WO2008135232A1

WO2008135232A1 - Use and compositions of purine derivatives for the treatment of proliferative disorders

Info

Publication number: WO2008135232A1
Application number: PCT/EP2008/003537
Authority: WO
Inventors: Riccardo Cortese; Andrea Musacchio
Original assignee: Riccardo Cortese; Andrea Musacchio
Priority date: 2007-05-02
Filing date: 2008-04-30
Publication date: 2008-11-13

Abstract

The present invention relates to inhibitors of Aurora A, Aurora B, Aurora C, CHK2, JNK1 α1, JNK3 and abl kinase and their biological applications. In particular, the invention relates to substituted purines and purine derivatives and compositions thereof featuring antiproliferative properties which are useful in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.

Description

Use and Compositions of Purine Derivatives for the Treatment of Proliferative

Disorders

The present invention relates to inhibitors of cell cycle kinases, in particualr Aurora A, Aurora

B, Aurora C, CHK2, JNKlαl, JNK3 and abl kinase and their biological applications. In particular, the invention relates to substituted purines and purine derivatives and compositions thereof showing antiproliferative properties which are useful in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.

Background of the Invention

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e. g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H₂O₂), cytokines (e. g., interleukin-1 (IL- 1) and tumor necrosis factor alpha (TNF-a)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, proliferation, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.

Many diseases are associated with abnormal cellular responses triggered by protein kinase- mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

Upon chemotherapy, due to their increased genomic mutation rate, cancer cells may become resistant against antiproliferative drugs because mutant forms of the drug target, e.g. a cell cycle kinase, which are unaffected by the drug have become prevalent in tumour tissue over the course of the therapy. For example, in some cases, resistance to Imatinib (also known as Gleevec, see blow) arises through one of two mechanisms, either overexpression of Bcr-Abl kinase as a result of gene amplification or, more frequently, selection of specific point mutations within the AbI kinase domain (Shah, N.P. et al. (2002) Cancer Cell 2:117-125). To date, over 30 point mutations have been identified which confer resistance to Imatinib either by directly disrupting the interaction between the protein and the inhibitor or by stabilising an open kinase conformation. This commonly results in constitutive enzyme activation and a protein conformation that lacks the key lipophilic pocket required for Imatinib binding (Weisberg, E. et al. (2005) Cancer Cell 7:129). One of the most common mutations is a threonine to isoleucine change at residue 315 (T315I), which accounts for 15-20% of the Bcr- Abl mutations. Transfection of the T3151 mutant in the 11-3 dependent BaF3 cell line promotes growth in the absence of the mitogen and renders the cells resistance to Imatinib (IC50 for viable cell count of >10μM vs. 0.6μM in cells transfected with wt Bcr- AbI) (Shah, N.P. et al. (2002) supra).

Inhibitors of the cell cycle kinases of the aurora kinase family and inhibitors of cell cycle kinases such as abl, v-abl, Bcr-abl, CHK2, JNKl al and JNK3 represent valuable tools for treating, ameliorating or preventing a hyperproliferative disease associated with increased activity of such a cell cycle kinase. In view of the problems arising from the presence of resistant kinase forms but also in view of patients that do not tolerate certain kinase inhibitors, it is desirable to develop new antiproliferative agents functioning as cell cycle kinase inhibitors, functioning by, for example, allosterically or non-allosterically binding and inhibiting a cell cycle kinase.

Summary of the invention

Reversine is a synthetic molecule that has been described to induce de-differentiation of C2C12, a murine myoblasts cell line, into multipotent progenitor cells which can be re- directed to differentiate in non muscle types under appropriate conditions (see, e.g. Shuibing Chen, et al. (2004) J. Am. Chem. Soc. 126:410-411).

The present invention is based on the surprising discovery that purine derivatives that are identical to or are structurally related to Reversine (Reversine may herein also be referred to as N6-cyclohexyl-N2-(4-morpholin-4-yl-phenyl)-9H-purine-2,6-diamine), are potent inhibitors of cell cycle kinases in a variety of cell lines. Reversine blocks at least one of the cell cycle kinases selected from the group consisting of Aurora A, Aurora B, Aurora C kinase, CHK2, JNKl αl, JNK3 and abl. Therefore, the present invention provides Reversine and structurally related compounds thereof as antiproliferative agents that can also be used for the preparation of a medicament for treating, ameliorating or preventing a disease associated with increased activity of a cell cycle kinase, such as, for example, Aurora A, Aurora B, Aurora C kinase, CHK2, JNKlαl, JNK3 and abl. Furthermore, the present invention discloses, that, surprisingly, said purine derivatives of the present invention may be combined with potent protein kinase inhibitors like Gleevec (see below) to reach a potentiated beneficial effect, since reversine or its structurally related forms appear to specifically and synergistically inhibit mutant kinases, preferably, abl kinase, that are less responsive to the treatment with Gleevec type protein kinase inhibitors alone. Therefore, the present invention provides, without limitation, the use of a compound according to formula (I) (see below) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, ameliorating or preventing a disease associated with increased activity of a cell cycle kinase. Furthermore, the present invention provides said use wherein the medicament further comprises one or more chemotherapeutic or antiproliferative agent. Furthermore, the present invention provides a pharmaceutical composition comprising a compound according to formula (I) (see below) and one or more chemotherapeutic or antiproliferative agent and optionally one or more excipients, buffers and/or auxiliary substances.

Detailed Description of the Invention

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H. G. W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

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

In the following definitions of the terms: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, 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.

Chemical Definitions

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, wo-butyl, tert-butyl, pentyl, hexyl, preferably 1,5- dimethyl-hexyl, heptyl, 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, wo-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. -0-CH₃, -S-CH₃, -CH₂-O-CH₃, -CH₂-O-C₂H₅, -CH₂-S-CH₃, -CH₂-S-C₂H₅, -C₂H₄-O-CH₃, -C₂H₄-O-C₂H₅, -C₂H₄-S-CH₃, - C₂H₄-S-C₂H₅ etc. Heteroalkyl groups are optionally substituted.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one cyclic ring is present such as in bicyclic, tricyclic and polycyclic versions, then these rings may also comprise one or more aryl- or heteroaryl ring. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include C₃-Ci₀-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl, decahydro- azulenyl, adamantly, or decahydro-naphthalenyl. Preferred examples of heterocycloalkyl include C₃-Cio-heterocycloalkyl, in particular l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, or 2-piperazinyl.

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. Accordingly, 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, wo-butyl, sec-butenyl, tert-butyl, 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, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl.

The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the 2- 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, wø-propyl, butyl, wo-butyl, sec-butenyl, 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, /so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, /sø-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. The term also comprises CH₂, i.e. methenyl, if the substituent is directly bonded via the double bond. Preferably the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl.

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.

The term "optionally substituted" in each instance, if not further specified refers to halogen, -NO₂, -CN, -OR'", -NR'R", -COOR'", -CONR'R", -NR'COR'", -NR'COR'", -NR'CONR'R", -NR⁵SO₂E, -COR'"; -SO₂NR'R", -OOCR'", -CR'"R""0H, R'"0H, and -E;

R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl;

R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";

E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted.

Cell Cycle Kinases

The Aurora family of serine/threonine kinases is essential for cell proliferation (Bischoff, J. R. & Plowman, G. D. (1999) Trends in Cell Biology 9:454-459; Giet, R. and Prigent, C. (1999) J. of Cell Science 112:3591-3601; Nigg, E. A. (2001) Nat. Rev. MoI. Cell Biol. 2:21-32; and Adams, R. R, et al. (2001) Trends in Cell Biology 11 :49-54).

Inhibitors of the Aurora kinase family, therefore, have the potential to block growth of all tumour types. The three known mammalian family members, Aurora-A ("Aurora 1 "), Aurora- B ("Aurora 2") and Aurora-C ("Aurora 3"), are highly homologous proteins responsible for chromosome segregation, mitotic spindle function and cytokinesis. Aurora expression is low or undetectable in resting cells, with expression and activity peaking during the G2 and mitotic phases in cycling cells. In mammalian cells proposed substrates for Aurora include histone H3, a protein involved in chromosome condensation, and CENP-A, myosin II regulatory light chain, protein phosphatase 1, TPX2, all of which are required for cell division.

Since its discovery in 1997 the mammalian Aurora kinase family has been closely linked to tumorigenesis. The most compelling evidence for this is that over- expression of Aurora- Atransforms rodent fibroblasts (Bischoff, J. R., et al. (1998) EMBO J. 17:3052-3065). Cells with elevated levels of this kinase contain multiple centrosomes and multipolar spindles, and rapidly become aneuploid. The oncogenic activity of Aurora kinases is likely to be linked to the generation of such genetic instability. Indeed, a correlation between amplification of the aurora-A locus and chromosomal instability in mammary and gastric tumours has been observed (Miyoshi, Y. , et al. (2001) Int. J. Cancer 92:370-373 and Sakakura, C. et al. (2001) British Journal of Cancer 84:824-831). The Aurora kinases have been reported to be over- expressed in a wide range of human tumours.

Elevated expression of Aurora-A has been detected in over 50% of colorectal (Bischoff, J. R., et al. (1998) supra; Takahashi, T., et al. (2000) Jpn.

J. Cancer Res. 91 :1007-1014), ovarian (Gritsko, T. M. et al. (2003) Clinical Cancer Res.

9:1420-1426), and gastric tumors (Sakakura, C. et al. (2001) British J. Cancer 84:824-831), and in 94% of invasive duct adenocarcinomas of the breast (Tanaka, T., et al., (1999) Cancer Res.. 59:2041-2044). High levels of Aurora-A have also been reported in renal, cervical, neuroblastoma, melanoma, lymphoma, pancreatic and prostate tumour cell lines. (Bischoff, J.

R., et al., (1998) supra; Kimura, M., et al. (1999) J. Biol. Chem. 274:7334-7340; Zhou et al.

(1998) Nature Genetics 20:189-193 and Li et al., (2003) Clin. Cancer Res. 9(3):991-7).

Amplification/overexpression of Aurora-A is observed in human bladder cancers and amplification of Aurora-A is associated with aneuploidy and aggressive clinical behaviour

(Sen S. et al. (2002) J. Nat. Cancer Inst. 94(17): 1320-9). Moreover, amplification of the aurora-A locus(20ql 3) correlates with poor prognosis for patients with node-negative breast cancer (Isola, J. J., et al. (1995) American J. Pathology 147:905-911).

Aurora-B is highly expressed in multiple human tumour cell lines, including leukemic cells (Katayama et al. (2000) Gene 244:1-7). Levels of this enzyme increase as a function of Duke's stage in primary colorectal cancers (Katayama, H. et al. (1999) J. Nat. Cancer Inst. 91 :1160-1162). Aurora-2 (also called Aurora-B or aurora kinase B herein) is also highly expressed in multiple human tumor cell lines and levels increase as a function of Duke's stage in primary colorectal cancers (Katayama, H. et al. (1999) J. Nat. Cancer Inst. 91 :1160-1162). Aurora-2 plays a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the Aurora-2 protein has been found to be over expressed (Bischoff et al. (1998), EMBO J. 1998 Jun l;17(l l):3052-65; Schumacher et al., (1998) J. Cell. Biol. 143:1635-1646; Kimura et al. (1997) J. Biol. Chem. 272:13766-13771). Aurora-2 is over-expressed in the majority of transformed cells. Bischoff et al found high levels of Aurora-2 in 96% of cell lines derived from lung, colon, renal, melanoma and breast tumors (Bischoff et al. (1998) supra). Two extensive studies show elevated Aurora-2 in 54% and 68% (Bischoff et al. (1998) supra and Takahashi et al. (2000) supra) of colorectal tumours and in 94% of invasive duct adenocarcinomas of the breast (Tanaka, et al. (1999) 59:2041- 2044).

Aurora-C, which is normally only found in germ cells, is also over-expressed in a high percentage of primary colorectal cancers and in a variety of tumour cell lines including cervical adenocarinoma and breast carcinoma cells (Kimura, M., et al. (1999) supra and Takahashi et al. (2000) supra). High levels of Aurora-3 (Aurora-C) have been detected in several tumour cell lines, although it is restricted to testis in normal tissues (Kimura et al. (1999) supra). Over-expression of Aurora-3 in a high percentage (c. 50%) of colorectal cancers has also been documented (Takahashi et al. (2000) supra). In contrast, the Aurora family is expressed at a low level in the majority of normal tissues, the exceptions being tissues with a high proportion of dividing cells such as the thymus and testis (Bischoff et al. (1998) supra).

In summary, elevated levels of all Aurora family members are observed in a wide variety of tumour cell lines. Aurora kinases are over-expressed in many human tumors and this is reported to be associated with chromosomal instability in mammary tumors (Miyoshi, Y. et al. (2001) Int. J. Cancer 92:370-373). The over-expression of Aurora kinases can also cause cells to rapidly develop an abnormal number of chromosomes.

For further review of the role Aurora kinases play in proliferative disorders, see Bischoff, J. R. & Plowman, G. D. (1999) supra; Giet, R. and Prigent, C. (1999) supra; Nigg, E. A. (2001) supra; Adams, R. R, et al. (2001) supra; and Dutertre, S. et al. (2002) Oncogene 21 :6175- 6183 (2002).

Based on the known function of the Aurora kinases, inhibition of their activity should disrupt mitosis leading to cell cycle arrest. In vivo, an Aurora inhibitor therefore slows tumor growth and induces regression. The inactivation of Chkl and Chk2 kinases abrogates the G2/M arrest which is induced by damaged DNA and sensitizes the resulting checkpoint deficient cells to the killing by DNA damaging events. As cancer cells are more sensitive towards the abrogation of the G2/M checkpoint than normal cells there is great interest in compounds, which inhibit Chkl, Chk2 or Chkl and Chk2, as a result abrogate the G2/M checkpoint and improve the killing of cancer cells by DNA damaging events.

"Jun N-terminal kinases" or "JNK's" are a family of protein kinases that represent the penultimate step in signal transduction pathways that result in activation of the c-jun transcription factor and expression of genes regulated by c-jun. JNKs, along with other mitogen-activated protein kinases, have been implicated in having a role in mediating cellular response to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic targets related to activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases. As a result of the importance of JNK activation associated with liver disease or episodes of hepatic ischemia, compounds of the invention may also be useful to treat various hepatic disorders. A role for JNK in cardiovascular disease such as myocardial infarction or congestive heart failure has also been reported as it has been shown JNK mediates hypertrophic responses to various forms of cardiac stress. It has been demonstrated that the JNK cascade also plays a role in T-cell activation, including activation of the IL-2 promoter. Thus, inhibitors of JNK may have therapeutic value in altering pathologic immune responses. A role for JNK activation in various cancers has also been established, suggesting the potential use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with HTLV-I mediated tumorigenesis [Oncogene 13:135-42 (1996)]. JNK may play a role in Kaposi's sarcoma (KS). Other proliferative effects of other cytokines implicated in KS proliferation, such as vascular endothelial growth factor (VEGF), IL-6 and TNFα, may also be mediated by JNK. In addition, regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, suggesting a role for JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) (see: Blood 92:2450-60 (1998)).

Abelson tyrosine kinase (i.e. AbI, c-Abl) is a non-receptor protein tyrosine kinase involved in the regulation of the cell cycle, in the cellular response to genotoxic stress, and in the transmission of information about the cellular environment through integrin signaling. Overall, it appears that the AbI protein serves a complex role as a cellular module that integrates signals from various extracellular and intracellular sources and that influences decisions in regard to cell cycle and apoptosis. Abelson tyrosine kinase includes sub-types derivatives such as the chimeric fusion (oncoprotein) BCR-AbI with deregulated tyrosine kinase activity or the v-Abl.

Reversine

The present invention is basd on the surprising observation that purine derivatives that are identical to or are structurally related to Reversine (Reversine may herein also be referred to as N6-cyclohexyl-N2-(4-moφholin-4-yl-phenyl)-9H-purine-2,6-diamine) are potent inhibitors of cell cycle kinases.

Accordingly, in a first aspect the present invention provides the use of a compound according to formula (I)

(I),

wherein R¹ is hydrogen, halogen, in particular F, Cl, Br or I; OR⁷, SR⁷, SO₂R⁷ or NR⁸R⁹;

R² is d-Cg-alkyl, preferably C₁, C₂, C₃, C₄, C₅, C₆ , C₇, C₈ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl, preferably not substituted with -OH; C₃-C₈cycloalkylCo-C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, Cg-cycloalkyl, C₃-C₈cycloalkylCialkyl, C₃- C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃-C₈cycloalkylC₄alkyl, C₃-

CgcycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; C₃-C₈heterocycloalkylC₀-C₆alkyl, preferably C₃-C₈heterocycloalkyl, i.e. e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈- heterocycloalkyl, Cs-Qheterocycloalkyldalkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃- C₈heterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; Cs-Cgalicyclic systemCo-C₆alkyl, e.g. C₃- Qalicyclic system, C₃-C₈alicyclic systemCj alkyl, C₃-C₈alicyclic systemC₂alkyl, C₃-C₈alicyclic systemCsalkyl, C₃-Cgalicyclic systemC₄alkyl, C₃-C₈alicyclic systemC₅alkyl, C₃-C₈alicyclic systemC₆alkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-C₀- C₆alkyl, e.g., aryl, ar-Cjalkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; and heteroar-Co-C_όalkyl, e.g. heteroaryl, heteroar-Cialkyl, heteroar- C₂alkyl, heteroar-Csalkyl, heteroar-C₄alkyl, heteroar-Csalkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional group selected from the group consisting of C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, Cn,

Ci₂, C₁₃ or Ci-rheterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl,

3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R³ to R⁶ are each individually selected form the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR¹⁰R¹¹, -OR¹², -COOR¹³, -CONR¹⁰R¹¹,

-NR¹⁰COR¹², -NR¹⁰COR¹², -NR¹⁰CONR¹⁰R¹¹, -NR¹⁰SO₂E, -COR¹²; -

SO₂NR¹⁰R¹¹, -OOCR¹³, -CR¹²R¹³OH, -R¹³OH, and -E;

R⁷ is selected from the group consisting of hydrogen, alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. C₁-, C₂-, C₃-, C₄-, C₅-, or C_ό-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, e.g. C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C_n, Cj₂, C₁₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl, 2-methylene- decahydro-naphthalenyl, or 2-methylene-decahydro-naphthalen-l-yl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C

₁₀, Cn, Ci₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; aralkyl, heteroaralkyl, and heteroaryl; in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; optionally substituted; R⁸ is hydrogen or alkyl, in particular Cj-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wø-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2- /so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; optionally substituted;

R is selected from the group consisting of hydrogen, C₅-C₈cycloalkenylC₀-C₆alkyl, e.g. C₅-C₈cycloalkenyl, C₅-C₈cycloalkenylCi alkyl, C₅-CgcycloalkenylC₂alkyl, , C₅-C₈cycloalkenylC₃alkyl, C₅-C₈cycloalkenylC₄alkyl, C₅-

CscycloalkenylCsalkyl, C₅-C₈cycloalkenylC₆alkyl; C₃-CgheterocycloalkylC₀- C₆alkyl, e.g., C₃-Cgheterocycloalkyl, C₃-C₈heterocycloalkylCialkyl, C₃-

C₈heterocycloalkylC₂alkyl, C₃-CgheterocycloalkylC₃alkyl, C₃-

C₈heterocycloalkylC₄alkyl, C₃-CgheterocycloalkylC₅alkyl, C₃-

CgheterocycloalkylCC_όalkyl; C₃-CgcycloalkylCo-C₆alkyl, e.g., C₃-Cgcycloalkyl, C₃-C₈cycloalkylCi alkyl, C₃-C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃- C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; ar-C₀-

C₆alkyl, , e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; heteroaryl and heteroar-C₂-C₆alkyl, e.g. heteroar-C₂alkyl, heteroar- C₃alkyl, heteroar-C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; wherein the heteroaryl is preferably selected from furanyl, thienyl, 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, benzofuranyl, in particular 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, in particular 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl; and

C₂-Ci₀alkyl, e.g. C₂, C₃, C₄, C₅, C₆, C₇, C_8, C_9, or Ci₀ -alkyl; optionally substituted; or R⁸ and R^y are taken together to form a heterocycloalkyl, e.g. C₃-C]₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, C₁₂, Ci₃ or CM-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza- spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; alicylic system, which may comprise one or more additional heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1 ,2-dihydropyridinyl, 1,2,5,6- tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl, 1,2,3,4- tetrahydropyrazyl; or heteroaryl, in particular, 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, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; optionally substituted;

R¹⁰ and R¹¹ are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C_ό-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, l-Zso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Ci₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or C_M- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Ci4-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cs, C₉, C ₁₀, C₁₁, C_J2, C₁₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Cj-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cii, Ci₂, Co or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-C₁4- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C_1O, Cn, Ci₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-C_H- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, C₁₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci -C^aIkOXy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, Cio, Cn, Ci₂, Co or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; A is N or CR⁴; B is N or CR⁵; D is N or CR⁶; and E is selected from the group consisting of alkyl, in particular C₁-C₆ alkyl, e.g. C₁,

C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, /ert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2- propenyl, l-iso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, C_n, C₁₂, Ci₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, in particular Cj-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-C_!-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Ci₀, Cn, Ci₂, Co or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or

4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyra2yl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, ameliorating or preventing a disease associated with increased activity of a cell cycle kinase. referred embodiment, R¹ is SO₂R⁷ or NR⁸R⁹; and/or

R⁸ is hydrogen or Ci-Cio-alkyl, and/or

R⁹ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, moφholinyl, tetrahydrofiiranyl, tetrahydrothienyl, and piperazinyl, optionally substituted; or C₂-Ci₀alkyl substituted with one or more substituents selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, and piperazinyl, optionally substituted.

In a preferred emodyment, R³ to R⁶ are each individually selected form the group consisting of hydrogen and -E.

In a preferred embodiment, R¹ is a functional group selected from one of the following:

(R¹⁴)n (R¹⁴)n (R¹⁴)n (R¹⁴)n

(R¹⁴)n

wherein

R > 8⁸ is hydrogen or C_M0 -alkyl, i.e. C₁, C_2> C₃, C₄, C₅, C₆, C₇, C_8, C_9, or C₁₀ -alkyl, optionally substituted; R¹⁴ is selected from the group consisting of halogen, in particular F, Cl, Br or I;

-NO₂, -CN, -NR¹⁶R¹⁷, -OR¹⁸, -COOR¹⁹, -CONR¹⁶R¹⁷, -NR¹⁶COR¹⁸, -NR¹⁶COR¹⁸, -NR¹⁰CONR¹⁶R¹', -NR¹⁶SO₂R¹*, -COR¹⁸; -SO₂NR¹⁶R¹', - 00CR¹⁹, -CR¹⁸R¹⁹OH, -R¹⁹OH, and -R¹⁹ is selected from the group consisting of hydrogen, -COOR¹⁹, C₃-C₈cycloalkylCo- C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈-cycloalkyl, C₃- CgcycloalkylCialkyl, C₃-C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃-

C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; C₃- C₈heterocycloalkylCo-C₆alkyl, C₃-C₈heterocycloalkyl, C₃-

CsheterocycloalkylCialkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-

C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃- C₈heterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemC₀-C₆alkyl, e.g. C₃- Qalicyclic system, C₃-C₈alicyclic systemCjalkyl, C₃-C₈alicyclic systemC₂alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemCsalkyl, C₃-C₈alicyclic systemC₆alkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-C₀- C₆alkyl, e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; and heteroar-C₀-C₆alkyl, e.g. heteroaryl, heteroar-Cjalkyl, heteroar-

C₂alkyl, heteroar-C₃alkyl, heteroar-Qalkyl, heteroar-Csalkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisiting of C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, Cn, Ci₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl,

2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R¹⁷ are each individually selected from the group consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /sø-butyl, tert-butyϊ, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-

Ci4-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C_n, C₁₂, Ci₃ or C_u- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Cj₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1 ,2,4-benzotriazinyl; aralkyl, preferably Cj-C₆ aralkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Cj-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /sO-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, C_J3 or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, C₁₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, Ci₃ or Ci-j-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; m is an integer from 1 to 3, i.e. 1, 2, or 3; n is an integer from 0 to 2, i.e. 0, 1, or 2 for three-membered rings, an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4 for five-membered rings and an integer from 0 to 5, i.e. 0, 1, 2, 3, 4, or 5 for six-membered rings; and * indicates the bond between R¹ and the compound of formula (I).

In a further preferred aspect of the invention, R¹⁵ is a functional group selected from one of the following:

wherein

* indicates the bond between the functional group and the nitrogen atom and the functional group is optionally substituted.

In another preferred embodiment, which may be combined with any of the above indicated embodiments and preferred embodiments, R² is a functional group selected from one of the following:

wherein

R- 20 is selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR²²R²³, -OR²⁴, -COOR²⁵, -CONR²²R²³, -NR²²COR²⁴,

-NR ,2^Z2^/COR 24 -NR²²CONR²²R²³, -NR²²SO₂R²⁵, -COR 24. -SO₂NR²²R²³,

OOCR²⁵, -CR²⁴R²⁵OH, -R²⁵OH, and -R²⁵

R 21 is selected from the group consisting of hydrogen, -COOR²⁵, -OR²⁵, C₃-

C₈cycloalkylC₀-C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈- cycloalkyl, C₃-C₈cycloalkylCjalkyl, C₃-C₈cycloalkylC₂alkyl, C₃- C₈cycloalkylC₃alkyl, C₃-C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃- C₈cycloalkylC₆alkyl; C₃-C₈heterocycloalkylCo-C₆alkyl, C₃-C₈heterocycloalkyl, C₃-C₈heterocycloalkylCialkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-

C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃-

CsheterocycloalkylCsalkyl, C₃-C₈heterocycloalkylCoalkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemCo-C_όalkyl, e.g. C₃- C₈alicyclic system, C₃-C₈alicyclic systemCjalkyl, C₃-C₈alicyclic systemC₂alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemC₅alkyl, C₃-C₈alicyclic systemCβalkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-Co- C₆alkyl, e.g., aryl, ar-Qalkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-Csalkyl, ar- C₆alkyl; and heteroar-C₀-C₆alkyl, e.g. heteroaryl, heteroar-Cjalkyl, heteroar- C₂alkyl, heteroar-C₃alkyl, heteroar-C₄alkyl, heteroar-Csalkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisiting of C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C₁₁, Ci₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R²³ are each individually selected from the group consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Cu-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C₁₁, C₁₂, C,₃ or Q₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, C₁], C]₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-

[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofliran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,

1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,

1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably C₁-C₆ aralkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, Ce, C₇, C₈, C₉, C _!o, C₁₁, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Cj-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl,

1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular C₁-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, iso-butoxy, tert-bvAoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl,

2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,

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

E and G are each individually selected from the group consisting of CH, CR²⁰, and N; L, M, Q and R are each individually selected from the group consisting of CH, CR²⁰, O, S and N, with the proviso that not more than two are O, S or N in monocycles;

T is selected from the group consisting of O, S, NH, NR²⁰, CHR²⁰, and CR²⁰R²⁰; o is an integer from O to 4, i.e. O, 1, 2, 3, or 4 for six membered rings an integer from 0 to 7, i.e. 0, 1, 2, 3, 4, 5, 6 or 7 for bicyclic nine membered rings and an integer from 0 to 8, i.e. 0, 1, 2, 3, 4, 5, 6, 7, or 8 for bicyclic ten-membered rings; p is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; q is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; and

* indicates the bond between R >2 and the compound according to formula (I).

In a preferred use of the invention, R²¹ is a functional group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 1,2,5,6-tetrahydropyrid-l-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, morpholin-3-yl, morpholin-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien- 2-yl, tetrahydrothien-3-yl, piperazin-1-yl, piperazin-2-yl, phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3- oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, and 1,2,4-benzotriazinyl; substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, , -NO₂, -CN, -NR²⁶R²⁷, -OR²⁸, -COOR²⁹, -CONR²⁶R²⁷, - NR²⁶COR²⁸, -NR²⁶COR²⁸, -NR²⁶CONR²⁶R²⁷, -NR²⁶SO₂R²⁹, -COR²⁸J -SO₂NR²⁶R²⁷, -OOCR²⁹, -CR²⁸R²⁹OH, -R²⁹OH, and -R²⁹, wherein

R²⁶ and R²⁷ are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1 -wo-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Ci₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Cn or C₁₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Cu or Cu-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzo furanyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably C₁-C₆ aralkyl, e.g. Cj, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-iso- propenyl, 2-zsø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃,

C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄,

C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-Cβ-alkoxy-Ci-Cό- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, C]₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1 ,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, l,2,3,4-tetrahydropyra2yl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C_ό-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /sø-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C _JO, Cn, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wø-butoxy, ter t-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C₁-C^aIkOXy-C₁-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,

C₁₀, C₁], Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyτazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted;

In especially preferred uses of the invention A, B, and D are N.

In a more preferred embodiment of the use of the invention, R¹ is a functional group selected from the group consisting of:

¹⁴)π (R¹⁴)n (R¹⁴)n

1⁴)n

and R is selected from the group consisting of:

wherein R⁸ is hydrogen or C_M0 -alkyl, i.e. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, or C₎₀ -alkyl, optionally substituted; most preferably R is hydrogen;

R¹⁴ is selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR¹⁶R¹⁷, -OR¹⁸, -COOR¹⁹, -CONR¹⁶R¹⁷, -NR¹⁶COR¹⁸, -NR¹⁶COR¹⁸, -NR¹⁶CONR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁹, -COR¹⁸; -SO₂NR¹⁶R¹⁷, - 0OCR¹⁹, -CR¹⁸R¹⁹OH, -R¹⁹OH, and -R¹⁹ R¹⁵ is selected from the group consisting of hydrogen, -COOR¹⁹, C₃-C₈cycloalkylC₀-

C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈-cycloalkyl, C₃- C₈cycloalkylCi alkyl, C₃-C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃- C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; C₃- C₈heterocycloalkylCo-C₆alkyl, C₃-C₈heterocycloalkyl, C₃- CsheterocycloalkylCi alkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-

C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃-

CgheterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemC₀-C₆alkyl, e.g. C₃-

Qalicyclic system, C₃-Cgalicyclic systemCi alkyl, C₃-C₈alicyclic systemC2alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemC₅alkyl, C₃-C₈alicyclic systemC₆alkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-C₀-

C_δalkyl, e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- Cβalkyl; and heteroar-Co-C₆alkyl, e.g. heteroaryl, heteroar-Cialkyl, heteroar- C₂alkyl, heteroar-C₃alkyl, heteroar-C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisiting of C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cu, C₁₂, Co or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl,

2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R¹⁷ are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1-wo-propenyl, 2-zso-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Cπ-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C_n, C,₂, C₁₃ or C₁₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Cj₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, C₁₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3 -diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-

[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,

1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably Ci-C₆ aralkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Cj₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wo-butoxy, ter/-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C]₀, Cn, Ci₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, /so-butyl, tørt-butyl, pentyl, hexyl; alkenyl, in particular Cj-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1 -/sø-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-C]₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, C₁₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /sø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-C_H- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, C₁₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl,

2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR²²R²³, -OR²⁴, -COOR²⁵, -CONR²²R²³, -NR²²COR²⁴, -NR²²COR²⁴, -NR²²CONR²²R", -NR^/ZSO₂R^, -C0R^Z4; -SO₂NR^Z2R^2J, - OOCR²⁵, -CR²⁴R²⁵OH, -R²⁵OH, and -R²⁵; is selected from the group consisting of hydrogen, -COOR²⁵, -OR²⁵, C₃- C₈cycloalkylC₀-C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈- cycloalkyl, C₃-C₈cycloalkylCialkyl, C₃-C₈cycloalkylC₂alkyl, C₃-

C₈cycloalkylC₃alkyl, C₃-C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃- C₈cycloalkylC₆alkyl; C₃-C₈heterocycloalkylCQ-C₆alkyl, C₃-C₈heterocycloalkyl, Cs-Csheterocycloalkyldalkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-

C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃- C₈heterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemC₀-C₆alkyl, e.g. C₃- C₈alicyclic system, C₃-C₈alicyclic systemQalkyl, C₃-C₈alicyclic systemC₂alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemC₅alkyl, C₃-Cgalicyclic systemC₆alkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-Co- C₆alkyl, e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; and heteroar-Co-C_δalkyl, e.g. heteroaryl, heteroar-dalkyl, heteroar-

C₂alkyl, heteroar-C₃alkyl, heteroar-C₄alkyl, heteroar-C₅alkyl, heteroar-C_όalkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisiting of C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, Cg, C io, Cn, C₁₂, Ci₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl,

2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R²³ are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /jo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-

Ci₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, C_n or Ci₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably C₁-C₆ aralkyl, e.g. Ci,

C₂, C₃, C₄, C₅, or C_δ-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Cu or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. Cj, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-C]-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Cj₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C _K), Cn, Cj₂, Ci₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular C₁-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular

alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxy ethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, Cio, Cn, C₁₂, Co or Ci₄-heterocycloalkyl, in particular piperidinyl, moφholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted;

E is selected from the group consisting of CH, CR²⁰, and N;

L, M, Q and R are each individually selected from the group consisting of CH, CR and N, with the proviso that not more than two are N;

T is selected from the group consisting of O, S, NH, NR²⁰, CHR²⁰, and CR²⁰R²⁰; m is an integer from 1 to 3, i.e. 1 , 2, or 3; n is an integer from 0 to 5, i.e. 0, 1, 2, 3, 4, or 5; most preferably n = 0; o is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4; most preferably o = 0; p is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; most preferably p = 0; q is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; most preferably q = 0; and * indicates the bond between R¹ and, respectively, R^z and the compound according to formula (I).

In a further preferred embodiment, the compound according to formula (I) has a structure according to structure (XVII):

(XVII)

wherein nl is an integer from 0 to 5, i.e. 0, 1 , 2, 3, 4 or 5; preferably nl = 1 ; n2 is an integer from 0 to 10, i.e. 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably n2 =0 and most preferably nl = 1 and n2 = 0;

R³⁰ is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso- butyl, tørt-butyl, pentyl, hexyl; heterocycloalkyl, -NO₂, -CN, -OR³⁴, -NR³⁴R³⁵,

-COOR³⁴, -CONR³⁴R³⁵, -NR³²COR³³, -NR³²COR³³, -NR³²CONR³⁴R³⁵, -COR³⁴, -

SO₂NR³⁴R³⁵, -OOCR³² and -CR³²R³³OH; most preferably, R³⁰ is heterocycloalkyl, e.g.

C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C₁₁, Ci₂, C_n or Ci₄- heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza- spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,11- 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, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro- quinazolinyl;

R³¹ is selected from the group consisting of halogen, in particular F, Cl₅ Br or I, alkyl, e.g.

C₁, C₂, C3, C₄, C₅, or C_ό-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; -NO₂, -CN, -OR³⁴, -NR³⁴R³⁵, -COOR³⁴, -CONR³⁴R³⁵, -

NR³²COR³³, -NR³²COR³³, -NR³²CONR³⁴R³⁵, -COR³⁴ _, -SO₂NR³⁴R³⁵, -OOCR³² and

-CR³²R³³OH;

R³² and R³³ is each independently selected from the group consisting of hydrogen, alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄,

C₅, or C_δ-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, C jo, Cn, Cj₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. Ci, C₂,

C₃, C₄, C₅, or C₆ -alkoxy, preferably methoxy, ethoxy, propoxy, wø-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, Cn, Ci₂, Q₃ or C₁₄- heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza- spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,11- dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro- quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3- benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; aralykl; and -NR³⁴R³⁵; optionally substituted; and

R³⁴ and R³⁵ is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl; optionally substituted.

In a further preferred embodiment, the compound according to formula (I) has a structure selected from a group consisting of structures (II) to (XVI):

(IV) (V)

(VI) (VII) (VIII)

(IX) (X) (XI)

(XII) (XIII) (XIV)

(XV) (XVI) optionally substituted.

In a most preferred embodiment, the compound according to formula (I) has a structure according to formula (VIII) as shown above.

In a further preferred use of the invention, the medicament further comprises a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof. Examples of such carriers are well known to the skilled person. Specific examples are provided below in the context of the pharmaceutical compositions of the present invention.

In another preferred use of the invention, the cell cycle kinase is selected from the group consisting of aurora kinase A, aurora kinase B, aurora kinase C, abl, CHK2, JNKlαl and JNK3. In a further embodiment of the use of the invention, the disease associated with increased cell cycle kinase activity is a hyperproliferative disease. This disease, when associated with increased aurora A kinase activity is preferably selected from the group consisting of laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, lung squamous cell carcinoma, adenocarcinoma, hormone-dependent breast cancer, hormone-independent breast cancer, ovarian cancer, testicular cancer, glioma, urothelial carcinomas, bladder cancer, endometrial carcinoma, colorectal cancer, pancreatic cancer, seminoma, leukemia, acute- myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis and gastrointestinal stromal tumor (GIST).

Most preferably, the cell cycle kinase in the use of the invention is aurora kinase B. When said hyperproliferative disease is associated with increased aurora B kinase activity, then said disease is preferably selected from a group consisting of colorectal cancer, laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, a lung cancer preferably lung squamous cell carcinoma or non-small cell lung carcinoma, adenocarcinoma, hormone- dependent breast cancer, hormone-independent breast cancer, ovarian cancer, testicular cancer, glioma, urothelial carcinomas, renal or bladder cancer, melanoma, endometrial carcinoma, pancreatic cancer, seminoma, leukemia, acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, gastrointestinal stromal tumor (GIST), a prostate cancer, a hepatocellular carcinoma and a thyroid carcinoma.

It has recently been shown that Aurora-B is overexpressed in various cancer cells and that although Aurora-B overexpression alone appears not to be oncogenic, it has been show that Aurora-B kinase activity augments Ras-mediated cell transformation (Akifumi Kanda, et. al. Oncogene (2005) 24, 7266-7272). Thus, in another aspect of the present invention, any compounds disclosed in the present invention as defined by any of the formulas (I) through (XVII) as defined above, which are potent Aurora kinase B inhibitors may be used to treat any form of cancer which is characterized in that the cancer cells overexpress aurora kinase B and ras protein. The overexpression of these proteins can be tested without undue burden using, for example, a Western blott assay and antibodies specific for Ras protein and Aurora B kinase which are available in the art. Aurora kinase B overexpression is especially strong in lung cancer, liver cancer, in a glioma, in prostate cancer and in thyroid carcinoma undifferentiated phenotype (see e.g., Barbara Vischioni, et. al, "Frequent overexpression of aurora B kinase, a novel drug target, in non- small cell lung carcinoma patients" , MoI Cancer Ther; 2006;5(l l); S. Tanaka et.al, "Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy", British Journal of Surgery 2008; 95: 611-619; Weifen F Zeng et. al, "Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme", J. Clin. Pathol. 2007;60;218-221; Paolo Chieffi et. al, "Aurora B expression Directly Correlates With Prostate Cancer Malignancy and Influence Prostate Cell Proliferation", The Prostate 66:326 -333 (2006); Rosanna Sorrentino et. al, "Aurora B Overexpression Associates with the Thyroid Carcinoma Undifferentiated Phenotype and Is Required for Thyroid Carcinoma Cell Proliferation", J Clin Endocrinol Metab, February 2005, 90(2):928-935; ). Furthermore, as mentioned already above, aurora kinase B is found in high levels in 96% of cancer cell lines derived from lung, colon, renal, melanoma and breast tumors (Bischoff et al. (1998) supra).

Thus, in a most preferred embodiment of the use of the invention, the disease associated with increased activity of a cell cycle kinase is selected from the group consisting of a lung cancer, preferably non-small cell lung carcinoma, hepatocellular carcinoma, a glioma, a prostate cancer, a colorectal cancer, a renal cancer, a melanoma, a breast cancer and a thyroid carcinoma, preferably a thyroid carcinoma undifferentiated phenotype.

When said hyperproliferative disease is associated with increased abl kinase activity then said disease is preferably selected from a group consisting of leukemia, in particular Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), leukemogenesis, lymphoma, ovarian carcinoma, laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, lung squamous cell carcinoma, adenocarcinoma, hormone-dependent breast cancer, hormone-independent breast cancer, testicular cancer, glioma, urothelial carcinomas, bladder cancer, endometrial carcinoma, colorectal cancer, pancreatic cancer, seminoma, leukemia, acute-myelogenous leukemia (AML), mastocytosis and gastrointestinal stromal tumor (GIST).

As will be clear to a person of skill, certain proliferative diseases comprise an increased activity of multiple kinases. Accordingly, the use of the invention can comprise inhibition of one or more cell cycle kinases and one or more diseases. It is further preferred that in the use of the invention the proliferative disorder is glomerulonephritis, rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disorder.

Gleevec

The compound 4-(4-Methylpiperazin- 1 -yl-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin- 2-yl-amino)phenyl]benzamide and its corresponding salts (also referred to as Gleevec or imatinib) (for synthesis, uses and pharmaceutical compositions thereof see also WO 99/03854 and EP 0 564 409) is a usefull anti-tumor agent.

AbI kinase, especially v-abl kinase, is inhibited by Gleevec and its corresponding salts. The inhibition of v-abl tyrosine kinase is determined by the methods of N. Lydon et al., Oncogene Research5 161-173 (1990) and J. F. Geissler etal., Cancer Research 52, 4492-8 (1992). In those methods [Val5]-angiotensinII and[γ-32P]-ATP are used as substrates.4-(4- Methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-yl- amino)phenyl]benzamide shows an IC50 of 38 nM.

Gleevec and its salts also inhibit BCR-abl kinase (see Nature Medicine2 561-566 (1996)) and is thus suitable for the treatment of BCR-abl-positive cancer and tumour diseases, such as leukaemias (especially chronic myeloid leukaemia and acute lymphoblastic leukaemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukaemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells).

In addition, Gleevec shows useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, especially tissue rejection, such as especially obliterative bronchiolitis (OB), i.e. a chronic rejection of allogenic lung transplants. In contrast to patients without OB, those with OB often show an elevated PDGF concentration in bronchoalveolar lavage fluids. If 4-(4-methylpiperazin-l -yimethyl)-N-[4- methyl-3-(4-pyridin-3- yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate, especially in thecrystal form, is administered to rats with tracheal allogenic transplants, for example in a dose of 50 mg/kg i.p., it can be shown after removal of 10 transplants per group after 10 and 30 days for morphometric analysis of possible epithelial lesions and occlusion of the airways, and investigation for immunohistochemical pathways of action that, although the methanesulfonic acid salt of Gleevec has no significant effect on epithelial necrosis or infiltration by inflammatory cells, it does markedly reduce fibroproliferation and occlusion of the lumen compared with controls. Synergistic effects with other immunomodulatory or antiinflammatory substances are possible, for example when used in combination with ciclosporin, rapamycin, or ascomycin, or immunosuppressant analogues thereof, for example ciclosporin A(CsA), ciclosporin G, FK-506, rapamycin, or comparable compounds; corticosteroids; cyclophosphamide; azathioprine; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualin; immunsuppressant antibodies, especially monoclonal antibodies for leucocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands; or other immunomodulatory compounds, such as CTLA41g. IfOsA (1 mg/kg s.c), for example, is combined with the acid addition salt of formulal(50 mg/kg), synergism may be observed.

The methanesulfonic acid addition salt of a Gleevec is also effective in diseases associated with vascular smooth-muscle cell migration and proliferation, such as restenosis and atherosclerosis. These effects and the consequences thereof for the proliferation or migration of vascular smoothmuscle cells in vitro and in vivo can be demonstrated by administration of the methanesulfonic acid addition salt of Gleevec and also by investigating its effect on the thickening of the vascular intima following mechanical injury in vivo.

Gleevec, as an inhibitor of the protein kinase AbI, works very well. However, its effectiveness is quickly impaired since under Gleevec therapy mutant forms of AbI kinase emerge rapidly that are resistant to Gleevec.

Surprisingly, compounds according to formula (I) also inhibit abl kinase (including, without limitation, v-abl and BCR-AbI kinase). Thus, reversine and its structurally related derivatives is not only a potent inhibitor of AbI but is an even better inhibitor of mutant forms of AbI kinases which are resistant to inhibition via Gleevec. The compositions of the present invention are, thus, suitable for the treatment of Bcr-abl-positive cancer and tumor diseases, such as leukemias, especially chronic myeloid leukemia and acute lymphoblastic leukaemia. Accordingly, the use of the present invention also includes the use of the cell cycle kinase inhibitor of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, ameliorating or preventing a disease associated with increased activity of a cell cycle kinase wherein the disease is or is in the process of becoming refractive to other kinase inhibitors.

Furthermore, the invention provides said use wherein the other kinase inhibitor is selected from the group consisting of Imatinib, Herceptin and Irressa.

In another preferred embodiment, the use of the invention comprises said use wherein the medicament further comprises one or more chemotherapeutic or antiproliferative agent selected from the group consisting of anti-tumor antibodies, imatinib, alkylating substances, anti-metabolites, antibiotics, epothilones, anti-androgens, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, 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, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or structurally related derivatives thereof.

Particularly preferred embodiments of the antiproliferative or chemotherapeutic agent are spindle poisons. The term "spindle poison" relates to compounds that modulate microtubule polymerization e.g. inhibits microtubule polymerization or depolymerization. Preferred spindle poisons comprise Taxanes (e.g Docetaxel, Paclitaxel), Vinca alkaloyds (e.g. Vinblastine, Vincristine, Vindesine, Vinorelbine), colchicine and nocodazole, or structurally related derivatives thereof.

Herein, in a preferred embodiment, the compound according to formula (I) and the one or more chemotherapeutic or antiproliferative agent are administered concomitantly or sequentially.

Another aspect of the invention is a pharmaceutical composition comprising a compound according to formula (I)

(I),

wherein

R¹ is hydrogen, halogen, in particular F, Cl, Br or I; OR⁷, SR⁷, SO₂R⁷ or NR⁸R⁹;

R² is d-Cs-alkyl, preferably C₁, C₂, C₃, C₄, C₅, C₆ , C₇, C₈ alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, ter/-butyl, pentyl, hexyl, preferably not substituted with -OH; C₃-C₈cycloalkylC₀-C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈-cycloalkyl, C₃-C₈cycloalkylCi alkyl, C₃-

C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃-C₈cycloalkylC₄alkyl, C₃- C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; C₃-C₈heterocycloalkylC₀-C₆alkyl, C₃-C₈heterocycloalkyl, C₃-C₈heterocycloalkylCialkyl, C₃-

C₈heterocycloalkylC2alkyl, C₃-C₈heterocycloalkylC₃alkyl, C₃-

C8heterocycloalkylC₄alkyl, C₃-C₈heterocycloalkylC₅alkyl, C₃- CsheterocycloalkylCβalkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemC₀-C₆alkyl, e.g. C₃-C₈alicyclic system, C₃-Cgalicyclic systemdalkyl, C₃-Cgalicyclic systemC₂alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃- C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemCsalkyl, C₃-C₈alicyclic systemCβalkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-C₀-C₆alkyl, e.g., aryl, ar-Cjalkyl, ar- C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar-C₆alkyl; and heteroar-C₀-C₆alkyl, e.g. heteroaryl, heteroar-dalkyl, heteroar-C₂alkyl, heteroar-C₃alkyl, heteroar-

C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional group selected from the group consisiting of C₃-Ci₄-heterocycloalkyl, e.g. C₃,

C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, C₁₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl;

R³ to R⁶ are each individually selected form the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR¹⁰R¹¹, -OR¹², -COOR¹³, -CONR¹⁰R¹¹, -NR¹⁰COR¹², -NR¹⁰COR¹², -NR¹⁰CONR¹⁰R¹¹, -NR¹⁰SO₂E, -COR¹²; - SO₂NR¹⁰R¹¹, -OOCR¹³, -CR¹²R¹³OH, -R¹³OH, and -E is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Cj-C₆ alkenyl, e.g. Ci-, C₂-, C₃-, C₄-, C₅-, or Cό-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular

C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, e.g. C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl, 2-methylene- decahydro-naphthalenyl, or 2-methylene-decahydro-naphthalen-l-yl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; aralkyl, heteroaralkyl, and heteroaryl; in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; optionally substituted;

R is hydrogen or alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2- wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; optionally substituted; R⁹ is selected from the group consisting of hydrogen, Cs-CgcycloalkenylCo-Qalkyl, e.g. C₅-C₈cycloalkenyl, Cs-CscycloalkenylCj alkyl, C₅-CgcycloalkenylC₂alkyl, , C₅-CgcycloalkenylC₃alkyl, , C₅-C₈cycloalkenylC₄alkyl, C₅- C₈cycloalkenylC₅alkyl, C₅-C₈cycloalkenylC₆alkyl; C₃-CgheterocycloalkylC₀-

C₆alkyl, e.g., C₃-C₈heterocycloalkyl, C₃-CgheterocycloalkylCi alkyl, C₃- C₈heterocycloalkylC₂alkyl, C₃-CgheterocycloalkylC₃alkyl, C₃-

CgheterocycloalkylC₄alkyl, C₃-CgheterocycloalkylC₅alkyl, C₃-

CgheterocycloalkylCC₆alkyl; C₃-CgcycloalkylCo-C₆alkyl, e.g., C₃-C₈cycloalkyl, CrCgcycloalkylCialkyl, C₃-C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃-

C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; ar-C₀- C₆alkyl, , e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; heteroar-C₂-C₆alkyl, e.g. heteroar-C₂alkyl, heteroar-C₃alkyl, heteroar- C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; heteroaryl, in particular furanyl, thienyl, 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, benzofuranyl, in particular 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, in particular 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; and C₂-Ci₀alkyl, e.g. C₂, C₃, C₄, C₅, C₆, C₇, C_8, C_9, or Ci₀ -alkyl; optionally substituted; or R⁸ and R⁹ are taken together to form a heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, Cg, C io, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza- spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- aza-7,1 l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro- quinoxalinyl, decahydro-quinazolinyl; alicylic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2-dihydropyridinyl, 1,2,5,6- tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1 ,2-dihydropyrazyl, 1,2,3,4- tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl, or heteroaryl, in particular, 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, indolyl, isoindolyl, IH- indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,

2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; optionally substituted;

R¹⁰ and R¹ ' are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1-wø-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Cw-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, C₁₃ or Ci₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-C]₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,

1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably Ci-C₆ aralkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Cj, C₂, C₃, C₄, C₅, or Cό-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Cj-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or Cβ-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃,

C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C9, C 1₀, Cn, C₁₂, C₁₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, Cio, Cn, Ci₂, Co or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,

1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C_ό-alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-buty\, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈,

C₉, C io, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, C_J2, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl,

1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; A is N or CR⁴; B is N or CR⁵;

D is N or CR⁶; and

E is selected from the group consisting of alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, zso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2- propenyl, 1-wø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, C_n, C₁₂, C_n or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.OJheptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /so-butoxy, ter/-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, C12, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; and furthermore one or more chemotherapeutic or antiproliferative agent and optionally one or more excipients, buffers and/or auxiliary substances. In a preferred embodiment of the composition of the invention,

R¹ is SO₂R⁷ or NR⁸R⁹; and/or

R⁸ is hydrogen or Ci-Qo-alkyl, and/or

R⁹ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, moφholinyl, tetrahydrofuranyl, tetrahydrothienyl, and piperazinyl, optionally substituted; or C₂-C₁₀alkyl substituted with one or more substituents selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, and piperazinyl, optionally substituted.

Especially preferred is the composition of the invention, wherein A, B, and D are N.

In a further preferred embodiment of the composition of the invention, R¹ is a functional group selected from the group consisting of: 1⁴)n (R¹⁴)π (R¹⁴)n (R¹⁴)π

and R² is selected from the group consisting of:

wherein

R⁸ is hydrogen or C_M0 -alkyl, i.e. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, or Ci₀ -alkyl, optionally substituted; most preferably R⁸ is hydrogen;

R¹⁴ is selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR¹⁶R¹⁷, -OR¹⁸, -COOR¹⁹, -CONR¹⁶R¹⁷, -NR¹⁶COR¹⁸, -NR¹⁶COR¹⁸, -NR¹⁶CONR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁹, -COR¹⁸; -SO₂NR¹⁶R¹⁷, - 0OCR¹⁹, -CR¹⁸R¹⁹OH, -R¹⁹OH, and -R¹⁹

R¹⁵ is selected from the group consisting of hydrogen, -COOR¹⁹, C₃-C₈cycloalkylCo- C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈-cycloalkyl, C₃- QcycloalkylCi alkyl, C₃-C₈cycloalkylC₂alkyl, C₃-C₈cycloalkylC₃alkyl, C₃- C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃-C₈cycloalkylC₆alkyl; C₃- C₈heterocycloalkylC₀-C₆alkyl, C₃-C₈heterocycloalkyl, C₃- CsheterocycloalkylCi alkyl, C₃-C8heterocycloalkylC₂alkyl, C₃-

CgheterocycloalkylCaalkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃-

C₈heterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemCo-C_όalkyl, e.g. C₃- C₈alicyclic system, Cs-Csalicyclic systemCialkyl, C₃-Cgalicyclic systemC₂alkyl, C₃-C₈alicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-Csalicyclic systemCsalkyl, C₃-C₈alicyclic systemCβalkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and

S, with the proviso that not more than two are O, S or N in monocycles; ar-C₀- Qalkyl, e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar- C₆alkyl; and heteroar-C₀-C₆alkyl, e.g. heteroaryl, heteroar-Cialkyl, heteroar- C₂alkyl, heteroar-C₃alkyl, heteroar-C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisting of C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C9, C ₁₀, Cn, C₁₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo [2.2.2] oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3 -yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R¹⁷ are each individually selected from the group consisting of hydrogen, alkyl, in particular Ci-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /50-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C_δ-alkynyl; cycloalkyl, in particular C₃- Ci₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, C₁₁, C₂, C₁₃ or C₁₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C₃-Ci₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C _to, Cn, C₁₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydroruran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,

1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably Ci-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; R^1S is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, /so-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃,

C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, C ₁₀, C₁₁, Cj₂, C₁₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-Cό- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, Ci₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl,

1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-buty\, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈,

C₉, C ₁₀, Cn, Ci₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wø-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl,

1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted;

R²⁰ is selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO₂, -CN, -NR²²R²³, -OR²⁴, -COOR²⁵, -CONR²²R²³, -NR²²COR²⁴,

-NR²²COR²⁴, -NR²²CONR²²R²³, -NR²²SO₂R²⁵, -COR²⁴; -SO₂NR²²R²³, - OOCR²⁵, -CR²⁴R²⁵OH, -R²⁵OH, and -R²⁵;

R²¹ is selected from the group consisting of hydrogen, -COOR²⁵, -OR²⁵, C₃- C₈cycloalkylCo-C₆alkyl, e.g, C₃-C₈cycloalkyl, e.g C₃-, C₄-, C₅-, C₆-, C₇-, C₈- cycloalkyl, C₃-C₈cycloalkyldalkyl, C₃-C₈cycloalkylC₂alkyl, C₃-

C₈cycloalkylC₃alkyl, C₃-C₈cycloalkylC₄alkyl, C₃-C₈cycloalkylC₅alkyl, C₃- C₈cycloalkylC₆alkyl; C₃-C₈heterocycloalkylCo-C₆alkyl, C₃-C₈heterocycloalkyl, C₃-C₈heterocycloalkylCialkyl, C₃-C₈heterocycloalkylC₂alkyl, C₃-

C₈heterocycloalkylC₃alkyl, C₃-C₈heterocycloalkylC₄alkyl, C₃- C₈heterocycloalkylC₅alkyl, C₃-C₈heterocycloalkylC₆alkyl, wherein each heterocycloalkyl individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles; C₃-C₈alicyclic systemC₀-C₆alkyl, e.g. C₃- C₈alicyclic system, C₃-C₈alicyclic systemCjalkyl, C₃-C₈alicyclic systemC2alkyl, C3-Cgalicyclic systemC₃alkyl, C₃-C₈alicyclic systemC₄alkyl, C₃-C₈alicyclic systemC₅alkyl, C₃-C8alicyclic systemCβalkyl wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, with the proviso that not more than two are O, S or N in monocycles; ar-Co- C₆alkyl, e.g., aryl, ar-Cialkyl, ar-C₂alkyl, ar-C₃alkyl, ar-C₄alkyl, ar-C₅alkyl, ar-

C₆alkyl; and heteroar-Co-Cδalkyl, e.g. heteroaryl, heteroar-Ci alkyl, heteroar- C₂alkyl, heteroar-C₃alkyl, heteroar-C₄alkyl, heteroar-C₅alkyl, heteroar-C₆alkyl, wherein each heteroaryl group individually preferably contains 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, with the proviso that not more than two are O, S or N in monocycles ; optionally substituted; and preferably substituted with a functional groups selected from the group consisiting of C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C io, C₁₁, Ci₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3- diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro-quinazolinyl; R²³ are each individually selected from the group consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, iso-pτopyl, butyl, /sø-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1- propenyl, 2-propenyl, 1 -/sø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3- butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃- Ci₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, Ci₂, Q₃ or Ci₄- cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; heterocycloalkyl, e.g. C3-Ci4-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, C₁₂, C₁₃ or Cπ-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro- [4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza- spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo- spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-aralkyl; an alicyclic system, preferably 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and heteroaralkyl, preferably 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl; all optionally substituted; is selected from the group consisting of hydrogen, alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /_?ø-propyl, butyl, wo-butyl, tert- butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C₆-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-ιsO-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆-alkynyl; cycloalkyl, in particular C₃-C₁₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C 1₀, Cn, C₁₂, Cu or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, /so-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Cio, Cn, Ci₂, Ci₃ or Ci₄-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; is selected from the group consisting of alkyl, e.g. Ci, C₂, C₃, C₄, C₅, or C_δ-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, /so-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C_ό-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ - alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C ₁₀, Cn, C₁₂, Co or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro- pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro- naphthalenyl; alkoxy, , in particular CpC₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ - alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, /sø-butoxy, ter/-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C₆-alkoxy-Ci-C₆- alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C9, Ci₀, Cn, Ci₂, Ci₃ or Cu-heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2- dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,

1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkylaryl, and alkylheteroaryl; optionally substituted; E is selected from the group consisting of CH, CR²⁰, and N; L, M, Q and R are each individually selected from the group consisting of CH, CR²⁰ and

N, with the proviso that not more than two are N; T is selected from the group consisting of O, S, NH, NR²⁰, CHR²⁰, and CR²⁰R²⁰; m is an integer from 1 to 3, i.e. 1, 2, or 3; n is an integer from 0 to 5, i.e. 0, 1, 2, 3, 4, or 5; most preferably n = 0; o is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4; most preferably o = 0; p is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; most preferably p = 0; q is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; most preferably q = 0; and

* indicates the bond between R¹ and, respectively, R² and the compound according to formula (I).

In a preferred embodiment, the the compound according to formula (I) of the composition of the invention has a structure according to formula XVIII:

(XVIII)

wherein nl is an integer from 0 to 5; preferably nl = 1 ; n2 is an integer from 0 to 10; preferably n2 =0 and most preferably nl = 1 and n2 = 0;

R³⁶ is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, e.g.

C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; heterocycloalkyl, -NO₂, -CN, -OR³⁴, -NR³⁴R³⁵, -COOR³⁴, -CONR³⁴R³⁵, -NR³²COR³³, -NR³²COR³³, -NR³²CONR³⁴R³⁵, -COR³⁴ _, -

SO₂NR³⁴R³⁵, -OOCR³² and -CR³²R³³OH; most preferably, R³⁶ is heterocycloalkyl, e.g.

C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C i₀, C₁₁, Ci₂, Ci₃ or C₁₄- heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza- spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,11- 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, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, or decahydro- quinazolinyl;

R³⁷ is selected from the group consisting of halogen, in particular F, Cl, Br or I, alkyl, e.g.

C₁, C₂, C₃, C4, C₅, or Cδ-alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; -NO₂, -CN, -OR³⁴, -NR³⁴R³⁵, -COOR³⁴, -CONR³⁴R³⁵, - NR³²COR³³, -NR³²COR³³, -NR³²CONR³⁴R³⁵, -COR³⁴ _, -SO₂NR³⁴R³⁵, -OOCR³² and

-CR³²R³³OH; R³³ is each independently selected from the group consisting of hydrogen, alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆-alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso- butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular Ci-C₆ alkenyl, e.g. Ci, C₂, C₃, C₄, C₅, or C_ό-alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl, \-iso- propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C_δ-alkynyl; cycloalkyl, in particular C₃-Ci₄- cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, Cg, C₉, C ₁₀, Cn, C₁₂, Ci₃ or Ci₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 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[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, in particular Ci-C₆ alkoxy, e.g. Ci, C₂, C₃, C₄, C₅, or C₆ -alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, iso-butoxy, ter/-butoxy, pentoxy, or hexoxy; heterocycloalkyl, e.g. C₃-Ci₄- heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, Ci₀, Cn, C_]2, Ci₃ or Ci₄- heterocycloalkyl, in particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza- spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza- spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, l-aza-7,11- dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl, decahydro- quinazolinyl; an alicyclic system, which may comprise one or more heteroatoms, e.g.

1, 2, 3, or 4, preferably selected from the group consisting of N, S, or O; in particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl, 1,2- dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3- benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; aralykl; and -NR³⁴R³⁵; optionally substituted; and

In a further preferred embodiment, the compound according to formula (I) of the composition of the invention has a structure selected from a group consisting of structures (II) to (XVI):

(H) (III)

(IV) (V)

(VI) (VII) (VIII)

(IX) W (XI)

(XII) (XIII) (XIV)

(XV) (XVI) optionally substituted.

In a most preferred embodiment, the compound according to formula (I) of the composition of the invention has a structure according to formula (VIII) as shown above.

In another preferred embodyment, of this composition, the one or more chemotherapeutic or antiproliferative agent is preferably selected from the group consisting of anti-tumor antibodies, imatinib, the methanesulfonic acid salt of imatinib, alkylating substances, antimetabolites, antibiotics, epothilones, anti-androgens, anti-estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, 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, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or structurally related derivatives thereof.

The examples of this specification show that reversine is also a surprisingly potent inhibitor of the spindle assembly checkpoint (S AC). Thus, the administration of reversine together with a spindle poison such as taxol or nocodazole, for example, leads to mitotic exit in the presence of spindle poisons, with resulting chromosome imbalances and cell death. Geert J. P. L. Kops et al. showed that inhibition of the mitotic checkpoint is invariably lethal to human cancer cells (PNAS, June 8, 2004, vol. 101, no. 23, p. 8699-8704). Thus, in the composition according to the invention, the one or more chemotherapeutic or antiproliferative agent is most preferably an agent which modulates microtubule polymerization such as a taxane (e.g. Docetaxel, Paclitaxel), a vinca alkaloyd (e.g. Vinblastine, Vincristine, Vindesine, Vinorelbine), colchicine, nocodazole, or structurally related derivatives thereof.

Agents which modulate microtubule polymerization can be used as chemotherapeutic substances. However, their cytotoxic effect can be slowed when these compounds activate the spindle assembly checkpoint in cancer cells. It is an unexpected finding that an Aurora kinase B inhibitor such as reversine can deactivate this safety checkpoint, leading to a more rapid cell death of cancer cells. The synergy between Aurora kinase B inhibitors such as reversine and an agent which modulates microtubule polymerization is, thus, surprising.

Therefore, another aspect of the invention is a pharmaceutical composition comprising: (i) an inhibitor, capable of specifically reducing the activity of Aurora kinase B by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or by at least 100% when compared with the activity said kinase has in the absence of said inhibitor;

(ii) an agent which modulates microtubule polymerization, such as a taxane, a vinca alkaloid, colchicine, nocodazole, or a structurally related derivative thereof; and, optionally, (iii) one or more excipients, buffers and/or auxiliary substances.

An advantage of said composition is that said specific Aurora kinase B inhibitor together with an agent which modulates microtubule polymerization provides a composition which has less side-effects.

A 100% reduction of Aurora kinase B means a complete inhibition, i.e. that the kinase is unable to phosphorylate any of its substrate/target molecules such as histone H3. A skilled person can apply routine methods to measure the activity of aurora kinase B. For example, the skilled person can perform, without undue burden, the methods described in example 10 and/or 12 (see also Fig. 7B) to measure the activity of aurora kinase B and, thus, also its inhibiton.

The phrase "capable of specifically reducing the activity of Aurora kinase B" means that said specific Aurora kinase B inhibitor specifically inhibits Aurora kinase B with an ICs₀ which is at least 2, 3, 4, 5, 10, 20, 30, 40, 50 or at least 60-fold, preferably at least 50-fold lower than an IC_5O obtained when measuring the inhibition of other Aurora kinases such as, for example, Aurora kinase A and/or C using said inhibitor. IC₅₀ represents the concentration of an inhibitor compound that is required for 50% inhibition in vitro.

The phrase "cell cycle kinase" as used herein refers to a kinase able to phosphorylate other proteins under consumption of ATP, and is thereby involved in the regulation of the cell cycle, e.g. formation of the nuclear envelope, exit from the quiescent phase of the cell cycle (G₀), Gi progression, chromosome decondensation, nuclear envelope breakdown, START, initiation of DNA replication, progression of DNA replication, termination of DNA replication, centrosome duplication, G₂ progression, activation of mitotic or meiotic functions, chromosome condensation, centrosome separation, microtubule nucleation, spindle formation and function, interactions with microtubule motor proteins, chromatid separation and segregation, inactivation of mitotic functions, formation of contractile ring, and cytokinesis functions, examples of such kinases include CDKs, aurora kinase A, aurora kinase B, aurora kinase C, abl, CHK2, JNKlαl and JNK3. The cell cycle kinases refered to herein also include all allelic and mutant forms of such kinases as they may appear in e.g. proliferative disorders such as cancer cells. In this context, "mutant forms of " means having a single or multiple amino acid changes compared to the wild-type amino acid sequence. With respect to mutant forms of the BCR-AbI kinase, over 22 mutations have been reported to date with the most common being G250E, E255V, T315I, F317L and M351T. A preferred cell cycle kinase target inhibited with a compound of the present invention leads to an anti- proliferative effect.

The "chemotherapeutic or antiproliferative agent" usable in the present invention have an antiproliferative effect. The term "antiproliferative effect" as used in this context is preferably demonstrated by the ability to inhibit cell proliferation in an in vitro whole cell assay, for example using a tumor cell line, preferably any of the cell lines A549, HeLa, HT- 29, MCF7, Saos-2, CCRF-CEM, HL-60 and K-562, C2C12, N TERA-2 (NT2), HTl 16, or by showing kinase inhibition, preferably cell cycle kinase inhibition, in an appropriate assay. Such assays are well known in the art and include those described in more detail in the accompanying examples. Using such assays it may be determined whether a compound is antiproliferative within the meaning of the present invention.

One preferred embodiment of the present invention therefore relates to the use of one or more compounds of the invention according to formula (I) and in the preparation of a medicament for treating a proliferative disorder.

The compositions of the invention may inhibit, without limitation, any of the steps or stages in the cell cycle, for example, formation of the nuclear envelope, exit from the quiescent phase of the cell cycle (G₀), Gi progression, chromosome decondensation, nuclear envelope breakdown, START, initiation of DNA replication, progression of DNA replication, termination of DNA replication, centrosome duplication, G₂ progression, activation of mitotic or meiotic functions, chromosome condensation, centrosome separation, microtubule nucleation, spindle formation and function, interactions with microtubule motor proteins, chromatid separation and segregation, inactivation of mitotic functions, formation of contractile ring, and cytokinesis functions. In particular, the compounds of the invention may influence certain gene functions such as chromatin binding, formation of replication complexes, replication licensing, phosphorylation or other secondary modification activity, proteolytic degradation, microtubule binding, actin binding, septin binding, microtubule organising centre nucleation activity and binding to components of cell cycle signalling pathways.

The term "proliferative disorder" is used herein in a broad sense to comprise any disorder that requires control of the cell cycle, for example cardiovascular disorders such as restenosis and cardiomyopathy, autoimmune disorders such as glomerulonephritis and rheumatoid arthritis, dermatological disorders such as psoriasis, anti-inflammatory, antifungal, antiparasitic disorders such as malaria, emphysema and alopecia. In these disorders, the compounds of the present invention may induce apoptosis or maintain stasis, i.e. prevent cell division within the desired cells as required. Preferably, the proliferative disorder is a cancer or leukaemia.

As used herein the phrase "preparation of a medicament" includes the use of a compound of the invention directly or in form of a composition as the medicament in addition to its use in a screening programme for further therapeutic agents or in any stage of the manufacture of such a medicament.

The term "Aurora" refers to any isoform or ortholog of the Aurora family of protein kinases, including Aurora- 1, Aurora-2, and Aurora-3. The term "Aurora" also refers to isoforms or orthologs of the Aurora family of protein kinases known as Aurora- A, Aurora-B, and Aurora- C, in particular human Aurora-A, Aurora-B, and Aurora-C kinase.

Within the meaning of this invention, a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

Pharmaceutical compositions

Any composition of the present invention may be admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof. Even though the compounds of the present invention (including their pharmaceutically acceptable salts, esters and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy. The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the

"Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), Edited by A Wade and PJ Weller.

Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985). Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

Salts / esters

The compounds within the compositions or compounds according to formula (I) usable according to the present invention can be present as salts or esters, in particular pharmaceutically acceptable salts or esters. Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. sulphuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Cl-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.

Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as

(Cl-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).

Enantiomers / tautomers

In all aspects of the present invention previously discussed, the compounds within the compositions or compounds according to formula (I) usable according to the present invention may, where appropriate include all enantiomers and tautomers of compounds of formula (I). The man skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.

Stereo and geometric isomers

Some of the compounds within the compositions or compounds according to formula (I) usable according to the present invention may exist as stereoisomers and/or geometric isomers - e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms. The present invention contemplates the use of all the individual stereoisomers and geometric isomers of those inhibitor agents, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).

The present invention also includes all suitable isotopic variations of the agent or a pharmaceutically acceptable salt thereof. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ³H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

Solvates The present invention also includes solvate forms of the compounds within the compositions or compounds according to formula (I) usable according to the present invention. The terms used in the claims encompass these forms.

Polymorphs The invention furthermore relates to compounds within the compositions of the present invention or compounds according to formula (I) usable according to the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds. Prodrugs

The invention further includes compounds within the compositions of the present invention or compounds according to formula (I) usable according to the present invention in prodrug form. Such prodrugs are generally compounds of formula 1 wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out be an esterase etc. Other such systems will be well known to those skilled in the art.

Administration The pharmaceutical compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration. For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops, and capsules. Preferably, these compositions contain from 1 mg to 1 g and more preferably from 10-500 mg, of active ingredient per dose.

Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions. The pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders. An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required. Injectable forms may contain between 10 - 1,000 mg, preferably between 10 - 250 mg, of active ingredient per dose. Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose. Dosage

A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. Depending upon the need, the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight. In an exemplary embodiment, one or more doses of 10 to 150 mg/day will be administered to the patient for the treatment of malignancy.

For in vivo administration of a composition comprising Gleevec, Gleevec and Reversine, or structurally related compound or salts thereof, are dissolved, for example, in DMSO at a concentration of 200 mg/ml and then diluted 1:20 with 1% Tween in 0.9 % saline solution. After sonication, a clear solution is obtained. The stock solutions are prepared fresh each day before administration. The mixture of Gleevec and Reversine, or structurally related compound of Reversine may also be dissolved simply in deionised water for oral administration or in 0.9% saline solution for parenteral administration. Administration is carried out 24 hours before the operation. Administration can occur, for exmaple, orally or via i.p. Preferably, the dose comprises 50 mg/kg of Gleevec i.p. per day for the entire observation period.

Therapeutic use

The compositions of the present invention have been found to possess antiproliferative activity and are therefore suitable in the treatment of proliferative disorders, such as cancers, leukaemias or other disorders associated with uncontrolled cellular proliferation such as, for example, psoriasis and restenosis as set out in more detail above. Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

The following figures and examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.

Brief Description of the Figures

Fig. 1 Effect of reversine on differentiation. (A, B) Microscopy image of C2C12 cells after 4 day treatment with DMSO (control) and 4 day treatment with 5 μM reversine.

Compared to control cells, reversine treated cells showed an evident change of morphology. (C) Taqman analysis of Myo D mRNA in C2C12 cells demonstrated that the expression of this muscle specific gene decreased after 24 h, 48 h, and 72 h of reversine treatment. MyoD mRNA levels were normalized to 18S mRNA levels. (D) Taqman analysis of reelin mRNA in NT2 cells treated with reversine 1 μM and 5 μM for 24 h, 48 h and 72 h showed that reelin mRNA levels increased in particular after

72 h of treatment. Reelin expression was normalized to GAPDH gene.

Fig. 2 Reversine causes polyploidy in C2C12 cells. (A) C2C12 cells were treated with 5 μM reversine for 24 h and 48h, harvested at these time points and analyzed by flow cytometry to determine DNA content. Reversine treatment induced accumulation of cells with DNA = 4N and DNA >4N.

Fig. 3 Reversine induces accumulation of cells with = 4N DNA. (A) HCT-116 cells were treated with 5 μM reversine for 12 h, 24 h, 48 h and 72 h. DNA content was assessed by flow cytometry analysis of cells labeled with propidium iodide. FACS analysis revealed that reversine produced a tetraploid population. (B) BrdU labeling: HCT-116 cells treated with 5 μM reversine for 12 h progressed into S phase for two consecutive cell cycles. BrdU was added at 10 μM concentration for 1 h, after 12 h of DMSO (control) and reversine treatment. (C) Western blot analysis of cyclin Bl showed that expression peaked and subsequently decreased in both reversine treated and control cells, indicating that the exit from mitosis was not blocked.

Fig. 4 Reversine inhibits Histone H3 phosphorylation on SerlO. (A) HCT-116 cells were treated with 5 μM reversine and 300 nM VX-680 for 12 h (top) and 24 h (bottom). Histone H3 phosphorylation on SerlO (white dots) was assessed by immunocytochemisty. Total population was visualized by DAPI staining (not shown). Both reversine and VX-680 resulted in significantly less Histone H3 phosphorylation on SerlO after 12h and after 24h. (B) Western blot analysis of serl0P-H3 at different time points of reversine treatment. Actin was used as loading control.

Fig. 5 Reversine is a potent inhibitor of colony formation using samples from acute- myelogenous leukemia (AML) patients. Clonogenic survival of samples from 4 different patients was assessed after 15 days of continuous exposure to reversine.

Squares : treated with Reversine; Circles: treated with a bona fide aurora kinase inhibitor VX680. Results are expressed in percentage of colonies formed in Reversine or VX-680-treated cells relative to control culture. Figure 5 shows that, surprisingly, in patient 5705 and patient 5482, reversine was a stronger inhibitor of colony formation than VX-680.

Fig.6-9 These figures show that Reversine is also an efficient Aurora B inhibitor which can abrogate the spindle checkpoint response in various human cancer cells and, thus, proves to be an efficient anti-neoplastic agent which becomes even more potent when combined with spindle toxins such as taxol or nocodazole or STLC, for example (see examples for details).

Examples

Example 1: Effect of reversine on cellular differentiation Mouse C2C12 myoblasts represent a model cell line which differentiates into characteristic multinucleated myotubes upon serum withdrawal. In order to confirm the data of Chen et al, C2C12 cells were grown for 4 days with 5 μM reversine in growth medium as described previously (Chen et al, 2004) while control cells were treated in the same volume of DMSO in which reversine was dissolved. Striking differences were observed between the untreated (Figure IA) and the reversine-treated cells (Figure IB) the latter of which appeared larger, flatter and more adhesive to cultured plate. No myotubes were observed after reversine treatment and expression levels of a muscle specific gene MyoD, decreased after 24, 48, and 72 h of treatment (Figure 1C) indicating a profound change in the process of myogenesis. Reversine has effect on the differentiation of other non muscle cell lines, for instance on the human embryonal carcinoma cell line N TERA-2 (NT2). NT2 cells treated with reversine showed elevated level of reelin, a neuronal marker selectively expressed in GABAergic neurons (Veldic et al, 2004), as assessed by Taqman analysis after treatment with 1 μM and 5 μM reversine for 24, 48 and 72 h. After 3 days of 1 or 5 μM reversine treatment reelin mRNA levels had significantly increased (Figure ID).

These results indicate that reversine influences cell fate in a cell-type specific manner further promoting the differentiation process in NT2 cells or inducing the opposite effect in C2C12 cells thus leading to a less differentiated phenotype.

Example 2: Reversine induces accumulation of cells with 4N and > 4N DNA

Cell cycle analysis by flow cytofluorimetry indicated that murine myoblasts C2C12 treated with reversine 5 μM for 24 h and 48 h were blocked in cell cycle progression (Figure 2A). Furthermore, flow cytofluorimetry of treated C2C12 cells showed reversine also induced accumulation of cells with = 4N DNA content, possibly as a consequence of aborted cytokinesis. However the generation of cells with > 4N content after treatment with reversine could have occurred either as a consequence of multiple rounds of DNA replication during S phase prior to mitosis or as a consequence of failure to undergo cytokinesis. To analyze how reversine causes polyploidy, we filmed HeLa cells expressing a GFP-tagged version of H2B in presence of 5 μM reversine. It was also observed that Reversine-treated cells condensed their chromosome entering in mitosis. The cells then exited mitosis but without separation in two daughter cells.

Reversine treatment perturbed the cell cycle of NT2 cell line (data not shown) and of the human colon cancer cell line HCTl 16. After treatment with 5 μM reversine for 12 h, 24 h, 48 h and 72 h, DNA content of HCTl 16 was assessed by flow cytometric analysis of cells labeled with propidium iodide. After 12 h of treatment, the vast majority (about 80%) of cells showed 4N DNA. Prolonged reversine treatment of HCTl 16 cells revealed endo- reduplication, accumulating a DNA content greater than 4N (Figure 3A). These results again suggest reversine acting through inhibition of cell division. Accumulation of multiple copies of DNA was also demonstrated by the incorporation of the thymidine analogue 5-bromo-2- deoxyuridine (BrdU) during two consecutive cell cycles in cells treated with 5 μM reversine for 12 h (Figure 3B), a phenomenon associated with aberrant mitosis subsequently leading to cell division failure. The effect of reversine on cell cycle progression was studied also by monitoring levels of cyclin Bl, which peaks during mitosis. Reversine treatment induced high levels of cyclin Bl 4 h after release from the Gl /S block, suggesting that cells were still able to commence mitosis (Figure 3C). Cyclin Bl expression subsequently decreased both in reversine treated and in control cells indicating that the compound does not block exit from mitosis. Therefore it appears that in cells treated with reversine, polyploidy is a consequence of impaired cytokinesis.

Example 3: Reversine inhibits protein kinases such as cell cycle kinases, including Aurora A, CHK2, JNKl αl, JNK3, abl kinase and abl-T315I mutant. Having identified cell cycle and cytokinesis as a major target of reversine action and in the light of the structure of reversine that shows common elements to know kinase inhibitors (Ding et al, 2002), we tested the effect of reversine on the activity of 30 kinases. The activity of Aurora kinases and c-Jun- N terminal kinases (JNKs) resulted > 90% inhibited at concentrations of reversine that have substantial biological effect on the cell cycle (data not shown) and de-differentiation (see next Results). In particular, as shown in Table I, Aurora A activity was inhibited by 80% already at a concentration of 0.5 μM and further reduced to 88%, 92% and 99% at 1 μM, 2.5 μM and 5 μM of reversine, respectively. Also Aurora B kinase was inhibited to a similar extent. Consistent with the role of Aurora kinases in cell cycle progression (Andrews et al, 2003; Nigg, 2001), chromosome segregation (Adams et al, 2001; Meraldi et al, 2004) and cytokinesis (Keen and Taylor, 2004), the molecular mechanism of reversine on arrest of cell cycle progression therefore could be induced by the inhibition Aurora kinases. Interestingly, several other studies have shown that common potent inhibitors of Aurora kinases also have an effect on cell cycle thus resembling the effect observed here by reversine (Harrington et al, 2004; Ditchfield et al, 2003). Reversine proved also to be a potent inhibitor of the abl kinase. Surprisingly, Reversine inhibits the mutant form abl-T315I of the Abl kinase even more strongly than the wild-type form (see table I). This mutant form of abl kianse has been shown to confer resistance to other therapeutic kinase inhibitor medicamtents such as Imatinib. This shows that Reversine or structurally related components can be administered in combination with other chemotherapeutic or anti- proliferative compounds to complement the treatment of diseases associated with increased activity of a cell cycle kinase.

Table I

Table I shows the activity (expressed as %) of a panel of protein kinases tested with an in vitro assay using 0.5 μM, lμM, 2.5 μM and 5μM of reversine.

Example 4: Reversine inhibits Histone H3 phosphorylation

To provide further evidence that reversine is an inhibitor of Aurora kinases A and B in vivo, we examined its effect on downstream signaling on cultured HCTl 16 cells. Among the large number of Aurora A and Aurora B kinases substrates identified, Histone H3 is the best characterized, a protein involved in chromosome condensation and mitotic entry (Wei et al, 1999). Phosphorylation of the highly conserved SerlO of H3 is crucial for entry into mitosis (Dong and Bode, 2006). After treating HCTl 16 cells with reversine 5 μM for 12 h and 24 h, we assessed Histone H3 phosphorylation by immunocytochemistry. Figure 4A shows that after 12 h of treatment H3 phosphorylation at SerlO was significantly reduced and totally disappeared after 24 h of treatment. As a positive control, HCTl 16 cells were treated with 300 nM of VX-680. As for immunocytochemistry, western blot analysis on HCTl 16 protein extracts revealed a marked reduction of serl0PH3 protein expression (Figure 4B) after only 4 h treatment with reversine. Levels of serl0P-H3 protein remained low also after 24 h of reversine treatment indicating effective inhibition of Aurora kinases.

Example 5: RNA preparation and TaqMan™ analysis

Total RNA was prepared from by using Qiagen's RNeasy® midi kit (Qiagen Inc., Valencia, CA). MyoD gene expression was measured 24 h, 48 h and 72 h after the treatments using TaqMan™ chemistry with the ABI 7700 Prism real-time PCR instrument (Applied Biosystems, Foster City, CA). The forward and reverse primers (200 nM) sequences for mouse MyoD were: 5'-TTCTTCACCACACCTCTGACA-S' (SEQ ID NO. 1) and 5'- GCCGTGAGAGTCGTCTTAACTT-3' (SEQ ID NO. 2) and the probe (100 nM) was 5 'AC AGCCGGTGTGC ATTCC AA-3' (SEQ ID NO. 3). Data analysis was performed using 18S as internal standard. The forward and reverse primers sequences for mouse 18S were: 5'CGGCTACCACATCCAAGGAA-S' (SEQ ID NO. 4) and 5'- GCTGGAATTACCGCGGCT-3' (SEQ ID NO. 5) and the probe sequence was 5'- TGCTGGCACCAGACTTGCCCTC-3' (SEQ ID NO. 6).

For human reelin expression, forward (400 nM) and reverse (800 nM) primers sequences were 5'-TGGGTGGAACCGAATAACAATT-S' (SEQ ID NO. 7) and 5 'AC ATGACGGGCC AATAT AAAC AT-3' (SEQ ID NO. 8) and the probe (200 nM) sequence was 5 'CCCTTCCT AACGC AGC ACT AACCCG -3' (SEQ ID NO. 9). Data analysis was performed using human GAPDH as internal standard (Applied Biosystems).

Example 6: Cell cycle analysis

C2C12 and HCTl 16 cells were incubated with either reversine 5 μM or DMSO 0.01%. Cells were harvested and fixed in 70% ethanol over night. After double washing with PBS, cells were labeled with cell-cycle staining reagent PBS/0.1% Triton X-100, 200 μg/ml DNAse-free RNAse, 25 μg/ml Propidium Iodidie (Invitrogen) and incubated at room temperature, in the dark, for 30 minutes. DNA content was analyzed using FACS Calibur (Becton Dickinson, San Jose, CA).

Example 7: Immunofluorescence

5^χlO⁴ cells were cultured on poly-lysine (Sigma) coated coverslips. For analysis of Histone H3 phosphorylation, cells were fixed in 4% paraformaldehyde for 10 min at room temperature and then permeabilized with PBS/0.1% Triton X-100 for 5 min at room temperature. Cells were incubated with the primary antibody anti-serlOP-H3 (5-10 μg/ml; Upstate, Lake Placid, NY), followed by a FITC-conjugate antibody to rabbit IgG (1 :3000, Sigma), and then counterstained with DAPI 0.5 μg/ml.

Example 8: Western blot analysis

Cells were rinsed three times with cold PBS and harvested at the time indicated. Cells were then lysed in 50 mM Tris/HCl buffer, pH 8.0, containing 150 mM NaCl, 1% Nonidet P-40, 2 μg/ml aprotinin, 1 μg/ml pepstatin, 2 μg/ml leupeptin and 1 mM Na3 VO4. The cell lysate was centrifuged at 13,000 g for 30 min at 4° C and the pellet was discarded. Protein concentration was determinated by Bradford assay. Equal amounts of extracted proteins (80 μg) were loaded and separated on SDS-polyacrylamide gels 4-12% (SDS-PAGE), and then transferred onto a nitrocellulose membrane (Schleicher & Schuell Biosciences, Sandford, ME) using a semi-dry transfer (Invitrogen). Immunodetection was performed using the following primary antibodies: anti-cyclin Bl (1 :200, Santa Cruz Biotecnology, Santa Cruz, CA) and anti-serlOP-

H3 (1 :500, Upstate). For cyclin Bl analysis, cells were synchronized in Gl/S phase according to Harrington et al 2004.

Example 9: BrdU incorporation

To measure the incorporation of BrdU after treatment with reversine, HCT-116 were labeled with 10 μM BrdU (Becton Dickinson) for 30 min at 37°C in 5 % CO2 incubator. After labeling, cells were fixed in 70% ethanol at -20⁰C for 30 min and were dehydrated in PBS. DNA was denatured by treating with a 2N HCl- 1% Triton solution for 30 min at room temperature after which cells were centrifuged (500 g, 10 min) and resuspended in 0.1 M Na2B4O7 10H2O pH 8.5. Cells were washed and incubated 30 min at room temperature with FITC-conjugated anti-BrdU antibody (Becton Dickinson) and then were then stained with Propidium Iodide as previously described. The analysis was done on the FACS Calibur (Becton Dickinson).

Example 10: In vitro Kinases assay Kinase activity was measured in an in vitro assay using 0.5, 1, 2.5 and 5 μM reversine according to Upstate protocols (Kinase Profilers Assay Protocols).

Example 11: Colony Formation assay

Bone Marrows cells were obtained from bone marrow aspirates from Acute myeloid leukemia (AML) patients at diagnosis. CFU-L cells were resuspended in Methocult H4100 (Stem Cell Technologies): 40 ml of methilcellulose solution 2.6% complemented with::30 ml FBS (Stem Cell Technologies cat 06150); Glutamine 2mM (GIBCO);BSA 1% (Stem Cell Technologies cat 09300);10 ng/ml GM-CSF (Stem Cell Technologies cat 02632); IMDM medium to final volume of 100 ml (Stem Cell Technologies cat 36150). Cells preparation: Put a vial of cells at 37°C; Transfer the cell in a 15 ml falcon and wash with 10ml of IMDM medium complemented with 10% FBS, 2 mM glutamine; Wash in 10 ml PBS; Resuspend in 1 ml of PBS ; Add Dnase I lOu/ml (Amersham); 30' at 37 ⁰C; Dilute drug in methylcellulose at desired concentration; Add 150.000 of cells/ml of methyl cellulose (from Bone Marrow in toto) ;Vortex for 5'; Incubation at Room temperature for 30';Add 1 ml of methylcellulose- cells-drug for plate of 3.5 cm; Incubation of plates for 15 days at 37°C. Colonies with >20 cells were scored using an inverted microscope.Table II shows the immunophaenotype of the isolated cells and the French- American-British (FAB) classification of the AML disease for each patient (see also figure 5).

Table II

Example 12: Aurora B experiments

The spindles of Reversine-treated cells appeared less focused relative to those in control cells. A notable effect from adding Reversine was the accumulation of a variable number of chromosomes in the proximity of spindle poles. Although we did not directly characterize the state of attachment of these sister chromatid pairs by high resolution fluorescence microscopy, we suspect based on strong previous evidence on the effects of Aurora B inhibitors [e.g. 1] that they represent syntelic attachments. A quantification of this effect is shown in Figures 6A and 6B. In Figure 6B, the percentage of cells refers to cells that had all their chromosomes aligned in a spindle-wide sector delimited by the central 30 % of the spindle axis.

We tested the ability of Reversine to inhibit the phosphorylation of histone H3 (P-H3) by crystallization-grade recombinant active versions of Aurora A and Aurora B in vitro [2, 3]. We used these kinases because they are likely to be structurally related to the active forms of Aurora A and Aurora B that must be targeted in living cells by different Aurora inhibitors. In agreement with the results in living cells, Reversine inhibited Aurora B with an IC₅₀ of 12 nM, while it inhibited Aurora A with an IC₅₀ of approximately 1 μM (Figures 7A and 7B). Thus, Reversine shows ~ 100-fold selectivity towards inhibition of Aurora B relative to Aurora A in vitro.

Example 13 : The role of Aurora B in the spindle assembly checkpoint

Next, the effect of reversine on the spindle assembly checkpoint (S AC) was examined. HeLa cells were synchronized in Gl with a single thymidine arrest. 6 hours after release from the arrest, different spindle poisons, including 330 nM nocodazole, 10 μM taxol or 5 mM STLC, were added and cells were filmed as they entered mitosis. 5 hours after addition of the drugs, all cells treated with the three spindle poisons were arrested in mitosis, as expected based on the reported ability of all three compounds to activate the spindle assembly checkpoint in HeLa cells. However, only few mitotic cells were found when the same cultures were supplemented with 1 μM reversine. Thus, reversine abrogates the spindle assembly checkpoint activated under three distinct conditions, at least one of which - nocodazole - entails the formation of unattached kinetochores.

A quantification of the effects of reversine showed that 1 μM reversine caused a very effective override of the SAC even under stringent conditions such as the presence of 330 nM nocodazole. The majority of mitotic HeLa cells in nocodazole had left mitosis 90 minutes after they had entered it (Figure 9). It was additionally found that Reversine was also able to cause an immediate checkpoint override in cells treated with the PIk inhibitor BI2536 [4], which causes a potent SAC-dependent prometaphase arrest with unseparated spindle poles. Overall, these results strongly suggest that Aurora B is necessary for the SAC response under a variety of SAC-activating stimuli, including conditions that result in lack of attachment. To provide a more detailed quantification of the effects of reversine on the attachment checkpoint, we carried out an experiment whose outline is shown schematically in Figure 9A. The SAC response elicited by 330 nM nocodazole, 500 nM Taxol, or 5 mM STLC in HeLa cells was monitored in the presence of increasing concentrations of Reversine (Figure 9B). In all cases, we observed that a concentration of 1 μM reversine produced essentially indistinguishable results with these different inhibitors. Thus, at 1 μM reversine does not make a distinction between taxol and nocodazole and completely abrogates the checkpoint in the presence of these spindle poisons.

To address the generality of this effect, we tested the effects of reversine on two additional cell types, the human osteosarcoma cell line U2OS and the immortalized diploid cell line RPEl-hTERT. Like in HeLa cells, 1 μM reversine caused a complete nocodazole checkpoint override in these two additional cell lines, even at high concentrations of nocodazole (Figure 9C).

Summary

Reversine is also an efficient Aurora B inhibitor which can abrogate the spindle checkpoint response in various human cancer cells and, thus, proves to be an efficient anti-neoplastic agent which becomes even more potent when combined with spindle toxins such as taxol or nocodazole or STLC, for example.

References

1. Lampson, M.A., Renduchitala, K., Khodjakov, A., and Kapoor, T.M. (2004).

Correcting improper chromosome-spindle attachments during cell division. Nat Cell

Biol 8, 8. 2. Bayliss, R., Sardon, T., Vernos, I., and Conti, E. (2003). Structural basis of Aurora- A activation by TPX2 at the mitotic spindle. MoI Cell 12, 851-862. 3. Sessa, F., Mapelli, M., Ciferri, C, Tarricone, C, Areces, L.B., Schneider, T.R.,

Stukenberg, P.T., and Musacchio, A. (2005). Mechanism of Aurora B activation by

INCENP and inhibition by Hesperadin. MoI Cell 18, 379-391. 4. Lenart, P., Petronczki, M., Steegmaier, M., Di Fiore, B., Lipp, J.J., Hoffmann, M.,

Rettig, W.J., Kraut, N., and Peters, J.M. (2007). The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 17, 304-315.

Claims

1. Use of a compound according to formula (I)

(I), wherein

R¹ is hydrogen, halogen, OR⁷, SR⁷, SO₂R⁷ or NR⁸R⁹;

R² is Ci-Cjj-alkyl, C₃-C₈cycloalkylC₀-C₆alkyl, C₃-C₈heterocycloalkylC₀-C₆alkyl, C₃-C₈alicyclic systemCo-C_όalkyl, wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, ar-

Co-C_όalkyl and heteroar-Co-C_δalkyl; optionally substituted; R³ to R⁶ are each individually selected form the group consisting of hydrogen, halogen,

-NO₂, -CN, -NR¹⁰R¹¹, -OR¹², -COOR¹³, -CONR¹⁰R¹¹, -NR¹⁰COR¹², -NR¹⁰COR¹², -NR¹⁰CONR¹⁰R¹¹, -NR¹⁰SO₂E, -COR¹²; -SO₂NR¹⁰R¹¹, -OOCR¹³,

-CR¹²R¹³OH, -R¹³OH, and -E R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted; R⁸ is hydrogen or alkyl; optionally substituted

R⁹ is selected from the group consisting of hydrogen, C₅-C₈cycloalkenylCo-C₆alkyl,

C₃-C₈heterocycloalkylCo-C₆alkyl, C₃-C₈cycloalkylCo-C₆alkyl, ar-C₀-C₆alkyl, heteroar-C₂-C₆alkyl, heteroaryl and C₂-C_!oalkyl; optionally substituted; or R⁸ and R are taken together to form a heterocycloalkyl, alicylic system or heteroaryl; optionally substituted; R¹⁰ and R ' are each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted; R¹² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted; R¹³ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted;

A is N or CR⁴;

B is N or CR⁵; D is N or CR⁶; and

E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, alkylaryl, alkylheteroaryl, and heteroaryl; optionally substituted; or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, ameliorating or preventing a disease associated with increased activity of a cell cycle kinase.

2. Use according to claim 1, wherein R¹ is SO₂R⁷ or NR⁸R⁹; R⁸ is hydrogen or C₁ -Cio-alkyl, and/or

R⁹ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, and piperazinyl, optionally substituted; or C₂-Ci₀alkyl substituted with one or more substituents selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, aryl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,

3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, 1,2,5,6-tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, and piperazinyl, optionally substituted. Use according to claims 1 or 2, wherein R¹ is a functional group selected from one of the following:

wherein

R⁸ is hydrogen or C 1 to C 10-alkyl;

R¹⁴ is selected from the group consisting of halogen, -NO₂, -CN, -NR¹⁶R¹⁷, -OR¹⁸, -COOR¹⁹, -CONR¹⁶R¹⁷, -NR¹⁶COR¹⁸, -NR¹⁶COR¹⁸, -NR¹⁶CONR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁹, -COR¹⁸; -SO₂NR¹⁶R¹⁷, -00CR¹⁹, -CR¹⁸R¹⁹OH, -R¹⁹OH, and -R¹⁹

R¹⁵ is selected from the group consisting of hydrogen, -COOR¹⁹, C₃-C₈cycloalkylCo- C_όalkyl, Cs-CsheterocycloalkylCo-C_όalkyl, C₃-C₈alicyclic systemCo-C₆alkyl, wherein 1 , 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, ar-C₀-C₆alkyl and heteroar-Co-C₆alkyl; optionally substituted;

R¹⁶ and R¹⁷ are each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted;

R 18 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted; R iy is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted; m is an integer from 1 to 3; n is an integer from 0 to 2 for three-membered rings, an integer from 0 to 4 for five-membered rings and from 0 to 5 for six-membered rings; and indicates the bond between R¹ and the compound of formula (I).

4. Use according to claim 3, wherein R¹⁵ is a functional group selected from one of the following:

wherein

5. Use according to any of claims 1 to 4, R² is a functional group selected from one of the following:

wherein

R²⁰ is selected from the group consisting of halogen, -NO₂, -CN, -NR²²R²³, -OR²⁴, -COOR²⁵, -CONR²²R²³, -NR²²COR²⁴, -NR²²COR²⁴, -NR²²CONR²²R²³,

-OOCR 25 , ^Z5O,

-R »2 H, and -R > 25 R²¹ is selected from the group consisting of hydrogen, -COOR²⁵, -OR²⁵, C₃- CgcycloalkylCo-Cβalkyl, C₃-C₈heterocycloalkylC₀-C₆alkyl, C₃-C₈alicyclic systemC₀-C₆alkyl, wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, ar-Co-Cβalkyl and heteroar-Co-C₆alkyl; optionally substituted; R²² and R²³ are each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted;

R²⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted;

R²⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted; E and G are each individually selected from the group consisting of CH, CR²⁰, and N;

L, M, Q and R are each individually selected from the group consisting of CH, CR²⁰, O,

S and N, with the proviso that not more than two are O, S or N in monocycles; T is selected from the group consisting of O, S, NH, NR²⁰, CHR²⁰, and CR²⁰R²⁰; o is an integer from 0 to 4 for six membered rings an integer from 0 to 7 for bicyclic nine membered rings and an integer from 0 to 8 for bicyclic ten- membered rings; p is an integer from 0 to 6; q is an integer from 0 to 6; and

* indicates the bond between R² and the compound according to formula (I).

6. Use according to any of claims 1 to 5, wherein R²¹ is a functional group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 1,2,5,6-tetrahydropyrid-l-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, morpholin-3-yl, morpholin-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazin-1-yl, piperazin-2-yl, phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2- benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl; substituted with 0, 1 or 2 substituents selected from the group consisting of halogen, -NO₂, -CN, -NR²⁶R²⁷, -OR²⁸, -COOR²⁹, - CONR²⁶R²⁷, -NR²⁶COR²⁸, -NR²⁶COR²⁸, -NR²⁶CONR²⁶R²⁷, -NR²⁶SO₂R²⁹, -COR²⁸; - SO₂NR²⁶R²⁷, -OOCR²⁹, -CR²⁸R²⁹OH, -R²⁹OH, and -R²⁹, wherein

R²⁶ and R²⁷ are each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted;

R 28 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted;

R 29 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted.

7. Use according to any of claims 1 to 6, wherein A, B, and D are N.

8. Use according to any of claims 1 to 7, wherein the compound according to formula (I) has a structure selected from a group consisting of structures (II) to (XVI):

(H) (III)

(IV) (V)

(VI) (VII) (VIII)

(XII) (XIII) (XIV)

(XV) (XVI) optionally substituted.

9. Use according to any of claim 1 to 8, wherein the medicament further comprises a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof.

10. Use according to any of claim 1 to 9, wherein the cell cycle kinase is selected from the group consisting of aurora kinase A, aurora kinase B, aurora kinase C, abl, CHK2, JNKlαl and JNK3.

11. Use according to claim 10, wherein the disease associated with increased kinase activity is a hyperproliferative disease.

10

12. Use according to claim 11, wherein the hyperproliferative disease associated with increased aurora A kinase activity is selected from the group consisting of laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, lung squamous cell carcinoma, adenocarcinoma, hormone-dependent breast cancer, hormone-independent breast cancer, ovarian cancer, testicular cancer, glioma, urothelial carcinomas, bladder cancer, endometrial carcinoma, colorectal cancer, pancreatic cancer, seminoma, leukemia, acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis and gastrointestinal stromal tumor (GIST).

13. Use according to claim 11, wherein the hyperproliferative disease associated with increased aurora B kinase activity is colorectal cancer, laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, a lung cancer, preferably lung squamous cell carcinoma or non-small cell lung carcinoma, adenocarcinoma, hormone-dependent breast cancer, hormone-independent breast cancer, ovarian cancer, testicular cancer, glioma, urothelial carcinomas, bladder or renal cancer, melanoma, endometrial carcinoma, pancreatic cancer, seminoma, leukemia, acute- myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, gastrointestinal stromal tumor (GIST), a prostate cancer, a hepatocellular carcinoma and a thyroid carcinoma.

14. Use according to claim 11, wherein the hyperproliferative disease associated with increased abl kinase activity is selected from the group consisting of leukemia, in particular Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), leukemogenesis, lymphoma, ovarian carcinoma, laryngeal carcinoma, in particular laryngeal squamous cell carcinoma, lung squamous cell carcinoma, adenocarcinoma, hormone-dependent breast cancer, hormone-independent breast cancer, testicular cancer, glioma, urothelial carcinomas, bladder cancer, endometrial carcinoma, colorectal cancer, pancreatic cancer, seminoma, leukemia, acute- myelogenous leukemia (AML), mastocytosis and gastrointestinal stromal tumor (GIST).

15. Use according to claim 11, wherein the proliferative disorder is glomerulonephritis, rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disorder.

11

16. Use according to any of claims 1 to 15, wherein the disease is or is in the process of becoming refractive to other kinase inhibitors.

17. Use according to claim 16, wherein the other kinase inhibitor is selected from the group consisting of Imatinib, Herceptin and Irressa.

18. Use according to any of claims 1 to 17 wherein the medicament further comprises one or more chemotherapeutic or antiproliferative agent selected from the group consisting of anti-tumor antibodies, alkylating substances, anti-metabolites, antibiotics, epothilones, anti-androgens, anti-estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), imatinib, platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, 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, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole,

12 sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or structurally related derivatives thereof.

19. Use according to claim 18, wherein the compound according to formula (I) and the one or more chemotherapeutic or antiproliferative agent are administered concomitantly or sequentially.

20. A pharmaceutical compositions comprising a compound according to formula (I)

(I),

wherein

R¹ is hydrogen, halogen, OR⁷, SR⁷, SO₂R⁷ or NR⁸R⁹;

R² is d-Cg-alkyl, C₃-C₈cycloalkylC₀-C₆alkyl, C₃-CgheterocycloalkylC₀-C₆alkyl, C₃-C₈alicyclic systemC₀-C₆alkyl, wherein 1, 2, or 3 carbon atoms may be replaced by a heteroatom selected from the group consisting of N, O and S, ar- Co-Cβalkyl and heteroar-Co-C_όalkyl; optionally substituted;

R³ to R⁶ are each individually selected form the group consisting of hydrogen, halogen,

-CR¹²R¹³OH, -R¹³OH, and -E

R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted; R⁸ is hydrogen or alkyl; optionally substituted

13 R^v is selected from the group consisting of hydrogen, Cs-CgcycloalkenylCo-C_όalkyl, C₃-C₈heterocycloalkylCo-C₆alkyl, C₃-C₈cycloalkylCo-C₆alkyl, ar-C₀-C₆alkyl, heteroar-C₂-C₆alkyl, heteroaryl and C₂-Ci_Oalkyl; optionally substituted; or R and R are taken together to form a heterocycloalkyl, alicylic system or heteroaryl; optionally substituted;

R¹⁰ and R¹¹ are each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaralkyl, and heteroaryl; optionally substituted; R¹² is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted;

R¹³ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, aralkyl, heteroaryl and heteroaralkyl; optionally substituted;

A is N or CR⁴; B is N or CR⁵; D is N or CR⁶; and

E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl, alkylaryl, alkylheteroaryl, and heteroaryl; optionally substituted; and one or more chemotherapeutic or antiproliferative agent and optionally one or more excipients, buffers and/or auxiliary substances.

21. Pharmaceutical composition according to claim 20, wherein the one or more chemotherapeutic or antiproliferative agent is an agent which modulates microtubule polymerization.

22. Pharmaceutical composition according to claim 21, wherein the agent is selected from the group consisting of a taxane, a vinca alkaloid, colchicine and nocodazole, or a structurally related derivative thereof.

23. Pharmaceutical composition according to claim 20, wherein the one or more chemotherapeutic or antiproliferative agent is selected from the group consisting of

14 ZM447439, VX-680, anti-tumor antibodies, imatinib, the methanesulfonic acid salt of alkylating substances, anti-metabolites, antibiotics, epothilones, anti-androgens, anti- estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), imatinib, platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, 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, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or structurally related derivatives thereof.

15

24. A pharmaceutical composition comprising:

(i) an inhibitor, capable of specifically reducing the activity of Aurora kinase B by at least 10% when compared with the activity said kinase has in the absence of said inhibitor,

(ii) an agent which modulates microtubule polymerization, such as a taxane, a vinca alkaloid, colchicine, nocodazole, or a structurally related derivative thereof, and, optionally,

(iii) one or more excipients, buffers and/or auxiliary substances.

16