

consisting of benzyl, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1 ,2,4-benzotriazinyl, in particular 1,2,3- benzotriazinyl or pyrrolyl, wherein said aryls or heteroaryls can be further substituted preferably by halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alky!, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, in particular benzyl, heteroaryl. heleroaralkyl, alkenyl, cycloalkenyl, alkynyl. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered

N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1 ,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning aralkyl; aralkyl, wherein the alkyl group is preferably a Ci to Cio alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O; heteroaralkyl;

heteroaralkyl, wherein the alkyl group is preferably a Cj to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1 , 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, preferably O; the aryl or heteroaryl moiety comprised in radical R ¹² , if radical R ¹² is selected from the group of aryls and heteroaryls consisting of benzyl, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1 ,2,4-benzotriazinyl, in particular 1,2,3- benzotriazinyl or pyrrolyl, wherein said aryls or heteroaryls can be further substituted preferably by halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, in particular benzyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, 2-diazacyclohexane, 1 ,3-diazacyclohexane, 1.4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1- oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I). OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a preferred embodiment of the compound of present invention radical R ¹⁵ is selected from the group of radicals consisting of phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1 -benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ³ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^λ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I). OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heleroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein R ³ is hydrogen or alkyl, preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ^! \ wherein R ^{1 "} ^ is phenyl, benzyl, furan, thiophen, 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, pyiϊdinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, bεnzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzo thiazolyl, 1 ,2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is O, 1, 2, 3, 4, or 5. In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered

N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4-

diazacyclohexane, l -oxa-2-azacyclohexane, l -oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ^"1 and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the piperidinyl, pyiϊdinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, l -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ^I3 -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ VR ¹⁵ , wherein

R ^{! 5} is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals and n is O, 1, 2, 3, 4, or 5. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the 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, or pyrolidinyl, preferably pyrolidinyl are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ^{I 3} -R ¹⁴ , wherein R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ ),,-R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 ,2-diazacyclohexane, 1,3-

diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R and R are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more of the hydrogens of the piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 , 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; are substituted independent of each other by one or more radicals R ¹ ' selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, or alkynyl preferably aryl, aralkyl, heteroaryl, or heteroaralkyl, most preferably heteroaryl or heteroaralkyl, wherein R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR -R , wherein

R ¹³ is alkyl, preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and

n is 0, 1 , 2, 3, 4, or 5, preferably 1 or 2. Preferably these compounds have a structure as outlined in formula (XXXIV). while having above indicated substituents and preferred substituents.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ¹¹ , wherein the radical is selected from 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, 2-alklypyridinyl, 3-alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl. indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein R ¹³ is hydrogen or alkyl preferably methyl, and R ¹⁴ is (CHz) _n -R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2-

benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1, 2, 3, 4, or 5. Additionally, one or more further hydrogen atoms of radical R ¹¹ having 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, or pyrolidinyl, preferably pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 ,3,5-triazinyl, 1,2-diazacyclohexane, 1,3 -diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl,

benzothiophenyl, 2-benzothiophenyl, l H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹ is hydrogen or alkyl preferably methyl, and R ¹⁴ is (CH ₂ J _n -R ¹⁵ , wherein R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1 , 2, 3, 4, or 5. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of 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, or pyrolidinyl, preferably pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ^D and R ⁶ are independent of each other hydrogen, halogen (F, Cl,

Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the 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, or pyrolidinyl, preferably pyrolidinyl, are substituted independent of each other by one or more, preferably one radicals R ¹¹ , wherein the radical is selected from 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, 2-alklypyridinyl, 3-alkylpyridinyl, in particular 2-methylpyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ¹ ' is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ _; wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ¹¹ having 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, or pyrolidinyl, preferably pyrolidinyl, may be substituted with one or more halogen

(F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, preferably piperidinyl, 2-diazacyclohexane, 1,3-diazacyclohexane, 1,4- diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4- azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ^{1 1} , wherein the radical is selected from the group consisting of 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl. quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably pyrrolyl, pyridinyl, 2-alklypyridinyl, 3-alkylpyridinyl, more preferably 2-methylpyridinyl, imidazolyl or pyrrolyl, wherein R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO-NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and R ¹⁴ is (CHz) _n -R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or 1), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1 , 2, 3, 4, or 5, preferably 1 or 2. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 ,2-diazacyclohexane, 1,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, preferably piperidinyl, 2- diazacyclohexane, 1.3-diazacyclohexane, 1,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a fϊve-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl. heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ³ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹¹ having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ^I3 -R ¹⁴ , wherein

R . 13 is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ ) _H -R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1 ,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1, 2, 3, 4. or 5. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl. In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered

N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ³ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹ ' having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ¹¹ is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ^I3 -R ¹⁴ , wherein

R ¹³ is hydrogen or alkyl preferably methyl, and

R ¹⁴ is (CH ₂ )H-R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1 , 2, 3, 4, or 5. Preferably these compounds have a structure as outlined in formula

(XXXIV), while having above indicated substituents and preferred substituents. Additionally, one or more further hydrogen atoms of radical R ^{1 1} having the meaning piperidinyl, 2- diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, 1 -oxa-2-azacyclohexane, 1-oxa- 3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a five-membered N-heterocycle selected from the group consisting of pyrolidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of pyrolidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹¹ having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl. wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ¹³ -R ¹⁴ , wherein R ¹³ is alkyl, preferably methyl, and

R ¹⁴ is (CH ₂ ) _n -R ¹⁵ , wherein

R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, l H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, or alkoxy radicals, and n is 0, 1 , 2, 3, 4, or 5, preferably 1 or 2. Additionally, one or more further hydrogen atoms of radical R ¹ ' having the meaning pyrolidinyl may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO?, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a certain preferred embodiment R ¹ and R ² are taken together to form a six-membered N-heterocycle selected from the group consisting of piperidinyl, 2-diazacyclohexane, 1,3- diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, preferably piperidinyl; R ³ and R ⁴ are independent of each other hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, or alkynyl, preferably hydrogen; R ⁵ and R ⁶ are independent of each other hydrogen, halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, cycloalkenyl, alkynyl or are taken together to form a cycloalkyl, aryl, or heteroaryl with one or more heteroatoms selected independent of each other from the group consisting of O, S and N, preferably R ⁵ and R ⁶ are hydrogen; R ⁷ is NO ₂ , CN, F, or Cl, preferably NO ₂ , wherein one or more, preferably one of the hydrogens of the piperidinyl, 2- diazacyclohexane, 1,3-diazacyclohexane, 1,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa- 3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, are substituted independent of each other by one or more, preferably one radical(s) R ¹¹ having the meaning 2- methylpyridinyl, imidazolyl or pyrrolyl, wherein radical(s) R ^{1 1} is(are) substituted independent of each other by one or more, preferably one radical(s) R ¹² , wherein R ¹² has the meaning -CO- NR ¹³ -R ¹⁴ , wherein

R ¹³ is alkyl, preferably methyl, and R ¹⁴ is (CH ₂ ) _n -R' ⁵ , wherein R ¹⁵ is phenyl, benzyl, furan, thiophen, 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, indoyl, isoindoyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl,

benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1 -benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or quinolinyl, 1,2,3-benzotriazinyl, and 1,2,4- benzotriazinyl, preferably furan, thiophen, phenyl, or indol; which may be substituted with one or more halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl. or alkoxy radicals, and n is 0, 1, 2, 3, 4, or 5, preferably 1 or 2. Preferably these compounds have a structure as outlined in formula (XXXIV), while having above indicated substituents and preferred substituents. Additionally, one or more further hydrogen atoms of radical R ¹¹ having the meaning piperidinyl, 2-diazacyclohexane, 1 ,3-diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2- azacyclohexane, l-oxa-3-azacyclo-hexane, or l-oxa-4-azacyclohexane, most preferably piperidinyl, may be substituted with halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, or alkynyl, preferably halogen (F, Cl, Br, or I), OH, CN, NO ₂ or alkyl.

In a preferred embodiment of the compounds of present invention the compound is selected from one of the compounds according to formulas (II) to (X)

(H) (III)

(IV) (V)

(Vl) (VII)

(VIII) (IX)

(X) (XI)

(XII) (XIII)

(XIV) (XV)

(XVI) (XVII)

(XVIII) (XIX)

(XX) (XXI)

(XXIV) (XXV)

(XXVI) (XXVII)

(XXVIII)

A further preferred compound of the present invention is selected from one of the compounds according to formulas (XXIX) to (XXXII)

(XXIX) (XXX)

(XXXI) (XXXII) In a preferred embodiment of the compound of present invention one or more hydrogens are substituted independent of each other by one or more, preferably 1, 2, 3, 4, 5, or 6, radicals selected from the group of radicals consisting of halogen (F, Cl, Br, or I), OH, CN, NO ₂ , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, aralkyl, wherein the alkyl group is preferably a Ci to Ci ₀ alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, heteroaryl, heteroaralkyl, wherein the alkyl group is preferably a Ci to C _1O alkyl group, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, pentyl, octyl, which may be interrupted one or more times, preferably 1, 2, 3, 4, 5, or 6 times, with a heteroatom independently selected form the group consisting of O and N, alkenyl, cycloalkenyl, alkynyl, or alkoxy.

Formulation and Administration of the Compounds (Compositions)

A further aspect of the present invention is a compound of the present invention for the use as a medicament.

The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly,

intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered topically, including transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) or a solvate of such a salt.

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 earners 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 reduced topoisomerase activity. In the past, topoisomerase inhibitors like, for example etoposide, teniposide, camptothecin or podophyllotoxin, have been 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).

The known topoisomerase inhibitors induce a cell cycle arrests at various points in the cell cycle and, therefore, in a preferred embodiment of the present invention the diseases, conditions and/or disorders, which can be prevented, ameliorated or treated with the compounds of the present invention are hyperproliferative diseases.

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, 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. Based on past experiences on the suitability of topoisomerase inhibitors for the treatment of various diseases the use of the compounds of the present invention is particularly preferred for treating, ameliorating and/or preventing acute 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 topoisomerase activity. In the past topoisomerase inhibitors like, for example etoposide, teniposide, camptothecin or podophyllotoxin, have been 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, 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, Wilms' 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. This particular suitability of the compounds of the present invention is based on the fact, that the compounds of the present invention potentially through the topoisomerase inhibitory activity 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.

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 m ² , preferably about 5 mg to about 150 mg/m ² 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 ₅ 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, preυssin, 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, suJfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, siilfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-Ol, 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 ot topoisomerase activity, 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. The use of, for example, etoposide has two serious limitations: cardiotoxicity (Pai and

Nahata, Drug Saf. 2000 Apr;22(4):263-302) and the induction of secondary malignancies arising from the mutagenic effect of the drug (Le Deley et al, Clin Oncol. 2003;21 :1074-81). Based on the finding that the compounds of the present invention inhibit topoisomerase II without inducing strand breaks in DNA. the present inventors envision that they are less mutagenic than, e.g. etoposide. Accordingly, it is particularly preferred to use combinations of the compounds of the present inventions and known topoisomerase inhibitors, e.g. etoposide or camptothecin, which will allow the lowering of the dose of the known topoisomerase inhibitor in the composition and reduce the side effects. The currently established dosages for topoisomerases range, e.g. from 50 to 100 mg per m for etoposide and 100 to 200 mg per m ² for camptothecin.

Thus, it is particularly preferred to reduce the dose of the known topoisomerase inhibitor in a formulation by at least 10%, preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50% or more. The formulation additionally comprises the compounds of the present invention in an amount to provide a formulation with a topoisomerase inhibitory activity, which is preferably at least as strong as that of the known topoisomerase before its amount was reduced. Thus, in a preferred embodiment formulations are used which comprise 50% or less of the dose of a known topoisomerase and a dose of the compounds of the present invention compensating this loss in topoisomerase inhibitory activity.

The starting materials used for the synthesis of the compounds of the present invention are generally commercially available or can be prepared using standard synthetic methodology.

In a further aspect the method of producing a compound of the present invention, wherein the five or six-membered N-heterocycle is pyrolidinyl, piperidinyl, 1 ,2-diazacyclohexane, 1,3- diazacyclohexane, 1 ,4-diazacyclohexane, l-oxa-2-azacyclohexane, l-oxa-3-azacyclo-hexane, or 1 -oxa-4-azacyclohexane comprising the step according to (XV)

(XV) wherein R ¹⁶ is a protection group and

Z is a nucleophile, preferably Br, Cl, or O-Ts.

Method of producing a compound of the present invention, wherein R has the meaning five or six-membered aryl or fused five or six-membered aryl, comprising the step according to reaction scheme (XVII)

VII)

wherein R ¹⁶ is a protection group and

Z is a leaving group, preferably Cl, Br, SOPh, SO ₂ Ph or p-nitrophenoxy.

A further step of the method of producing the compounds of the present invention involves the removal of all protection groups including R ¹⁶ , which might be required to protect the respective functionality.

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: Depicts structures and effects of exemplary compounds on estrogen receptor signalling at various molar concentrations. The % inhibition of estrogen receptor signalling is plotted over the concentration of the respective compound.

Fig. 4: Depicts the effect of the nitrofuran 1542-01308 on the ability of topoisomerase II to deconcatonate kinetoplast DNA.

Fig. 5: Panel A depicts the effect of the nitrofuran 1542-01308 on the ability of topoisomerase

II to relax supercoiled plasmid DNA in comparison with the known topoisomerase II inhibitor etoposide. Panel B depicts the abrogation of estrogen signaling by the known inhibitor of ERa function (ICI 370,182), inhibitors of topoisomerase I (camptothecin) and topoisomeras II (etoposide) in comparison with the nitrofuran 1542-01308.

Fig. 6: Depicts the Go/Gl cell cycle arrest induced by 1542-01308, which is in contrast to the G2/M arrest induced by etoposide. a widely used inhibitor of topoisomerase II.

Fig. 7: Depicts that, in contrast to the known topoisomerase II inhibitor etoposide, 1542-01308 does not induce phosphorylation of histone H2AX, a marker of double stranded DNA break formation in cells.

Fig. 8: Depicts that 1542-01308 does inhibit topoisomerase I activity, but to a lesser extent than the inhibition of topoisomerase II.

Fig. 9: Depicts structures and effects of exemplary compounds on estrogen receptor signalling and cell viability. Depicted are from left to right IC ₅₀ for ERE-luc transfection, cytotoxicity on MCF-7 (human breast cancer cells), HeLa Kyoto (human cervix carcinoma cells), human forskin fibroblasts (HFF-I), beta-actin promoter luciferase, and

QuantiLUM-luciferase.

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 5x10 ^"8 M (100% inhibition). Britlite (Perkin Elmer cat 6016979) was reconstituted as desctribe in the kit maual and equlibrated at room temperature. The assay plates were also equilibrated to room temperature for at least 30 minutes prior to adding 75 μl of Britelite substrate buffer solution. Luciferase levels were measured using an Envision HTS (Perkin Elmer). Percentage inhibition was calculated with respect to the posititive and negative controls: faslodex and DMSO respectively.4.

This assay was screened against the Tripos pilot library. Tripos (Bude, UK) provide chemically diverse libraries of drug like molecules, including a pilot library of 3000 compounds that is representative of their largest library of 50,000 compounds. A series of nitrofurans were identified in this initial screen. These hits were then confirmed by determination of the IC _5O 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 the full Tripos 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 and 9.

Evaluation of topoisomerase 11 inhibition Charactarization of topoisomerase Il activity was performed using catenated DNA substrate prepared from the kinetoplast of the insect trypanosome Crithidia fasciculate (Purchased from TopoGEN Inc, Florida, USA). KDNA is an aggregate of interlocked DNA minicircles (mostly 2.5 kb) that form extremely large networks of high molecular weight. As a result, these networks fail to enter an agarose gel. Upon incubation with topo II, which engages DNA in a double stranded breaking and reunion cycle, minicircular DNAs are effectively released (decatenated). The decatenated minicircles move rapidly into the gel owing to their small size. In this assay, 200 ng of kDNA was incubated with 2 units of topoisomerase II for 30 minutes at 3O ⁰ C in a buffer solution containing salts, divalent cations and ATP as recommended by the manufacturer. Differing amounts of the nitrofuran 1542-03108 were incubated throughout the reaction, with compound being added to the complete assay mix prior to the addition of kDNA substrate. The resulting products were then analysed on a 2% agarose gel and visualized by uv transillumination following staining with ethidium bromide. It is apparent that 1542-03108 inhibits the ability of topo II to deconcatonate DNA (see Fig. 4).

Topoisomerase Il activity was also determined using a plasmid relaxation assay. Plasmid DNA (pUC19) prepared from E. coli exists as negatively supercoiled DNA, which in consequence of altered physical properties, migrates slower in an agarose gel than relaxed plasmid DNA. Topoisomerase II activity acts to induce a double stranded DNA break in the plasmid DNA, which then unwinds, after which topoisomerase II ligates the double stranded DNA break to produce relaxed plasmid DNA. In the assay presented, 250 ng of supercoiled pUC19 DNA was incubated with 10 units of Topoisomerase II for 30 minutes at 3O ⁰ C, either with 500 μM etoposide, 10 μM 1542-03108 or with a combination of 500 μM etoposide and 10 μM 1542-03108. These test samples were compared with reactions where no topoisomerase was present and where topoisomerase without inhibition was present. Finally, pUC19 DNA was linerarised with the restriction enzyme HinDIII, which makes a single double stranded DNA break in the plasmid (see Fig. 5 A).

In addition the effect of the known inhibitor of ERa function ICI 370,182, the topoisomerase inhibitor I camptothecin and the topoisomerase inhibitor II etoposide on estrogen receptor activation was compared to the effect of the nitrofuran 1542-03108 using the cellular assay described above (see Fig. 5 B).

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 with either 10 μM 1542-03108, 50 μM etoposide, 5xlO ^"8 M faslodex or with DMSO used to dissolve compounds for addition to cells. 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 debri and aggregates consisting of 2 or more cells (see Fig. 6).

Analysis of HA2X phosphorylation

Phosphorylation of histone HA2X on serine 139 occurs at sites flanking double stranded breaks in DNA. This is one of the earliest events following such damage and can be used as a surrogate marker to detect any insult to cells that results in double stranded break lesions in DNA (Banath and Olive, (2003) Cancer Res. 63 4347-4350). We reasoned that as 1542-03108 does not induce the characteristic arrest in G2/M associated with double stranded breaks in DNA, but rather an arrest in Gl, that the mode of action of 1542-03108 is different from etoposide, which inhibits the final ligation step in the cycle of events catalysed by topoisomerase II, thereby inducing the formation of double stranded DNA breaks in DNA. MCF-7 cells were treated for 16 hours with DMSO (solvent control), 10 mM 1543-03108 or 50 mM etoposide. Cells were washed twice in phosphate buffered saline and then scrapped into 0.2 M H2SO4. Following pelleting of cell debri. acid soluble proteins were precipitated by the addition of trichloroacetic acid to a final concentration of 20%. The precipitate was collected by centrifugation, washed with chloroform, dissolved in Laemmli buffer and subject to electrophoresis through a 15% polyacrylamide gel. Proteins were transferred to a PVDF membrane, which after blocking, was probed with rabbit anti-phosphorylated H2AX from AbCAM, (ab2893; Cambridge, UK). This interaction was detected on film through horse raddish peroxide conjugated goat anti rabbit antibody following exposure to a chemiluminescent substrate (see Fig. 7).

Evaluation of topoisomerase 1 inhibition

Inhibition of Topoisomerase I activity by 1542-03108, camptothecin ( a known inhibitor of topoisomerase I activity) and etoposide was determined using a plasmid relaxation assay. Plasmid DNA (pUC19) prepared from E. coli exists as negatively supercoiled DNA, which in consequence of altered physical properties, migrates slower in an agarose gel than relaxed

plasmid DNA. Topoisomerase I activity acts to induce a single stranded DNA break in the plasmid DNA, which then unwinds, after which topoisomerase I ligates the single stranded DNA break to produce relaxed plasmid DNA. In the assay presented, 250 ng of supercoiled pUC19 DNA was incubated with 1 unit of Topoisomerase II for 30 minutes at 3O ⁰ C, either with 500 μM etoposide, 100 μM camptothecin or 100, 50 or 10 μM 1542-03108. These test samples were compared with reactions where no topoisomerase was present and where topoisomerase without inhibition was present. Moreover, as the compounds under test were added from a concentrated stock solution prepared in DMSO, a DMSO only control was evaluated to ensure this did not reault in inhibition of topoisomerase I activity. Finally, pUC19 DNA was linerarised with the restriction enzyme HinDIII, which makes a single double stranded DNA break in the plasmid.

Gels were run in the presence of the interchelating dye ethidium bromide, which reveals relaxed and supercoiled plasmid DNA. Gels run in the absence of ethidium bromide that are subsequently stained with ethidium bromide reveal the relaxed and partially relaxed topological isomers of plasmid DNA. Compound 1542-03108 inhibits topoisomerase I activity, albeit less effectively than the inhibition of topoisomerase II activity (see Fig. 8).

Determination of cytotoxicity of preferred compounds of the invention

Compounds were analysed for their ability to inhibit growth of tumour cells (e.g. HeLa cells) and normal human cells (e.g. foreskin fibroblasts). Growth inhibition was tested from 50 μM to 97.7 nM in a 10 point two-fold serial dilution and cells incubated under standard mammalian tissue culture conditions for 72 hours in triplicate. Cell viability was measured by measuring ATP levels in viable cells using the ATPLite kit (PerkinElmer) as described in the user manual. Raw data was transformed to percentage inhibition of growth compared to a DMSO only control and values are expressed as IC ₅₀ (see Fig. 9).

Identification of compounds that inhibit luciferase

Luciferase inhibitors were identified by screening against recombinant firefly luciferase (Quantilum recombninat luciferase; Promega Corp. Madison) diluted in cell culture media and incubated with the screening concentration of the tested compound in white 96 well plates. The pates were equilibrated for 30 minutes at room temperature before adding 75 μl of Britelite substrate buffer solution the incubated for a further 15-20 minutes. Luciferase levels were measured using an Envision HTS (Perkin Elmer). One hundred percent inhibition was signal observed by incubation of Britelite with medium alone (Alam, J. and Cook, J. L. Reporter genes: application to the study of mammalian gene transcription. Anal. Biochem. 188, 245-254 (1990))