WO2011057892A1

WO2011057892A1 - 2,3-dihydrobenzoxazine and 2,3-dihydrobenzothiazine derivates as hif-inhibitors for the treatment of cancer and inflammatory diseases

Info

Publication number: WO2011057892A1
Application number: PCT/EP2010/066175
Authority: WO
Inventors: Jorge Alonso; Arantxa Encinas Lopez; Marcel MÜLBAIER; Christoph Schultes; Bernd Wendt; Bernd Janssen
Original assignee: Elara Pharmaceuticals GmbH
Current assignee: Elara Pharmaceuticals GmbH
Priority date: 2009-10-27
Filing date: 2010-10-26
Publication date: 2011-05-19
Anticipated expiration: 2012-04-27
Also published as: TW201120018A; AR078770A1

Abstract

The present invention provides novel 2,3-dihydrobenzazine compounds of the formula (I), the pharmaceutically acceptable salts thereof, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides. Formula (I) X is O or S(=O)_n with n being 0, 1 or 2; R¹ is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1, 2 or 3 radicals R^1a which are identical or different; R^1a is selected from the group consisting of halogen, cyano, NO₂, NH₂, OH, SH, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, hydroxy-C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₂-alkyl, SF₅, fluorinated C₁-C₂-alkoxy, C(O)R³, NR⁴R⁵, N(OR⁶)R⁷ and C(O)OR⁸, or two radicals R^1a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk-O, wherein AIk is selected from CH₂, CH₂CH₂, CHF and CF₂; R² is phenyl or C- or N-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1, 2 or 3 radicals R^2awhich are identical or different; R^2a is selected from the group consisting of halogen, cyano, NO₂, NH₂, OH, SH, C1-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, hydroxy-C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₂-alkyl, SF₅, fluorinated C₁-C₂-alkoxy, C(O)R³, NR⁴R⁵, N(OR⁶)R⁷ and C(O)OR⁸, or two radicals R^2a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk'-O, wherein AIk' is selected from CH₂, CH₂CH₂, CHF and CF₂; and where R³ to R⁸ are as defined in the claims and the specification. The invention relates to use of these compounds in therapy, in particular in the therapy of a disease or disorder selected from the group consisting of inflammatory diseases, a hyperproliferative disease or disorders, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation.

Description

2, 3 -DIHYDROBENZOXAZ INE AND 2 , 3-DIHYDROBENZOTHIAZINE DERIVATES AS HIF-INHIBITORS FOR THE TREATMENT OF CANCER AND INFLAMMATORY DISEASES

The present invention provides novel 2,3-dihydrobenzazine compounds that are useful in therapy of diseases and disorders. The novel compounds inhibit cell prolifera- tion and cell division and they also inhibit the activation of Hypoxia Inducible Factor (HIF)-mediated transcription and signaling under hypoxic conditions. In one aspect, the compounds of the present invention are useful for the preparation of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia-related pathology and a disease characterized by excessive vascularisation. Also provided is a pharmaceutical composition, comprising a compound of the invention and a second therapeutic agent or radiation, useful for the treatment or prevention of the mentioned diseases or disorders. BACKGROUND OF THE INVENTION

The normal response of cells to inadequate oxygen supply is mediated by the hypoxia signaling pathway. This response is important for a number of physiolocial functions such as tumor development and metastasis, resistance to apoptosis, induc- tion of new blood vessel formation, and metabolism among others. For a general review on hypoxia signaling see e.g. Qingdong Ke and Max Costa, Molecular Pharmacology (2006), vol. 70, no. 5.

As a result of hypoxia, augmented levels of a heterodimeric complex of transcription factors (Hypoxia Inducible Factor, HIF), most notably HIF-1 a and HIF-1 β, are observed in e.g. tumors to compensate in cooperation with additional co-factors for the reduced availability of oxygen and nutrients in this fast growing tissue type. Under anaerobic conditions, homeostasis of HIF-1 a is imbalanced by its reduced degradation, thus enabeling enhanced signaling through the Hypoxia Responsive Element (HRE) and resulting in increased expression of a large number of survival and growth factors.

Hypoxic conditions are also found in non-tumor tissue. For example, retinopathy is a general term that refers to non-inflammatory damage to the retina of the eye. This condition is most commonly caused by an insufficient blood supply leading to hypoxia. Particularly people with diabetes mellitus are at risk of retinopathy. The lack of oxygen in the retina of diabetics causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humour that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause fractional retinal detachment. The new blood vessels can also grow into the anterior chamber of the eye and cause neovascular glaucoma. Recently, evidence has accumulated that inhibition of HIF-1 activity could also act to prevent inflammation, by virtue of its role in the activation and infiltration of macrophages and neutrophils into affected tissues (see e.g. Giaccia et al., Drug Discovery, vol. 2, October 2003).

For the above-outlined reasons, compounds that inhibit HIF function are valuable medicaments for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia-related pathology and a disease characterized by excessive vascu- larisation.

Because of the importance of HIF-1 in tumor development, progression and metastasis, a considerable amount of effort has been devoted to identify HIF-1 inhibitors for cancer therapy. A number of small molecules and RNA constructs, like siRNA, have been reported to exhibit inhibition of the HIF-1 pathway, e.g. Kung AL et al, Cancer Cell (2004), vol. 6, p. 33 ff; Rapisarda A, et al. Cancer Res. (2002), vol. 62, p. 4316 ff.; Tan C.et al, Cancer Res. (2005), vol. 65, p. 605 ff; Mabjeesh NJ, et al, Cancer Cell, (2003), vol. 3, p. 363ff;. Kong X, et al, Mol Cell Biol (2006) , vol. 26, p. 2019 ff.; Kong D, et al, Cancer Res. (2005), vol. 65, p. 9047 ff.; Chau N. et al., Cancer Res. (2005), vol. 65, p. 4918 ff; Welsh S, et al., Mol Cancer Ther (2004), vol. 3, p. 233 ff. However, these compounds often have activities other than HIF-1 inhibition, and most of them lack the de- sired pharmacokinetic properties or toxicity profiles required for a useful pharmaceutical agent. Furthermore, some of the compounds have the disadvantage that they can not be administered orally, such as the HIF-1 inhibitor EZN-2968, which is a locked nucleic acid antisense oligonucleotide.

WO 2005/007828 discloses S-2-amino-3-[4'-amino-N,N-bis-(2-chloroethyl)- amino]phenyl propionic acid N-oxide dihydrochloride, which is also known as PX-478, to be useful for regulating HIF-1 a levels under normoxid or hypoxic conditions.

WO 2006/050734 discloses LNA oligonucleotides which are suitable for down- regulating HIF-1 a expression.

WO 2006/066846 discloses thiazolidinone compounds which inhibit HIF-1 acti- vation by inhibiting the interaction of HIF-1 with the coactivator p300 of HIF-1 expression.

WO 2007/025169 discloses certain chromene compounds which in the 6- position carry a N-(arylsulfonyl) aminomethyl radical. The compounds are mentioned to be HIF-1 inhibitors.

WO 2007/130037 suggests that bidentate zinc chelates of aromatic 1 ,3- diketones which inhibit HIF-1 are useful for treating cancer or tumor.

WO 2008/004798 discloses phenoxyacetic acid anilides or N-pyridylamides and 2-(phenoxymethyl) benzazoles as inhibitors of HIF-1 . The scientific literature cited above emphasizes the high medical need for new therapeutic agents to provide more efficient treatment of different proliferative and inflammatory diseases or disorders, hypoxia-related pathologies and diseases characterized by excessive vascularisation.

WO 2004/056820 discloses 2,3-dihydobenzazine compounds which in the 6- position carry an (azoline-2-one-3-yl)methylene radical. The compounds are mentioned to be suitable for the treatment of disorders which respond to the inhibition of phosphi- nositide-3-kinases including certain inflammatory diseases and certain cancer diseases.

US 2007/191603, inter alia, discloses inter alia 2,3 dihydrobenzazine compounds which in the 6-position carry an arylaminocarbonyl radical. The compounds are mentioned to be suitable for the treatment of disorders which respond to the inhibition of liver carnithine palmitoleyl transferase including hyperglycemia disorders and glucose tolerance disorders.

WO 2009/03599 pounds of the formula A

wherein A is e.g. CO, CONH or S0₂, Y is (CH₂)_P with p = 1 , 2 or 3, Z is O, S, SO or SO2, Ri is alkyl, cycloalkyl, optionally substituted aryl or optionally substituted het- erocyclyl, R², R³ are hydrogen or alkyl and R⁴ is selected from COOR5, CONR5R6, aryl which is optionally substituted by 1 , 2 or 3 radicals selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, CF3 or OCF3, and heterocyclyl, which is optionally substituted by 1 , 2 or 3 radicals selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Cs-Cs-cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, CF3 or OCF3. The compounds bind to cannabinoid receptors CB1 or CB2 on the surface of mammalian cells thereby modulating the intracellular cAMP concentration. Therefore compounds are suggested to be useful in the treatment of cannabinoid receptor associated disorders including treatment of pain, pruritis, skin disorders, inflammatory diseases, neurodegenerative, neuroinflammatory or psychiatric disorders, lung disorders, ophthalmic disorders, car- diosvascular disorders, gastrointestinal disorders and certain cancer diseases.

SUMMARY OF THE INVENTION

The present invention provides novel compounds capable of prevention or treatment of a disease or disorder. Data presented herein establish that compounds accord- ing to the present invention are surprisingly very potent inhibitors of (i) the activation of HIF mediated transcription under hypoxic conditions and of (ii) cell proliferation.

In a first aspect the present invention relates to 2,3-dihydrobenzazine compounds having a structure according to formula (I):

wherein:

X is O or S(=0)_n with n being 0, 1 or 2;

R¹ is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1 , 2 or 3 radicals R^{1 a} which are identical or different;

R^{1 a} is selected from the group consisting of halogen, cyano, NO2, N H2, OH , SH , Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-C6-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluorinated Ci-C2-alkyl, SF₅, fluorinated Ci-C₂-alkoxy, C(0)R³, N R⁴R⁵, N(OR⁶)R⁷ and C(0)OR⁸, or two radicals R^{1 a}, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk-0, wherein Alk is selected from CH2, CH2CH2, CH F

R² is phenyl or C- or N-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1 , 2 or 3 radicals R^2a which are identical or different;

R^2a is selected from the group consisting of halogen, cyano, NO2, N H2, OH , SH , Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-C6-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluorinated Ci-C2-alkyl, SF₅, fluorinated Ci-C₂-alkoxy, C(0)R³, N R⁴R⁵, N(OR⁶)R⁷ and C(0)OR⁸, or two radicals R^2a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk'-O, wherein Alk' is selected from CH₂, CH2CH2, CH F

R³ is Ci-C₄-alkyl;

R⁴ is hydrogen or d-C₆-alkyl;

R⁵ is d-Ce-alkyl, hydroxy-C₂-C₆-alkyl, Ci-C₄-alkoxy-C2-C₄-alkyl or a radical C(0)R^x, wherein R^x is Ci-C4-alkyl; or

R⁴, R⁵ together with the nitrogen atom, to which they are bound, form an N-bound, 5- or 6-membered saturated nitrogen heterocycle;

R⁶ is hydrogen or Ci-C6-alkyl; R⁷ is hydrogen or Ci-C6-alkyl;

R⁸ is hydrogen, Ci-C6-alkyl, hydroxy-C2-C6-alkyl or Ci-C4-alkoxy-C2-C4-alkyl;

the pharmaceutically acceptable salts thereof, and, if one or both of R¹ and R² are a nitrogen containing 5- or 6-membered heteroaryl, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.

In a further aspect the invention relates to use of the compounds of the formula I, or their pharmaceutically acceptable salts, or, if one or both of R¹ and R² are a nitrogen containing 5- or 6-membered heteroaryl, the N-oxides thereof or the pharmaceutically acceptable salts of said N-oxides in therapy, in particular in the therapy of a a disease or disorder selected from the group consisting of inflammatory diseases, a hyperprolif- erative disease or disorders, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation.

In a further aspect the present invention relates to a pharmaceutical composition comprising at least one compound of the formula I, or a pharmaceutically acceptable salt thereof, or, if one or both of R¹ and R² are a nitrogen containing 5- or 6-membered heteroaryl, an N-oxides thereof or a pharmaceutically acceptable salt of said N-oxide, optionally in combination with at least one second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation, and, optionally, a pharmaceutically acceptable carrier or auxiliary substance (excipi- ent).

In a further aspect the present invention relates to a method for treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hypervascularisation, said method comprising administering an effective amount of at least one compound of the formula I, or a pharmaceutically acceptable salt thereof, or, if one or both of R¹ and R² are a nitrogen containing 5- or 6-membered heteroaryl, a N-oxides thereof or a pharmaceutically acceptable salt of said N-oxide, optionally in combination with a second therapeutic agent useful for the treatment or prevention of such a disease or disorder to a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

It is 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 other- wise, 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: (lUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

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

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

Provided the compounds of the formula (I) of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, the invention also relates to enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers (ennatiomerically pure), diastereomers and tautomers of the compounds of formula (I) and/or of their salts and/or their N-oxides. Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfo- nic acids, such as -camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent (for example dini- trobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropa- nol/acetonitrile mixture. The diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystal- lization. It is also possible to obtain optically active compounds of formula (I) by the methods described below by using starting materials which are already optically active.

The invention also relates to "pharmaceutically acceptable salts" of the compounds of the formula (I), especially acid addition salts with physiologically tolerated, i.e. pharmaceutically acceptable acids. Examples of suitable physiologically tolerated organic and inorganic acids include, but are not limited to, hydrochloric acid, hydro- bromic acid, phosphoric acid, sulfuric acid, Ci-C4-alkylsulfonic acids, such as methane- sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfo- nic acid, carboxylic acids such as oxalic acid, malic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid, mandelic acid, salicylic acid, phenylpropionic acid, nicotinic acid, benzoic acid acetate, alginic acid, ascorbic acid, aspartic acid, tannic acid, butyric acid, camphoric acid, citric aicd, clavulanic acid, cyclopentanepropionic acid, gluconic acid, formic acide, acetic acid, propionic acid, pivalic acid, valeric acid, hexoic acid, heptoic acid, oleic acid, palmitic acid, pantothenic acid, pectinic acid, stearic acid, hexylresorcinic acid, hydroxynaphthoic acid, lactobionic acid and mucic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966 and in Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1 -19. Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, bu- tyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dode- cylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsani- late, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobro- mide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malo- nate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persul- fate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teo- clate, tosylate, triethiodide, undecanoate, valerate, and the like. Certain specific com- pounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).

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

The invention also relates to N-oxides of the compounds of the formula (I), pro- vided that those compounds contain a basic nitrogen atom, such as the nitrogen atom of a N-heteroaromatic radical which may be present in R¹ and/or R². Examples of N- heteroaromatic radicals, where the nitrogen may be present in the form of an N-oxide, include pyridinyl, pyrimdinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl and the like.

In addition to salt forms, the N-oxides and the salts of the N-oxides, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of general formula (I). A prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988), and Bundgaard, Design of Prodrugs, Elsevier (1985). Examples of a masked acidic anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 1 1 , 1981 ) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

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

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. 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, nitro- gen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹ P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, 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. All isotopic variations of the compounds and compositions of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In the following definitions of the terms: alkyl, aryl, heteroaryl, alkenyl, alkynyl, hydroxyalkyl and alkoxyalkyl are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings. Nevertheless in some instances of their use throughout the specification preferred meanings of these terms are indicated.

The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix C_n-C_m indicates in each case the possible number of carbon atoms in the group. If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term "Ci-Cio-alkyl" denotes a straight-chain or branched alkyl group having from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, pentyl, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1 ,1 - dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl, 1 -ethyl-2-methylpropyl, heptyl, octyl, nonyl and decyl.

The term "fluorinated C1-C2 alkyl" denotes an alkyl group having 1 or 2 carbon atoms as defined above, wherein at least one hydrogen atom, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine. Examples of such a group include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1 ,1 ,2,2-tetrafluoroethyl and 1 ,1 ,2,2,2-pentafluoroethyl.

The term "pentafluorosulfanyl" relates to the radical SF₅.

The term "hydroxy-Ci-C6-alkyl" denotes a straight-chain or branched alkyl group having from 1 to 6, especially 1 to 4 carbon atoms (=hydroxy-Ci-C4 alkyl), wherein one of the hydrogen atoms is replaced by a hydroxy group, such as in hydroxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, hydroxy-iso-propyl, 1 -hydroxybutyl or 2- hydroxybutyl.

The term "hydroxy-C2-C6-alkyl" denotes a straight-chain or branched alkyl group having from 2 to 6, especially 2 to 4 carbon atoms (=hydroxy-C2-C4 alkyl), wherein one of the hydrogen atoms, which is preferably not located at Ci, is replaced by a hydroxy group, such as in 2-hydroxyethyl or 3-hydroxypropyl. The term "C1 " refers to the carbon atom by which hydroxy-C2-C6-alkyl is bound to the remainder of the molecule.

The term "Ci-C6-alkoxy" denotes a straight-chain or branched alkyl group having 1 , 2, 3, 4, 5 or 6 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso- propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy, pentyloxy, 1 - methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 2,2-dimethylpropyloxy, 1 - ethylpropyloxy, hexyloxy, 1 ,1 -dimethylpropyloxy, 1 ,2-dimethylpropyloxy, 1 - methylpentyloyx, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy,

1 ,1 -dimethylbutyloyx, 1 ,2-dimethylbutyloxy, 1 ,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3-dimethylbutyloyx, 3,3-dimethylbutyloxy, 1 -ethylbutyloxy, 2-ethylbutyloxy, 1 ,1 ,2- trimethylpropyloxy, 1 ,2,2-trimethylpropyloxy, 1 -ethyl-1 -methylpropyloxy and 1 -ethyl-2- methylpropyloxy.

The term "fluorinated Ci-C2-alkoxy" denotes an alkoxy group having 1 or 2 carbon atoms, wherein at least one hydrogen atom, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine. Examples of such a group include fluoromethoxy, difluoro- methoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy and 1 ,1 ,2,2,2-pentafluoroethoxy.

The term "Ci-C4-alkoxy-Ci-C4-alkyl" denotes a straight-chain or branched alkyl group having from 1 to 4 carbon atoms, wherein one of the hydrogen atoms is replaced by a C1-C4 alkoxy group, such as in methoxymethyl, ethoxymethyl, propoxymethyl,

1 - methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl,

2- ethoxypropyl, 3-methoxypropyl or 3-ethoxypropyl.

The term "Ci-C4-alkoxy-C2-C4-alkyl" denotes a straight-chain or branched alkyl group having from 2 to 4 carbon atoms, wherein one of the hydrogen atoms, which is preferably not located at C1 , is replaced by a C1-C4 alkoxy group, such as in 2- methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 3-methoxypropyl or 3- ethoxypropyl. The term "C1 " refers to the carbon atom by which Ci-C4-alkoxy-C2-C4- alkyl is bound to the remainder of the molecule.

The term "Ci-C6-alkylthio" denotes a straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as mentioned above) which are attached to the skeleton via a sulfur atom (-S-).

The term "C2-Cio-alkenyl" denotes a straight-chain or branched hydrocarbon groups having 2 to 4, 6, 8 or 10 carbon atoms and one or more, e.g. 2 or 3, carbon- carbon double bonds in any position, preferably one carbon-carbon double bond, e.g. vinyl, allyl (2-propen-1 -yl), 1 -propen-1 -yl, 2-propen-2-yl, methallyl (2-methylprop-2-en- 1 -yl), 2-buten-1 -yl, 3-buten-1 -yl, 2-penten-1 -yl, 3-penten-1 -yl, 4-penten-1 -yl, 1 -methyl- but-2-en-1 -yl, 2-ethylprop-2-en-1 -yl, hexenyl, heptenyl or octenyl.

The term "C2-C10 alkynyl" denotes a straight-chain or branched hydrocarbon groups having 2 to 4, 6, 8 or 10 carbon atoms and one or more, e.g. 2 or 3, carbon- carbon triple bonds in any position, preferably one carbon-carbon triple bond, for example ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 -methyl-2- propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-2-butynyl, 1 -methyl-

3- butynyl, 2-methyl-3-butynyl, 3-methyl-1 -butynyl, 1 ,1 -dimethyl-2-propynyl, 1 -ethyl-2- propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1 -methyl-2-pentynyl,

1 -methyl-3-pentynyl, 1 -methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3- methyl-1 -pentynyl, 3-methyl-4-pentynyl, 4-methyl-1 -pentynyl, 4-methyl-2-pentynyl, 1 ,1 -dimethyl-2-butynyl, 1 ,1 -dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimethyl-

3- butynyl, 3,3-dimethyl-1 -butynyl, 1 -ethyl-2-butynyl, 1 -ethyl-3-butynyl, 2-ethyl-3-butynyl and 1 -ethyl-1 -methyl-2-propynyl, heptynyl, octynyl, nonynyl or decynyl.

The term "heteroaryl" (also referred to as hetaryl) denotes a monocyclic 5- or 6- membered heteroaromatic radicals comprising as ring members in addition to carbon atom(s) 1 , 2, 3 or 4 heteroatoms selected from N, O and S. C-bound heteroaryl denotes a heteroaromatic radical which is bound via a carbon ring atom while N-bound heteroaryl denotes a heteroaromatic radical which is bound via a nitrogen ring atom.

Examples of 5- or 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or

4- pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e.1 -, 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thia- zolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1 -, 3- , 4- or 5-pyrazolyl, imidazolyl, i.e. 1 -, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1 ,3,4]oxadiazolyl, 4- or 5-[1 ,2,3]oxadiazolyl, 3- or 5-[1 ,2,4]oxadiazolyl, 2- or

5-[1 ,3,4]thiadiazolyl, thiadiazolyl, e.g. 2- or 5-[1 ,3,4-thiadiazol]yl, 4- or

5-[1 ,2,3]thiadiazolyl, 3- or 5-[1 ,2,4]thiadiazolyl, triazolyl, e.g. 1 H-, 2H- or

3H-1 ,2,3-triazol-4-yl, 2H-triazol-3-yl, 1 H-, 2H-, or 4H-1 ,2,4-triazolyl and tetrazolyl, i.e. 1 H- or 2H-tetrazolyl.

The term "N-bound, 5- or 6- membered saturated nitrogen heterocycle" denotes a saturated heteromonocyclic radical containing one nitrogen atom as a ring member, which is attached to the remainder of the molecule, and optionally one or more, e.g. 1 or 2 further heteroatoms such as O, S or N as ring member, having a total of 5 or 6 ring member atoms. Examples for "N-bound, 5- or 6-membered saturated nitrogen hetero- cycles" are pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl, 4-methylpiperazin-1 -yl, mor- pholin-4-yl, thiomorpholin-4-yl, imidazolidin-1 -yl, oxazolidin-3-yl or thiazolidin-3-yl, es- pecially pyrrolidin-1 -yl, piperazin-1 -yl, 4-methylpiperazin-1 -yl, piperidin-1 -yl and mor- pholin-4-yl.

Hereinafter particular embodiments of the compounds according to the present invention are explained by giving particular or preferred meanings of the variables X, R¹, R^1a, R², R^2a, R³, R⁴, R⁵, R⁶, R⁷ and R⁸. It is well understood by a skilled person that any particular or preferred meaning of any of these variables can be combined with the general definition or a particular or preferred meaning of any other variables, e.g. any definition of a particular or preferred embodiment of R¹ can be combined with any particular or preferred meaning of R².

According to a first embodiment, the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is O. These compounds are hereinafter also denominated as dihydrobenzoxazines or compounds of the formula 1.1 .

According to a second embodiment, the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is S. These compounds are hereinafter also denominated as dihydroben- zothiazines or compounds of the formula 1.2.

According to a third embodiment, the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is S=0. These compounds are hereinafter also denominated as dihydrobenzothiaz- ine oxides or compounds of the formula 1.3.

According to a forth embodiment, the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is S(=0)2. These compounds are hereinafter also denominated as dihydrobenzothi- azine dioxides or compounds of the formula 1.4. Particular preference is given to the first embodiment, i.e. to compounds of the formula 1.1 .

According to a particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R¹ is phenyl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different. Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R^1a. Preferably, one of the radicals R^1a, if present, is located in the para-position with respect to the sulfonyl group.

According to another particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R¹ is 6-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different. Amongst these compounds, those are preferred, wherein the one or more nitrogen ring atom(s) are not located in the ortho position with respect to the sulfonyl moiety. Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R^1a. Preferably, one of the radicals R^1a, if present, is located in the para-position with respect to the sulfonyl group.

According to a further particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R¹ is 5-membered C-bound heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different.

Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R^1a.

In these embodiments, the radicals R^1a, if present, have the aforementioned meanings and are preferably selected from halogen, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoro- methoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 - methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propionyl, NR⁴R⁵ especially methylamino or dimethylamino, and C(0)OR⁸; especially methoxycarbonyl, eth- oxycarbonyl or carboxy, or two radicals R^1a, which are bound to adjacent carbon atoms, together may also form a moiety O-Alk-0, wherein Alk is selected from CH2, CH2CH2, CHF and CF2. Especially, the radicals R^1a, if present, are selected from the group consisting of halogen, in particular fluorine or chlorine, CN (= cyano), NO2 (nitro), OH, SH, Ci-C4-alkyl, in particular methyl, ethyl or isopropyl, Ci-C4-alkoxy, in particular methoxy or ethoxy, NH₂, NR⁴R⁵, in particular NH(CH₃), or N(CH₃)2, fluorinated Ci-alkyl, in particular difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-alkoxy, in particular difluoromethoxy or trifluoromethoxy, or two radicals R^1a, which are bound to adjacent carbon atoms, together may also form a moiety O-Alk-0, wherein Alk is selected from CH₂, CH2CH2, CHF and CF₂.

Amongst the compounds of the present invention, where R¹ in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R^1a which are identical or different, preference is given to those compounds, wherein R¹ in the formulae I, 1.1 , I.2, 1.3 or I.4 is a radical of the formula AM :

wherein # indicates the point of attachment to the SO2 group,

K is N or C-R¹¹,

L is N or C-R¹²,

M is N or C-R¹³,

wherein R¹¹, R¹² and R¹³, independently of each other, are hydrogen or have one of the meanings given for R^1a, in particular one of the preferred meanings.

Amongst the compounds of the present invention, where R¹ in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different, preference is given to those compounds, wherein R¹ in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is selected from radicals of the formulae Ar1 .1 to Ar1 .5, with particular preference given to the formulae Ar1 .1 and Ar1 .3:

A .1 AM .2 AM .3

AM .4 AM .5 wherein # indicates the point of attachment to the SO2 group, and wherein R¹¹, R¹² and R¹³, independently of each other, are hydrogen or have one of the meanings given for R^1a, in particular one of the preferred meanings.

In the compounds of the formulae I, 1.1 , I.2, 1.3 or 1.4, where R¹ is a radical of the formulae A , AM .1 , AM .2, AM .3, AM .4 or AM .5, particular embodiments of the invention relate to compounds, wherein, the variables R¹¹, R¹² and R¹³, if present, individu- ally or in particular in combination have the following meanings:

R¹¹, R¹³, if present, are independently of each other selected from the group consisting of hydrogen, halogen, OH, CN, SH, C1-C4 alkyl, especially methyl, ethyl or iso- propyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, NR⁴R⁵ such as NHCH3 or N(CH3)2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci- C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2- methoxyethyl;

R¹² if present, is selected from the group consisting of hydrogen, halogen, OH,

SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-C2-alkoxy, especially di- fluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propio- nyl, NR⁴R⁵ especially methylamino or dimethylamino, and C(0)OR⁸, especially meth- oxycarbonyl or ethoxycarbonyl. In particular, R¹², if present, is selected from halogen, especially fluorine or chlorine, CN (= cyano), NO2 (nitro), OH, SH, Ci-C4-alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, NH2, NR⁴R⁵, in particular NH(CH3), or N(CH3)2, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoro- methoxy,

or, if K is C-R¹¹ and L is C-R¹², R¹¹ and R¹² together may also form a moiety

O-Alk-0, wherein Alk is selected from CH₂, CH2CH2, CHF and CF₂.

In the compounds of the formulae I, 1.1 , I.2, 1.3 or 1.4, where R¹ is a radical of the formulae Ar1 , Ar1 .1 , Ar1 .2, Ar1 .3, Ar1 .4 or Ar1 .5, more preferred embodiments of the invention relate to compounds, wherein, the variables R¹¹ , R¹² and R¹³, if present, indi- vidually or in particular in combination have the following meanings:

R¹¹ is selected from the group consisting of hydrogen, halogen, OH, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy;

R¹² is selected from the group consisting of halogen, OH , SH, CN , NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 al- kynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 - methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propionyl, NR⁴R⁵, especially methylamino or dimethylamino,

or, if K is C-R¹¹ and L is C-R¹², R¹¹ and R¹² together may also form a moiety O-Alk-0, wherein Alk is selected from CH₂, CH2CH2, CHF and CF₂;

and R¹³, if present, is hydrogen.

Amongst the compounds of the present invention, where R¹ in the formulae I, 1.1 ,

1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different, preference is given to those compounds, wherein R¹ in the formulae I, 1.1 , I.2, 1.3 or I.4 is a radical of the formulae Ar2 or Ar2':

(Ar2) (Ar2') wherein # indicates the point of attachment of R¹ to the SO2 group,

is N or C-R¹⁴,

is N or C-R¹⁵,

is N or C-R¹⁶,

is N or C-R¹⁷,

G is O, S or N-R ⁸,

G' is O, S or N-R¹⁹,

wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷, independently of each other, are hydrogen or have one of the meanings given for R^1a, and wherein R¹⁸ and R¹⁹ are hydrogen, cyano, NH2, OH, Ci-Cio-alkyl, in particular Ci-C4-alkyl, especially methyl, ethyl or isopropyl, C2-C10- alkenyl, in particular C2-C4-alkenyl, especially ethenyl or 3-propenyl, C2-Cio-alkynyl, in particular C2-C4-alkynyl, especially ethynyl or 3-propynyl, Ci-C6-alkoxy, in particular Ci- C4-alkoxy, especially methoxy or ethoxy, hydroxy-C2-C6-alkyl, in particular hydroxy-C2- C4-alkyl, especially 2-ethoxyethyl, Ci-C4-alkoxy-C2-C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl, fluorinated Ci-C2-alkyl, in particular fluorinated Ci-alkyl, fluorinated Ci-C2-alkoxy, in particular fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, C(0)R³, in particular acetyl or propionyl, NR⁴R⁵, especially methyl- amino or dimethylamino, and C(0)OR⁸, especially methoxycarbonyl or ethoxycarbonyl.

Amongst the compounds of the present invention, where R¹ in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different, preference is given to those compounds, wherein R¹ in the formulae I, 1.1 , I.2, 1.3 or I.4 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12 with particular preference given to the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2:

Ar2.1 Ar2.2 Ar2.3

Ar2.4 Ar2.5 Ar2.6 

Ar2'.4 Ar2'.5

wherein # indicates the point of attachment of R¹ to the SO2 group, wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ have the meanings given above.

In the compounds of the formulae I, 1.1 , 1.2, 1.3 or 1.4, where R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, particular embodiments of the invention relate to compounds, wherein, the variables R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹, if present, individually or in particular in combination have the following meanings:

R¹⁴ if present, is hydrogen;

R¹⁵ if present, is hydrogen;

R¹⁶ if present, is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci- C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propionyl, and NR⁴R⁵, especially methylamino or dimethylamino;

R¹⁷ if present, is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci- C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propionyl, and NR⁴R⁵, especially methylamino or dimethylamino.

R¹⁸ if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, fluorinated Ci-alkyl, especially difluoromethyl or trifluoro- methyl, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl and Ci-C4-alkoxy-C2-C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl; in particular, R¹⁸ is hydrogen or methyl.

R¹⁹ if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, fluorinated Ci-alkyl, especially difluoromethyl or trifluoro- methyl, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl and Ci-C4-alkoxy-C2-C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl. In particular, R¹⁹ is hydrogen or methyl.

Examples of radicals R¹ are given in the following tables A, which are particular embodiments according to the present invention.

Table A: Meanings of R¹

# R

1 phenyl

2 3-methylphenyl

3 3-methoxyphenyl

4 3-trifluoromethylphenyl

5 3-trifluoromethoxyphenyl

6 4-acetylphenyl

7 4-methylphenyl

8 4-ethylphenyl

9 4-methoxyphenyl

10 4-trifluoromethylphenyl

1 1 4-trifluoromethoxyphenyl

12 4-hydroxyphenyl # R

13 4-chlorophenyl

14 4-(methylthio)phenyl

15 4-mercaptophenyl

16 2-cyanophenyl

17 3-cyanophenyl

18 4-cyanophenyl

19 4-aminophenyl

20 4-nitrophenyl

21 4-(dimethylamino)phenyl

22 3-fluoro-4-methylamino-phenyl

23 3-fluoro-4-methylphenyl

24 3-fluoro-4-methoxyphenyl

25 3-methyl-4-fluorophenyl

26 4-chloro-3-cyanomethyl

27 4-carboxyphenyl

28 3,4-dicyanophenyl

29 3-methyl-4-cyanophenyl

30 3-fluoro-4-cyanophenyl

31 3-methoxy-4-cyanophenyl

32 3-hydroxy-4-cyanophenyl

33 3,5-difluoro-4-cyanophenyl

34 4-pentafluorosulfanyl

35 2-pyridyl

36 3-pyridyl

37 4-pyridyl

38 5-fluoropyridine-2-yl

39 5-hyd roxypyrid i ne-2-yl

40 5-cyanopyridine-2-yl

41 5-ethynyl pyrid i ne-2-yl

42 5-methylpyridine-2-yl

43 5-methoxypyridine-2-yl

44 5-trifluoromethoxypyridine-2-yl

45 5-trifluoromethylpyridine-2-yl

46 5-acetylpyridine-2-yl

47 5-nitropyridine-2-yl

48 5-cyanopyridine-3-yl

49 5-ethynyl pyrid i ne-3-yl # R

50 5-fluoropyridine-3-yl

51 5-bromopyridine-3-yl

52 5-methoxypyridine-3-yl

53 5-trifluoromethoxypyridine-3-yl

54 5-methylpyridine-3-yl

55 5-trifluoromethylpyridine-3-yl

56 6-cyanopyridine-3-yl

57 6-fluoropyridine-3-yl

58 6-chloropyridine-3-yl

59 6-methylpyridine-3-yl

60 6-ethylpyridine-3-yl

61 6-trifluoromethylpyridine-3-yl

62 6-methoxypyridine-3-yl

63 6-ethoxypyridine-3-yl

64 6-methylthiopyridine-3-yl

65 6-trifluoromethoxypyridine-3-yl

66 6-fluoropyridine-2-yl

67 6-cyanopyridine-2-yl

68 6-methylpyridine-2-yl

69 6-ethylpyridine-2-yl

70 6-(dimethylamino)pyridine-2-yl

71 6-acetylpyridine-2-yl

72 6-trifluoromethylpyridine-2-yl

73 6-methoxypyridine-2-yl

74 6-trifluoromethoxypyridine-2-yl

75 2-fluoropyridine-3-yl

76 2-cyanopyridine-3-yl

77 2-methylpyridine-3-yl

78 2-methoxypyridine-3-yl

79 2-trifluoromethoxypyridine-3-yl

80 2-trifluoromethylpyridine-3-yl

81 6-aminopyridine-3-yl

82 6-dimethylaminopyridine-3-yl

83 3-fluoropyridine-2-yl

84 3-cyanopyridine-2-yl

85 3-methylpyridine-2-yl

86 3-methoxypyridine-2-yl # R

87 3-trifluoromethylpyridine-2-yl

88 3-trifluoromethoxypyridine-2-yl

89 4-fluoropyridine-2-yl

90 4-cyanopyridine-2-yl

91 4-methylpyridine-2-yl

92 4-methoxypyridine-2-yl

93 4-trifluoromethylpyridine-2-yl

94 4-trifluoromethoxypyridine-2-yl

95 6-isopropylpyridine-3-yl

96 3-fluoropyridine-4-yl

97 3-cyanopyridine-4-yl

98 3-methylpyridine-4-yl

99 3-methoxypyridine-4-yl

100 3-trifluoromethylpyridine-4-yl

101 3-trifluoromethoxypyridine-4-yl

102 2-fluoropyridine-4-yl

103 2-cyanopyridine-4-yl

104 2-methylpyridine-4-yl

105 2-methoxypyridine-4-yl

106 2-trifluoromethylpyridine-4-yl

107 2-trifluoromethoxypyridine-4-yl

108 5-fluoro-6-methylpyridine-2-yl

109 5-f I u o ro-6-m eth oxypy ri d i n e-2-y I

1 10 4,6-dimethylpyridine-2-yl

1 1 1 4-cyano-6-methoxypyridine-3-yl

1 12 4-methyl-6-methoxypyridine-3-yl

1 13 5-cyano-3-fluoro-4-methoxypyridine-2-yl

1 14 5-cyano-4-fluoropyridine-2-yl

1 15 5-cyano-4-methylpyridine-3-yl

1 16 2-cyano-6-methylpyridine-4-yl

1 17 6-cyano-5-hydroxypyridine-3-yl

1 18 pyrimidine-2-yl

1 19 pyrimidine-5-yl

120 pyrimidine-4-yl

121 5-cyanopyrimidine-2-yl

122 6-cyanopyrimidine-4-yl

123 2-hydroxy-4-methylpyrimidine-5-yl # R

124 5-ethynyl pyri m id i n-2-yl

125 4,6-dimethylpyrimidine-2-yl

126 4-chloro-5-methoxypyrimidine-2-yl

127 2-methylthiopyrimidine-5-yl

128 2-trif I uorom ethoxypyri m id i ne-5-yl

129 5-methylpyrazin-2-yl

130 5-cyanopyrazin-2-yl

131 5-cyano-6-fluoropyrazin-2-yl

132 5-methoxypyridazin-3-yl

133 6-chloropyridazin-3-yl

134 6-cyano-5-methoxy-1 ,2,4-triazin-2-yl

135 furan-2-yl

136 furan-3-yl

137 5-methylfuran-2-yl

138 5-ethylfuran-2-yl

139 5-hydroxymethylfuran-2-yl

140 2-methylfuran-3-yl

141 3-cyanofuran-2-yl

142 5-nitrofuran-2-yl

143 2,5-dimethylfuran-3-yl

144 2-thienyl

145 3-thienyl

146 5-methyl-2-thienyl

147 5-ethyl-2-thienyl

148 3-methyl-2-thienyl

149 2-methyl-3-thienyl

150 5-methyl-3-thienyl

151 4-methyl-3-thienyl

152 5-cyano-2-thienyl

153 4-cyano-2-thienyl

154 3-cyano-2-thienyl

155 2-cyano-3-thienyl

156 5-cyano-3-thienyl

157 4-cyano-3-thienyl

158 5-hydroxymethyl-3-thienyl

159 4-trifluoromethoxy-3-thienyl

160 5-ethynyl-2-thienyl # R

161 5-cyano-4-fluoro-2-thienyl

162 4-chloro-5-ethyl-2-thienyl

163 2,5-dimethyl-3-thienyl

164 1 -methylpyrrol-2-yl

165 1 -methyl-5-hydroxypyrrol-3-yl

166 1 -methylpyrazol-3-yl

167 1 -methylpyrazol-4-yl

168 1 -ethylpyrazol-4-yl

169 1 ,3-dimethylpyrazol-4-yl

170 1 ,5-dimethylpyrazol-4-yl

171 1 -oxopyrazol-4-yl

172 1 -methylimidazol-4-yl

173 1 -methylimidazol-5-yl

174 1 ,2-dimethylimidiazol-4-yl

175 1 ,2-dimethylimidiazol-5-yl

176 4-methylthiazol-2-yl

177 2,4-dimethylthiazol-5-yl

178 2-hydroxy-4-methylthiazol-5-yl

179 isothiazol-3-yl

180 isothiazol-4-yl

181 isothiazol-5-yl

182 4-methylisothiazol-3-yl

183 5-methylisothiazol-3-yl

184 3-methylisothiazol-4-yl

185 3-methylisothiazol-5-yl

186 4-methylisothiazol-5-yl

187 5-methylisothiazol-4-yl

188 3-cyanoisothiazol-5-yl

189 4-cyanoisothiazol-5-yl

190 5-cyanoisothiazol-4-yl

191 3,5-dimethylisothiazol-4-yl

192 4-methyl-5-trifluoromethylisothiazol-3-yl

193 2-methyloxazol-5-yl

194 oxazol-5-yl

195 3,5-dimethylisoxazol-4-yl

196 1 ,2,3-thiadiazol-4-yl

197 1 ,2,3-thiadiazol-5-yl # R

198 4-methyl-1 ,2,3-thiadiazol-5-yl

199 5-methyl-1 ,2,3-thiadiazol-4-yl

200 5-cyano-1 ,3,4-thiadiazol-2-yl

201 4-cyano-1 ,2,3-thiadiazol-5-yl

202 1 ,3,4-thiadiazol-2-yl

203 1 ,3,4-oxadiazol-2-yl

204 5-methyl-1 ,3,4-oxadiazol-2-yl

205 5-cyano-1 ,3,4-oxadiazol-2-yl

206 1 ,2,4-triazol-4-yl

207 1 ,2,4-[4H]triazol-3-yl

208 1 ,2,3,4-tetrazol-5-yl

209 1 ,2,3,4-tetrazol-1 -yl

210 2-methyl-1 ,2,3,4-tetrazol-5-yl

21 1 benzo-1 ,4-dioxan-6-yl

212 benzo-1 ,3-dioxol-5-yl

According to a particular embodiment, R² is phenyl or a 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R^2a which are identical or different.

According to a particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R² is phenyl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R^2a which are identical or different. Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the point of attachment to the benzazine core of (I) do not carry a radical R^2a. Preferably, the CN group is located in the para-position with respect to the point of attachment to the benzazine core of (I). In particular, phenyl carries a CN radical and may additionally carry 1 or 2 radicals R^2a, which are identical or different.

According to another particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R² is 6-membered heteroaryl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R^2a which are identical or different. In particular, 6-membered heteroaryl carries a CN radical and may additionally carry 1 radical R^2a. Amongst these compounds, those are preferred, wherein the one or more nitrogen ring atom(s) are not located in the ortho position with respect to the point of attachment to the benzazine core of (I). Amongst these com- pounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the point of attachment to the benzazine core of (I) do not carry a radical R^2a. Preferably, the CN group is located in the para-position with respect to the point of attachment to the benzazine core of (I).

According to a further particular embodiment, the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R² is 5-membered C-bound heteroaryl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R^2a which are identical or different. Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R^2a. In particular, 5-membered heteroaryl carries a CN radical and may additionally carry 1 radical R^2a.

In these embodiments, the radicals R^2a, if present, have the aforementioned meanings and are preferably selected from halogen, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 - methoxyethyl or 2-methoxyethyl, C(0)R³, especially acetyl or propionyl, NR⁴R⁵ especially methylamino or dimethylamino, and C(0)OR⁸; especially methoxycarbonyl, eth- oxycarbonyl, or two radicals R^2a, which are bound to adjacent carbon atoms, together may also form a moiety O-Alk-0, wherein Alk is selected from CH2, CH2CH2, CHF and CF2. Especially, the radicals R^2a, if present, are selected from the group consisting of halogen, in particular fluorine or chlorine, CN (= cyano), NO2 (nitro), OH, SH, C1-C4- alkyl, in particular methyl, ethyl or isopropyl, Ci-C4-alkoxy, in particular methoxy or ethoxy, NH₂, NR⁴R⁵, in particular NH(CH₃), or N(CH₃)2, fluorinated Ci-alkyl, in particular difluoromethyl or trifluoromethyl, SF₅, fluorinated Ci-alkoxy, in particular difluorometh- oxy or trifluoromethoxy, or two radicals R^2a, which are bound to adjacent carbon atoms, together may also form a moiety O-Alk-0, wherein Alk is selected from CH2, CH2CH2, CHF and CF2. Particularly preferably, R^2a is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy

Amongst the compounds of the present invention, where R² in the formulae I, 1.1 ,

1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R^2a which are identical or different, preference is given to those compounds, wherein R² in the formulae I, 1.1 , I.2, 1.3 or I.4 is a radical of the formula Ar3:

wherein # indicates the point of attachment to the benzazine core of (I),

K' is N or C-R²¹,

L' is N or C-R²²,

M' is N or C-R²³,

Q is N or CH,

P is N or CH,

wherein R²¹, R²² and R²³, independently of each other, are hydrogen or have one of the meanings given for R^2a, provided that 1 or 2 of the variables K', L' or M', are C- CN.

Amongst the compounds of the present invention, where R² in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R^2a which are identical or different, preference is given to those compounds, wherein R² in the formulae I, 1.1 , 1.2, 1.3 or I.4 is selected from radicals of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 and Ar3.12, with particular preference given to the formulae Ar3.1 and Ar3.3:

Ar3.7 Ar3.8 Ar3.9

wherein # indicates the point of attachment to the benzazine core of (I), and wherein R²¹ , R²² and R²³, independently of each other, are hydrogen or have one of the meanings given for R^2a provided that one of the radicals R²¹ , R²² or R²³ is CN. In the radicals Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6 and Ar3.1 1 , R²² is preferably CN while R²¹ , and, if present, R²³ are different from CN.

In the compounds of the formulae I, 1.1 , I.2, 1.3 or 1.4, where R² is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, preferred embodiments of the invention relate to compounds, wherein, the variables R²¹ , R²² and R²³, if present, individually or in particular in combination have the following meanings, provided that one of the radicals R²¹ , R²² or R²³ is CN.

R²¹ , if present, is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxym ethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.

R²², if present, is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.

R²³, if present, is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl,

1 - methoxyethyl or 2-methoxyethyl.

In the compounds of the formulae I, 1.1 , 1.2, 1.3 or 1.4, where R² is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, more preferred embodiments of the invention relate to compounds, wherein, the variables R²¹, R²² and R²³, if present, individually or in particular in combination have the following meanings, provided that one or two of R²¹, R²² or R²³ is (are) CN:

R²¹, if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy;

R²² if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy; and

R²³, if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy

In the compounds of the formulae I, 1.1 , I.2, 1.3 or 1.4, where R² is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6 or Ar3.1 1 , particular embodiments of the invention relate to compounds, wherein, the variables R²¹, R²² and R²³, if present, individually or in particular in combination have the following meanings:

R²¹ is selected from hydrogen, halogen, OH, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4- alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, and Ci-C4-alkoxy-Ci- C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.

R²² is CN.

R²³ , if present, is selected from hydrogen, halogen, OH, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or

2- methoxyethyl.

In the compounds of the formulae I, 1.1 , 1.2, 1.3 or 1.4, where R² is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6 or Ar3.1 1 , special embodiments of the invention relate to compounds, wherein, the variables R²¹, R²² and R²³, if present, individually or in particular in combination have the following meanings: R²¹ is selected from the group consisting of hydrogen, halogen, OH, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

R²² is CN.

R²³, if present, is selected from the group consisting of hydrogen, halogen, OH, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

Amongst the compounds of the present invention, where R² in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which carries a CN radical and which may additionally carry 1 , 2 or 3 radicals R^2a which are identical or different, preference is given to those compounds, wherein R¹ in the formulae I, 1.1 , I.2, 1.3 or 1.4 is a radical of the formulae Ar4, Ar5 or Ar6:

Ar4 Ar5 Ar6 wherein # indicates the point of attachment of R² to the benzazine core of (I), A is N or C-R²⁴,

A' is N or C-R²⁵,

D is N or C-R²⁶,

E is N or C-R²⁷,

G is O, S or N-R²⁸,

G' is O, S or N-R²⁹,

wherein R²⁴, R²⁵, R²⁶ and R²⁷, independently of each other, are hydrogen or have one of the meanings given for R^2a, and wherein R²⁸ and R²⁹ are selected from hydrogen, cyano, NH2, OH, Ci-Cio-alkyl, in particular Ci-C4-alkyl, especially methyl, ethyl or isopropyl, C2-Cio-alkenyl, in particular C2-C4-alkenyl, especially ethenyl or 3-propenyl, C2-Cio-alkynyl, in particular C2-C4-alkynyl, especially ethynyl or 3-propynyl, C1-C6- alkoxy, in particular Ci-C4-alkoxy, especially methoxy or ethoxy, hydroxy-C2-C6-alkyl, in particular hydroxy-C2-C4-alkyl, especially 2-ethoxyethyl, Ci-C4-alkoxy-C2-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl, fluorinated Ci-C2-alkyl, in particular fluorinated Ci-alkyl, fluorinated Ci-C2-alkoxy, in particular fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, C(0)R³, in particular acetyl or propionyl, NR⁴R⁵, especially methylamino or dimethylamino, and C(0)OR⁸, especially methoxycarbonyl or ethoxycarbonyl. In the formulae Ar4 and Ar6 one of the ring members A or D or E is C-CN.

Amongst the compounds of the present invention, where R² in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which carries a CN radical and which may additionally carry 1 , 2 or 3 radicals R^2a which are identical or different, preference is given to those compounds, wherein R² in the formulae I, 1.1 , I.2, 1.3 or 1.4 is selected from radicals of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 and Ar6.3 with particular preference given to the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 and Ar5.8:

Ar4.7 Ar4.8 Ar4.9

Ar4.13 Ar4.14 Ar4.15

Ar5.1 Ar5.2

Ar5.4 Ar5.5 Ar5.6

wherein # indicates the point of attachment of R² to the benzazine core of (I), wherein R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ have the meanings given above and wherein either R²⁴ or R²⁶ or R²⁷ in the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.15, Ar6.1 , Ar6.2 and Ar6.3 is CN.

In the compounds of the formulae I, 1.1 , 1.2, 1.3 or 1.4, where R² is selected from radicals of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 and Ar6.3, particular embodiments of the invention relate to compounds, wherein, the variables R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹, if present, individually or in particular in combination have the following meanings:

R²⁴ is selected from the group consisting of hydrogen and cyano, more preferably hydrogen; R²⁵ is selected from the group consisting of hydrogen and halogen, more preferably hydrogen;

R²⁶ is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, CN (= cyano), NO2 (nitro), OH, SH, Ci-C4-alkyl, in particular methyl, ethyl or isopropyl, Ci-C4-alkoxy, in particular methoxy or ethoxy, NH2, NR⁴R⁵, in particular NH(CH3), or N(CH3)2, fluorinated Ci-alkyl, in particular difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, in particular difluoromethoxy or trifluoromethoxy.

R²⁷ is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, CN (= cyano), NO2 (nitro), OH, SH, Ci-C4-alkyl, in particular methyl, ethyl or isopropyl, Ci-C4-alkoxy, in particular methoxy or ethoxy, NH2, NR⁴R⁵, in particular NH(CH3), or N(CH3)2, fluorinated Ci-alkyl, in particular difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, in particular difluoromethoxy or trifluoromethoxy.

R²⁸ is selected from the group consisting of hydrogen, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl, and Ci-C4-alkoxy-C2- C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl.

R²⁹ is selected from the group consisting of hydrogen, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl, and Ci-C4-alkoxy-C2- C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl.

R²⁴ is hydrogen.

R²⁵ is hydrogen.

R²⁶ is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoro- methoxy and trifluoromethoxy.

R²⁷ is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

R²⁸ is hydrogen or C1-C4 alkyl, especially hydrogen or methyl. R²⁹ is hydrogen or C1-C4 alkyl, especially hydrogen or methyl.

Examples of radicals R² are given in the following tables B, which are particular embodiments according to the present invention. Table B: Meanings of R²

R²

1 3-cyanophenyl

2 4-cyanophenyl

3 4-cyano-3-fluorophenyl

4 4-cyano-3-chlorophenyl

5 3,4-dicyanophenyl

6 3-methyl-4-cyanophenyl

7 3-ethyl-4-cyanophenyl

8 3-methoxy-4-cyanophenyl

9 3-hydroxy-4-cyanophenyl

10 3,5-difluoro-4-cyanophenyl

1 1 5-cyanopyridine-2-yl

12 5-cyanopyridine-3-yl

13 6-cyanopyridine-3-yl

14 6-cyanopyridine-2-yl

15 4-cyanopyridine-2-yl

16 2-cyanopyridine-4-yl

17 5-cyano-6-methoxypyridine-3-yl

18 6-cyano-5-methoxypyridine-3-yl

19 6-cyano-5-fluoropyridine-3-yl

20 5-cyano-4-fluoropyridine-2-yl

21 5-cyano-4-methylpyridine-2-yl

22 2-cyano-6-methylpyridine-4-yl

23 6-cyano-5-hyd roxypyrid ine-3-yl

24 5-cyanopyrimidine-2-yl

25 2-cyanopyrimidine-4-yl

26 2-cyanopyrimidine-5-yl

27 6-cyanopyrimidine-4-yl

28 5-cyanopyrazin-2-yl

29 5-cyano-6-fluoropyrazin-2-yl

30 5-cyanopyridazin-3-yl

31 6-cyanopyridazin-3-yl

32 6-cyanopyridazin-4-yl 6-cyano-1 ,2,4-triazin-3-yl

6-cyano-5-methoxy-1 ,2,4-triazin-3-yl

3-cyano-1 ,2,4-triazin-6-yl

3-cyanofuran-2-yl

5-cyanofuran-2-yl

4-cyanofuran-2-yl

2-cyanofuran-3-yl

5-cyanofuran-3-yl

5-cyano-4-fluorofuran-2-yl

5-cyano-4-chlorofuran-2-yl

3-cyano-2-thienyl

5-cyano-2-thienyl

2-cyano-3-thienyl

5-cyano-3-thienyl

4-cyano-2-thienyl

5-cyano-4-fluoro-2-thienyl

5-cyano-4-chloro-2-thienyl

2-cyanopyrol-1 -yl

3-cyanopyrrol-1 -yl

3-cyano-4-methylpyrrol-1 -yl

4-cyanopyrol-2-yl

5-cyanopyrrol-2-yl

3-cyano-1 -methylpyrrol-2-yl

1 -methyl-5-cyanopyrrol-2-yl

1 -methyl-4-cyanopyrrol-2-yl

5-cyano-4-methyl-pyrrol-2-yl

1 -methyl-2-cyanopyrrol-3-yl

5-cyano-pyrrol-3-yl

1 -methyl-5-cyanopyrrol-3-yl

2-cyanoimidazol-4-yl

2-cyanoimidazol-5-yl

2-cyano-1 -methylimidazol-4-yl

4-cyanoimidazol-1 -yl

2-cyano-1 -methylimidazol-5-yl

4-cyanoimidazol-2-yl

5-cyanoimidazol-2-yl

4-cyano-1 -methylimidazol-2-yl 70 5-cyano-1 -methylimidazol-2-yl

71 5-cyanothiazol-2-yl

72 4-cyanothiazol-2-yl

73 2-cyanothiazol-4-yl

74 2-cyanothiazol-5-yl

75 2-cyanooxazol-4-yl

76 2-cyanooxazol-5-yl

77 4-cyanooxazol-2-yl

78 5-cyanooxazol-2-yl

79 3-cyanoisoxazol-5-yl

80 5-cyanoisoxazol-3-yl

81 3-cyanoisothiazol-5-yl

82 5-cyanoisothiazol-3-yl

83 3-cyanopyrazol-5-yl

84 5-cyanopyrazol-3-yl

85 3-cyano-1 -methylpyrazol-5-yl

86 5-cyano-1 -methylpyrazol-3-yl

87 3-cyanopyrazol-1 -yl

88 4-cyanopyrazol-1 -yl

89 3-cyano-4-chloropyrazol-1 -yl

90 3-cyano-4-fluoropyrazol-1 -yl

91 5-cyano-1 ,3,4-oxadiazol-2-yl

92 5-cyano-1 ,3,4-thiadiazol-2-yl

93 5-cyano-1 ,2,4-triazol-3-yl

94 5-cyano-4-methyl-1 ,2,4-triazol-3-yl

A particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R¹ is a radical of the formula Ar1 and wherein R² is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6,

Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.

Another particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formula Ar1 and wherein R² is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

A further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formulae Ar2 or Ar2' and wherein R² is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formulae Ar2 or Ar2' and wherein R² is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formula Ar1 .1 to Ar1.5, in particular a radical Ar1 .1 or Ar1 .3, and wherein R² is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.

A further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , I.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formula Ar1 .1 to Ar1 .5, in particular a radical Ar1 .1 or Ar1 .3, and wherein R² is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, in particular from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R² is a radical of the formula Ar3, in particu- lar a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, in particular from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R² is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6,

Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

A further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formulae Ar1 .1 or Ar1 .3, and wherein R² is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.

A further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is a radical of the formulae Ar1 .1 or Ar1 .3, and wherein R² is a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R² is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 and Ar3.3.

A further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R² is a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.

With regard to the radical C(0)R³ the following meanings are particular embodiments of R³: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl. In particu- lar the radical C(0)R³ is selected from acetyl or propionyl.

With regard to the radical NR⁴R⁵ the following meanings are particular embodiments of R⁴: hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl. The following meanings are particular embodiments of R⁵: C1-C4- alkyl, in particular methyl, ethyl, n-propyl, isopropyl or n-butyl. In other embodiments, R⁴, R⁵ together with the nitrogen atom, to which they are bound, form an N-bound, 5- or 6-membered saturated nitrogen heterocycle, such as pyrrolidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1 -yl or 4-methylpiperazin-1 -yl. In particular the radical NR⁴R⁵ is selected from methylamino, ethylamino, n-propylamino, isopropylamino, di- methylamino, diethylamino, N-methyl-N-ethylamino, N-methyl-N-isopropylamino, N- methyl-N-propylamino, pyrrolidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1 -yl and 4-methylpiperazin-1 -yl.

With regard to the radical N(OR⁶)R⁷ the following meanings are particular embodiments of R⁶: hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n- propyl, isopropyl or n-butyl. The following meanings are particular embodiments of R⁷: hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n-propyl, isopropyl or n- butyl.

With regard to the radical C(0)OR⁸ the following meanings are particular embodiments of R⁸: Ci-C4-alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl. In particular the radical C(0)OR⁸ is selected from methoxycar- bonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl or tert.-butoxycarbonyl.

With regard to the radical C(0)R^x the following meanings are particular embodiments of R^x: Ci-C4-alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl. In particular the radical C(0)R^x is selected from acetyl or propionyl.

Examples of suitable compounds according to the present invention are the compounds of the formula (I) as given in the following tables 1 to 94, 95 to 188, 189 to 282 and 283 to 376, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides.

Table 1 Compounds of the formula (I), wherein X is O and R² is 3-cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A

(Compounds 1-1 to 1-212);

Table 2 Compounds of the formula (I), wherein X is O and R² is 4-cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A

(Compounds 1-213 to I-424

Table 3 Compounds of the formula (I), wherein X is O and R² is 4-cyano-3- fluorophenyl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds I-425 to I-636);

Table 4 Compounds of the formula (I), wherein X is O and R² is 4-cyano-3- chlorophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-637 to I-848);

Table 5 Compounds of the formula (I), wherein X is O and R² is 3,4- dicyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-849 to 1-1060); Table 6 Compounds of the formula (I), wherein X is O and R² is 3-methyl-4- cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1061 to 1-1272);

Table 7 Compounds of the formula (I), wherein X is O and R² is 3-ethyl-4- cyanophenyl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1273 to 1-1484);

Table 8 Compounds of the formula (I), wherein X is O and R² is 3-methoxy-4- cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1485 to 1-1696);

Table 9 Compounds of the formula (I), wherein X is O and R² is 3-hydroxy-4- cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1697 to 1-1908);

Table 10 Compounds of the formula (I), wherein X is O and R² is 3,5-difluoro-4- cyanophenyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1909 to 1-2120);

Table 1 1 Compounds of the formula (I), wherein X is O and R² is 5-cyanopyridine-

2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-2121 to I-2332);

Table 12 Compounds of the formula (I), wherein X is O and R² is 5-cyanopyridine-

3- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-2333 to I-2544);

Table 13 Compounds of the formula (I), wherein X is O and R² is 6-cyanopyridine-

3- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-2545 to I-2756);

Table 14 Compounds of the formula (I), wherein X is O and R² is 6-cyanopyridine- 2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-2757 to I-2968);

Table 15 Compounds of the formula (I), wherein X is O and R² is 4-cyanopyridine- 2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-2969 to 1-3180);

Table 16 Compounds of the formula (I), wherein X is O and R² is 2-cyanopyridine-

4- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-3181 to I-3392);

Table 17 Compounds of the formula (I), wherein X is O and R² is 5-cyano-6- methoxypyridine-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-3393 to I-3604);

Table 18 Compounds of the formula (I), wherein X is O and R² is 6-cyano-5- methoxy-pyridine-3-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-3605 to 1-3816); Table 19 Compounds of the formula (I), wherein X is O and R² is 6-cyano-5-fluoro- pyridine-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-3817 to I-4028);

Table 20 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- fluoropyridine-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-4029 to I-4240);

Table 21 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- methylpyridine-2-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-4241 to I-4452);

Table 22 Compounds of the formula (I), wherein X is O and R² is 2-cyano-6- methylpyridine-4-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-4453 to I-4664);

Table 23 Compounds of the formula (I), wherein X is O and R² is 6-cyano-5- hydroxypyridine-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-4665 to I-4876);

Table 24 Compounds of the formula (I), wherein X is O and R² is 5- cyanopyrimidine-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-4877 to I-5088);

Table 25 Compounds of the formula (I), wherein X is O and R² is 2- cyanopyrimidine-4-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-5089 to I-5300);

Table 26 Compounds of the formula (I), wherein X is O and R² is 2- cyanopyrimidine-5-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-5301 to 1-5512):

Table 27 Compounds of the formula (I), wherein X is O and R² is 6- cyanopyrimidine-4-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-5513 to I-5724);

Table 28 Compounds of the formula (I), wherein X is O and R² is 5-cyanopyrazin-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-5725 to I-5936);

Table 29 Compounds of the formula (I), wherein X is O and R² is 5-cyano-6- fluoropyrazin-2-yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds I-5837 to 1-6148);

Table 30 Compounds of the formula (I), wherein X is O and R² is 5-cyano- pyridazin-3-yl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds 1-6149 to I-6360);

Table 31 Compounds of the formula (I), wherein X is O and R² is 6-cyano- pyridazin-3-yl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds 1-6361 to I-6572); Table 32 Compounds of the formula (I), wherein X is O and R² is 6-cyano- pyridazin-4-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-6573 to I-6784);

Table 33 Compounds of the formula (I), wherein X is O and R² is 6-cyano-1 ,2,4- triazin-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-6785 to I-6996);

Table 34 Compounds of the formula (I), wherein X is O and R² is 6-cyano-5- methoxy-1 ,2,4-triazin-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-6997 to I-7208);

Table 35 Compounds of the formula (I), wherein X is O and R² is 3-cyano-1 ,2,4- triazin-6-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-7209 to I-7420)

Table 36 Compounds of the formula (I), wherein X is O and R² is 3-cyanofuran-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-7421 to I-7632);

Table 37 Compounds of the formula (I), wherein X is O and R² is 4-cyanofuran-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-7633 to I-7844);

Table 38 Compounds of the formula (I), wherein X is O and R² is 5-cyanofuran-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-7845 to I-8056);

Table 39 Compounds of the formula (I), wherein X is O and R² is 2-cyanofuran-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-8057 to I-8268);

Table 40 Compounds of the formula (I), wherein X is O and R² is 5-cyanofuran-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-8269 to I-8480);

Table 41 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- fluorofuran-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-8481 to I-8692);

Table 42 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- chlorofuran-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-8693 to I-8904);

Table 43 Compounds of the formula (I), wherein X is O and R² is 3-cyano-2-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-8905 to 1-91 16);

Table 44 Compounds of the formula (I), wherein X is O and R² is 4-cyano-2-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-91 17 to I-9328); Table 45 Compounds of the formula (I), wherein X is O and R² is 5-cyano-2-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-9329 to I-9540);

Table 46 Compounds of the formula (I), wherein X is O and R² is 2-cyano-3-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-9541 to I-9752);

Table 47 Compounds of the formula (I), wherein X is O and R² is 5-cyano-3-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-9753 to I-9964);

Table 48 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4-fluoro- 2-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds I-9965 to 1-10176);

Table 49 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4-chloro- 2-thienyl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10177 to 1-10388);

Table 50 Compounds of the formula (I), wherein X is O and R² is 2-cyanopyrrol-1 -yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10388 to 1-10600);

Table 51 Compounds of the formula (I), wherein X is O and R² is 3-cyanopyrrol-1 -yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10601 to 1-10812);

Table 52 Compounds of the formula (I), wherein X is O and R² is 3-cyano-4- methyl-pyrrol-1 -yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10813 to 1-1 1024)

Table 53 Compounds of the formula (I), wherein X is O and R² is 4-cyano-pyrrol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1 1025 to 1-1 1236);

Table 54 Compounds of the formula (I), wherein X is O and R² is 5-cyano-pyrrol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1 1237 to 1-1 1448);

Table 55 Compounds of the formula (I), wherein X is O and R² is 3-cyano-1 - methyl-pyrrol-2-yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds 1-1 1449 to 1-1 1660);

Table 56 Compounds of the formula (I), wherein X is O and R² is 1 -methyl-5- cyano-pyrrol-2-yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds 1-1 1661 to 1-1 1872);

Table 57 Compounds of the formula (I), wherein X is O and R² is 1 -methyl-4- cyano-pyrrol-2-yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds 1-1 1873 to 1-12084); Table 58 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- methyl-pyrrol-2-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12085 to 1-12296);

Table 59 Compounds of the formula (I), wherein X is O and R² is 1 -methyl-2- cyano-pyrrol-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12297 to 1-12508);

Table 60 Compounds of the formula (I), wherein X is O and R² is 5-cyano-pyrrol-3- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12509 to 1-12720);

Table 61 Compounds of the formula (I), wherein X is O and R² is 1 -methyl-5- cyanopyrrol-3-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12721 to 1-12932);

Table 62 Compounds of the formula (I), wherein X is O and R² is 2-cyanoimidazol-

4- yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12933 to 1-13144);

Table 63 Compounds of the formula (I), wherein X is O and R² is 2-cyanoimidazol-

5- yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13145 to 1-13356);

Table 64 Compounds of the formula (I), wherein X is O and R² is 2-cyano-1 - methylimidazol-4-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13357 to 1-13568);

Table 65 Compounds of the formula (I), wherein X is O and R² is 4-cyano-imidazol- 1 -yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13569 to 1-13780);

Table 66 Compounds of the formula (I), wherein X is O and R² is 2-cyano-1 - methyl-imidazol-5-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13781 to 1-13992)

Table 67 Compounds of the formula (I), wherein X is O and R² is 4-cyano-imidazol- 2-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13993 to 1-14204);

Table 68 Compounds of the formula (I), wherein X is O and R² is 5-cyano-imidazol- 2-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14205 to 1-14416);

Table 69 Compounds of the formula (I), wherein X is O and R² is 4-cyano-1 - methylimidazol-2-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14417 to 1-14628);

Table 70 Compounds of the formula (I), wherein X is O and R² is 5-cyano-1 - methylimidazol-2-yl, and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14629 to 1-14840); Table 71 Compounds of the formula (I), wherein X is O and R² is 5-cyanothiazol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14841 to 1-15052);

Table 72 Compounds of the formula (I), wherein X is O and R² is 4-cyanothiazol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15053 to 1-15264);

Table 73 Compounds of the formula (I), wherein X is O and R² is 2-cyanothiazol-4- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15265 to 1-15476);

Table 74 Compounds of the formula (I), wherein X is O and R² is 2-cyanothiazol-5- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15477 to 1-15688);

Table 75 Compounds of the formula (I), wherein X is O and R² is 2-cyanooxazol-4- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15689 to 1-15900);

Table 76 Compounds of the formula (I), wherein X is O and R² is 2-cyanooxazol-5- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15901 to 1-1612);

Table 77 Compounds of the formula (I), wherein X is O and R² is 4-cyanooxazol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-161 13 to 1-16324);

Table 78 Compounds of the formula (I), wherein X is O and R² is 5-cyanooxazol-2- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16325 to 1-16536);

Table 79 Compounds of the formula (I), wherein X is O and R² is 3-cyanoisoxazol- 5-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16537 to 1-16748);

Table 80 Compounds of the formula (I), wherein X is O and R² is 5-cyanoisoxazol- 3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16749 to 1-16960);

Table 81 Compounds of the formula (I), wherein X is O and R² is 3- cyanoisothiazol-5-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16961 to 1-17172);

Table 82 Compounds of the formula (I), wherein X is O and R² is 5- cyanoisothiazol-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17173 to 1-17384);

Table 83 Compounds of the formula (I), wherein X is O and R² is 3-cyanopyrazol-5- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17385 to 1-17596); Table 84 Compounds of the formula (I), wherein X is O and R² is 5-cyanopyrazol-3- yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17597 to 1-17808);

Table 85 Compounds of the formula (I), wherein X is O and R² is 3-cyano-1 - methylpyrazol-5-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17809 to 1-18020);

Table 86 Compounds of the formula (I), wherein X is O and R² is 5-cyano-1 - methylpyrazol-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18021 to 1-18232);

Table 87 Compounds of the formula (I), wherein X is O and R² is 3-cyano-pyrazol- 1 -yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18233 to 1-18444);

Table 88 Compounds of the formula (I), wherein X is O and R² is 4-cyano-pyrazol- 1 -yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18445 to 1-18656);

Table 89 Compounds of the formula (I), wherein X is O and R² is 3-cyano-4- chloropyrazol-1 -yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds 1-18657 to 1-18868);

Table 90 Compounds of the formula (I), wherein X is O and R² is 3-cyano-4- fluoropyrazol-1 -yl and wherein R¹ has one of the meanings given in rows

1 to 212 of table A (Compounds 1-18869 to 1-19080);

Table 91 Compounds of the formula (I), wherein X is O and R² is 5-cyano-1 ,3,4- oxadiazol-2-yl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds 1-19081 to 1-19292);

Table 92 Compounds of the formula (I), wherein X is O and R² is 5-cyano-1 ,3,4- thiadiazol-2-yl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds 1-19293 to 1-19504);

Table 93 Compounds of the formula (I), wherein X is O and R² is 5-cyano-1 ,2,4- triazol-3-yl and wherein R¹ has one of the meanings given in rows 1 to

212 of table A (Compounds 1-19505 to 1-19716);

Table 94 Compounds of the formula (I), wherein X is O and R² is 5-cyano-4- methyl-1 ,2,4-triazol-3-yl and wherein R¹ has one of the meanings given in rows 1 to 212 of table A (Compounds 1-19717 to 1-19928). Tables 95 to 188: Compounds of the formula (I), which correspond to the compounds of tables 1 to 94 wherein X = O has been replaced by X = S (Compounds 1-19929 to I-39856). Tables 189 to 282: Compounds of the formula (I), which correspond to the compound of tables 1 to 94 wherein X = O has been replaced by X = SO

(Compounds I-39856 to I-59784).

Tables 283 to 376: Compounds of the formula (I), which correspond to the compound of tables 1 to 94 wherein X = O has been replaced by X = SO2

(Compounds I-59785 to 1-79712).

Examples of particular preferred compounds according to the present invention are the compounds listed below, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides:

5-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile,

4-(4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(4-nitrophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile, 4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

5-(4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5- (4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4- (4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5- (4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(6-methylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene- 2-carbonitrile,

5-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4- (4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5- (4-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)thiophene-2-carbonitrile,

5-(4-(4-fluoro-3-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

2-methoxy-4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile, 4-(4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

4-(4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile,

4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

2,3-dihydro-4-[(4-methylphenyl)sulfonyl]-6-(3-cyano-2-fui7l)-4H-benz-[1 ,4]-oxazin, 4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

4-[4-(4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile, 4-[4-(6-methoxypyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4- [4-(6-(4-morpholinyl)pyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin yl)benzonitrile,

5-[4-(3-fluoro-4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5- [4-(5-methyl-2-thienyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile,

5-[4-(4-chlorophenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophen carbonitrile,

4-[4-(4-methoxyphenyl)sulfonyl-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4-[4-(4-methoxyphenyl)sulfonyl-1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile.

2-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-3-carbonitrile,

4-(4-((4-acetylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-((5-methylthiophen-2-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-((6-(5-cyanothiophen-2-yl)-2H-benzo[b][1 ,4]oxazin-4(3H)-yl)sulfonyl)benzoic acid,

4-(4-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-((6-chloropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile, 5- (4-((6-chloropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4-(4-((6-(methylthio)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5-(4-((4-(pentafluorothio)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4- (4-((6-methylpyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

6- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)nicotinonitrile,

5-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)picolinonitrile,

5- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)pyrimidine-2-carbonitrile, 2-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-5-carbonitrile,

4- (4-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile,

5-(4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-

6-yl)thiophene-2-carbonitrile,

5- (4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)picolinonitrile,

6- (4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)nicotinonitrile,

5- (4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)pyrimidine-2-carbonitrile,

6- (4-((6-aminopyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)nicotinonitrile,

5-(4-((6-aminopyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile.

Further examples of particular preferred compounds according to the present invention are the compounds listed below, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides:

2-methoxy-4-(4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)benzonitrile,

4-(4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

2-methoxy-4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

4-(4-(4-mercaptophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile, 2-methoxy-4-(4-(4-(methylthio)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(4-ethylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

2-methoxy-4-(4-(4-(trifluoromethoxy)phenylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4-(4-(4-ethylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile, 4-(4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H-pyrrole-2- carbonitrile,

4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 -methyl-1 H- pyrrole-2-carbonitrile,

4-(4-(4-chloro-3-cyanophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

2-fluoro-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

2-ethyl-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(6-isopropylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

2-methoxy-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

4-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- fluorobenzonitrile,

4-(4-(6-ethylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

2-chloro-4-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile, 4-(4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

4-(4-(6-(dimethylamino)pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4-(4-(6-aminopyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2-carbonitrile,

4-(4-(4-ethylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2- carbonitrile,

4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile,

4- (4-(3-fluoro-4-(methylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile,

5- (4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H-pyrrole- 2-carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2- carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-2- carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- fluoropicolinonitrile,

5-(4-(4-chloro-5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- methoxypicolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3-methyl-1 H- pyrrole-2-carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3-fluoro-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3-methoxy-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-2- carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene- 2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-2- carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2- carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H-pyrrole- 2-carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-2- carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-

2- carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)picolinonitrile, 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- fluoropicolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- methoxypicolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)picolinonitrile,

3- fluoro-5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3-methoxy-5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2- carbonitrile,

4- (4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile, 2-methoxy-4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile, 2-fluoro-4-(4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-2- chlorobenzonitrile,

4-(4-(4-chlorophenylsulfonyl)-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-2- methoxybenzonitrile,

2-fluoro-4-(4-tosyl-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile, 4-(4-(3-fluoro-4-methoxyphenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

4-(4-tosyl-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4- (4-(4-(methylthio)phenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

5- (4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile,

5-(4-(phenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile,

5-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile,

4-(4-(4-aminophenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

4- (4-(phenylsulfonyl)-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)furan-2- carbonitrile,

5- (4-tosyl-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-2-carbonitrile, 5-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-3- carbonitrile,

5-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-2-carbonitrile,

4- (4-(4-chlorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-2- methoxybenzonitrile;

2-fluoro-4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile;

4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)furan-2-carbonitrile;

5- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-2-carbonitrile;

4- (4-(4-(methylthio)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile;

5- (4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2-carbonitrile; and

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile.

The compounds herein were named according to lUPAC standard using the software Struct=Name in ChemDraw Ultra version 10 from Cambridgesoft.

The compounds I according to the invention are prepared in analogy with methods known from the literature. Compounds of the formula I, wherein X is oxygen or sulfur can be prepared e.g. starting from 6-halogen-3,4-dihydro-2H- benzo[b][1 ,4]oxazine II and 6-halogen-3,4-dihydro-2H-benzo[b][1 ,4]thiazine II, respectively, or the salts thereof as depicted in schemes 1 , 2 and 3.

Scheme 2:

Scheme 3:

In schemes 1 , 2 and 3, R¹ and R² have the aforementioned meanings. R^a and R^b are hydroxyl or Ci-C4-alkoxy such as methoxy or ethoxy or R^a and R^b together form a moiety 0-R-O, wherein R is ethan-1 ,2-diyl, 1 ,1 ,2,2-tetramethylethan-1 ,2-diyl, propan- 1 ,3-diyl, 2, 2-dimethylpropan-1 ,3-diyl or 1 ,1 ,3-trimethylpropan-1 ,3-diyl. Hal and Hal' are each independently chlorine, bromine or iodine, preferably bromine or chlorine. "Pd" denominates a Pd(0) catalyst or a Pd(0) precursor compound, optionally in combination with a suitable ligand. "Base" denominates a suitable basic compound which assists in the formation of the sulfonylamide formation.

According to the first step of scheme 1 , the halogen compound II or a salt thereof, e.g. an acid addition salt such as the salt with a hydrohalic acid, is treated with a boronic compound III, in a known manner, under conditions of a Suzuki coupling in the presence of a palladium catalyst to give a compound IV intermediate. The reaction is usually carried out in the presence of a base and a palladium catalyst, such as for example described in the following literature: Synth. Commun. Vol. 1 1 , p. 513 (1981 ); Acc. Chem. Res. Vol. 15, pp. 178-184 (1982); Chem. Rev. Vol. 95, pp. 2457-2483 (1995); Organic Letters Vol. 6 (16), p. 2808 (2004); "Metal catalyzed cross coupling reactions", 2^nd Edition, Wiley, VCH 2005 (Eds. De Meijere, Diederich); "Handbook of organopalladium chemistry for organic synthesis" (Eds Negishi), Wiley, Interscience, New York, 2002; "Handbook of functionalized organometallics", (Ed. P. Knochel), Wiley, VCH, 2005 or in the experimental part of this application.

Suitable catalysts are in tetrakis(triphenylphosphine)palladium(0);

bis(triphenylphosphine)palladium(ll) chloride; bis(acetonitrile)palladium(ll) chloride;

[1 ,1 '-bis(diphenylphosphino)ferrocene]-palladium(ll) chloride/methylene chloride (1 :1 ) complex; bis[bis-(1 ,2-diphenylphosphino)ethane]palladium(0);

bis(bis-(1 ,2-diphenylphosphino)butane]-palladium(ll) chloride; palladium(ll) acetate; palladium(ll) chloride; and palladium(ll) acetate/tri-o-tolylphosphine complex or mixtures of phosphines and Pd salts or phosphines and Pd-complexes e.g. diben- zylideneacetone-palladium and tri-tert-butylphosphine (or its tetrafluoroborate), triscy- clohexylphosphine; or a polymer-bound Pd-triphenylphosphine catalyst system.

Suitable bases are, in general, inorganic compounds, such as alkali metal and al- kaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, caesium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, po- tassium ethoxide and potassium tert.-butoxide, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, preferably potassium carbonate.

The reaction is usually carried out in an inert organic solvent. Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, ethers, such as diisopropyl ether, tert. -butyl methyl ether, 1 ,4-dioxane, anisole and tetrahydrofuran and dimethoxyethane, alkanol, e.g. Ci-C6-alkanols such as methanol, ethanol or n- propanol, or mixtures of these solvents, particularly preferably ethers, such as dioxane or a mixture of toluene/methanol.

According to the second step of scheme 1 , the compound IV intermediate is reacted with a sulfonylchloride V in accordance with standard methods of organic chem- istry and as described in the experimental part of this application. This reaction is usually carried out in an inert organic solvent. Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloro- methane, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert. -butyl methyl ether, dioxane, anisole and tetrahydrofuran.

The reaction of compound IV intermediate with compound V is customarily carried out in the presence of an auxiliary base. Suitable bases are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogen carbonate or potassium hydrogen carbonate, and organic bases, for example trialkylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine, 4-dimethylamino- pyridine and the like. The auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound IV.

If not indicated otherwise, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the Suzuki coupling (with regard to reactions using microwaves, see Tetrahedron 2001 , 57, p. 9199 ff. and p. 9225 ff. and also, in a general manner, "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002.

A skilled person will appreciate that the first step of scheme 2 can be performed under conditions as described for the second step of scheme 1 . Similarly, the second step of scheme 2 can be performed under conditions as described for the first step of scheme 1.

It may be advantageous that schemes 1 and 2 include an additional step as shown in scheme 3. According to scheme 3, compound II is first converted into the arylboronic compound I la under conditions of a Suzuki coupling. The conversion can be performed e.g. as described above for the first step of scheme 1 . Preferably, the diboron ester Ilia is bis(pinacolato)diboron, bis(neopentyl glycolato)diboron or bis(hexylene glycolato)diboron, especially bis(pinacolato)diboron. Then, compound I la can be converted into compound I either by reacting I la with an appropriate heteroaro- matic or aromatic halogenide VII to give compound IV intermediate and reacting the obtained compound IV intermediate with a sulfonylchloride V as described in scheme 1 or by reacting I la with an appropriate sulfonylchloride V to give compound Via interme- diate and then reacting the obtained compound Via intermediate with a (het)arylhalide R²Hal' (compound VII) under conditions of a Suzuki coupling as described in scheme 2.

The starting materials of the formula II required for preparing the compounds I are known from the literature or commercially available or can be prepared by the av- erage skilled person trained in organic chemistry without undue burden following routine laboratory practice.

Boronic compounds III and Ilia are commercially available or can be prepared according to "Science of Synthesis" Vol. 6, Thieme, 2005.

If sulfonylchlorides V are not commercially available, they can be obtained ac- cording to procedures known in the art without undue burden following routine laboratory practice.

Compounds of the formula I, wherein X is S=0, can be prepared by treating compounds I, wherein X is sulphur with an appropriate amount of an oxidizing agent, in particular an inorganic or organic peroxide or hydroperoxide, e.g. a percarboxylic acid such as 3-chloroperbenzoic acid or monoperphthalic acid or with an appropriate amount of alkali metal periodate or hydroperoxide.

Compounds of the formula I, wherein X is SO2, can be prepared by, for example, treating the compound of formula I, wherein X is S or SO, with an appropriate amount of an oxidizing agent, in particular an inorganic or organic peroxide or hydroperoxide, e.g. a percarboxylic acid such as 3-chloroperbenzoic acid or monoperphthalic acid or with an appropriate amount of alkali metal periodate or hydroperoxide.

The N-oxides of compounds of formula I can be prepared by, for example, treating a compound of the formula I with an oxidizing agent, in particular an inorganic or organic peroxide or hydroperoxide, such as hydrogen peroxide, or percarboxylic acids, such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid.

Besides the guidance provided in the general procedures below, alternative synthetic transformations that may be employed in the synthesis of compounds of formula I and in the synthesis of intermediates involved in the synthesis of compounds of formula I are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as: J. March. Advanced Organic Chemistry, 4th ed.; John Wiley : New York (1992) R. C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH : New York (1999); F. A. Carey; R. J.

Sundberg. Advanced Organic Chemistry, 2nd ed.; Plenum Press: New York (1984) T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley : New York (1999) . L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed.; University Science Books: Mill Valley, CA (1994) L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis ; John Wiley : New York (1994) . A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive Organic Functional Group Transformations ; Pergamon Press: Oxford, UK (1995). G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive Organometallic Chemistry ; Pergamon Press: Oxford, UK (1982) . B. M. Trost; I. Fleming. Comprehensive Organic Synthesis ; Pergamon Press: Oxford, UK (1991 ) A. R. Katritzky ; C. W. Rees Eds. Comprehensive Heterocylic Chemistry ; Pergamon Press: Oxford, UK (1984) A. R. Katritzky; C. W. Rees ; E. F. V. Scriven, Eds. Comprehensive Heterocylic Chemistry; Pergamon Press : Oxford, UK (1996) . C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal Chemistry : Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and related topics include Organic Reactions ; John Wiley : New York; Organic Syntheses ; John Wiley : New York; Reagents for Organic Synthesis : John Wiley : New York; The Total Synthesis of Natural Products ; John Wiley : New York; The Organic Chemistry of Drug Synthesis ; John Wiley : New York ; Annual Reports in Organic Synthesis ; Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben- Weyl) ; Thieme : Stuttgart, Germany. Furthermore, databases of synthetic transformations include Chemical Abstracts, which may be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which may be searched using SpotFire, and RE- ACCS.

As shown in the examples below, the advantageous properties of the compounds of the invention include their ability of effectively inhibiting cell proliferation and their activity as HIF inhibitors. For example, the compounds of the present invention were shown to inhibit the activation of HIF-mediated transcription under hypoxic conditions. Thus, the compounds of the invention can be used for the preparation of a medicament for the treatment of a disorder characterized by pathophysiological HIF signaling. A person skilled in the art of medical, biological and/or pharmacological science can de- termine with routine methodology if a disorder is characterized by undesirable HIF signaling. Tissues affected by such diseases will overexpress genes that are induced by activation of the HIF responsive element (HRE). HIF-1 acts by binding to HIF- responsive elements (HREs) in promoters that generally contain the sequence

NCGTG. The genes affected by HIF activity which are regulated by said promoters are well known in the art and were also described in multiple reviews (see e.g. figure 3 of Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3).

In animal studies, HIF-1 overexpression is associated with increased tumor growth, increased vascularisation, metastasis and fibrosis, e.g. renal fibrosis (see: Semenza, G, Drug Discovery Today, vol. 12, no. 19/20, October 2007; Kimura, Kuniko, et al., American Journal of Physiology (2008), 295(4, Pt. 2), F1023-F1029 and for a review see N.J. Mabjeesh et al., Histol. Histopathol (2007) 22:559-572). Fibrosis is the formation or development of excess fibrous connective tissue in an organ or tissue. Recently, it has become clear that inhibition of HIF-1 activity also acts to prevent inflammation, by virtue of its essential role in the activation and infiltration of macro- phages and neutrophils into affected tissues (see e.g. Giaccia et al., Drug Discovery, vol. 2, October 2003).

For the above mentioned reasons, a compound of the present invention can be used to treat an inflammatory disease, a hyperproliferative disease or disorder, a hy- poxia related pathology and also diseases characterized by pathophysiological hyper- vascularisation. Therefore, as a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of the present invention, optionally together with at least one physiologically acceptable carrier or auxiliary substance.

As a further aspect, the invention provides a therapeutical composition which, in addition to the compound of the invention comprises at least one further pharmaceutically active compound that is useful to treat one of the aforementioned diseases or disorders. Such therapeutical compositions are useful because the therapeutic efficiency of the compounds of the invention can be amplified by the presence of said at least one further pharmaceutically active compound and vice versa. For example, it was shown that inhibiting HI F1 a activity via antisense gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma (see Liu, Feng- jun et. al., Cancer Science (2008), 99(10), 2055-2061 ).

In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention and a second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper- vascularisation, and, optionally, a pharmaceutically acceptable carrier or excipient. Such compositions are also useful to obtain synergistic therapeutic effects and also to prevent drug resistance of tumor cells, for example. It is also for these reasons, that current chemotherapy generally involves administering a cocktail of different cytotoxic and/or cytostatic compounds to improve the effectiveness of the treatment and reduce the possibility of tumor cell adaptation.

In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention in combination with radiation therapies.

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 pharmaceu- tically acceptable salts, their N-oxides, the salts of said N-oxides, ester derivatives 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).

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

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

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

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Interestingly, HIF inhibitors, such as the compounds of the invention, can prevent the development of tumor resistance towards chemotherapeutic drugs and can make cancer cells more sensitive towards radiotherapy (see e.g. Palayoor ST, et al., Int J Cancer. 2008 Nov 15;123(10):2430-7 and Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3). Thus, useful second therapeutic agents that can be combined with a compound of the invention to produce the pharmaceutical composition of the invention include, without limitation, a (further) HIF-1 inhibitor, a cytotoxic compound and cy- tostatic compounds.

A HIF-1 inhibitor can be, e.g. selected from the group consisting of PX-478 (S-2- amino-3-[4'-/S/,A/,-bis(2-chloroethyl)amino]phenyl propionic acid A/-oxide dihydrochlo- ride); a topoisomerase-1 inhibitor such as 8,9-Dimethoxy-5-(2-/S/,/V- dimethylaminoethyl)-2,3-methylenedioxy-5/-/-dibenzo[c, ?][1 ,6] naphthyridin-6-one (also known as ARC-1 1 1 or topovale) or (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9- dihydroxy-1 H-pyrano[3' ,4' :6,7] indolizino [1 ,2-b]quinoline-3,14-(4H ,12H)-dione monohydrochloride (also referred to as tropotecan); echinomycin; chetomin

(NSC289491 ); cyclosporine A; 3-[2-[4-[bis(4-fluorophenyl)methylene]-1 -piperidinyl]-2,3- dihydro-2thioxo-4(1 H)-quinazolinone (R59949); an inhibitor of the PIK3K/Akt/mTor sig- nailing cascade, e.g., LY294002, wortmannin or rapamycin; an inhibitor of the MAPK signalling cascade, e.g. the MEK1 inhibitor PD98059; a soluble guanyl cyclase stimulator such as 3-(5'hydroxymethyl-2' -furyl)-1 -benzylindazole (YC-1 ); a heat-shock protein 90 inhibitor, in particular radicicol, the radicicol analogue KF58333 or geldanamy- cin; a microtubule disrupting agent, in particular e.g. taxol, vincristine or 2- methoxyestradiol; a histone deacetylase inhibitor, e.g. FK228; a thioredoxin inhibitor, in particular PX-12 or pleurotin; UCNO-1 ; diphenylene iodonium, genestein and car- boxyamido-triazole.

Many cytotoxic or cytostatic compounds are known to the expert artisan skilled in the therapy of hyperproliferative diseases or disorders such as a tumor or cancer dis- ease. For example, cytotoxic and cytostatic compounds include, but are not limited to, pure or mixed anti-estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling such as herceptin; any compound that interchelates DNA, such as doxorubicin. Particularly preferred cytostatic or cytotoxic drugs, which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hor- mones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracen- diones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, acla- rubicine, ambazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxyme- sterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon Y , irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepa- crine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mito- tane, 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, rapa- mycin, rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sul- fadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine,

sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sul- fathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tenyposide, testo- lactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, tri- aziquone, treosulfan, trimethoprim, trofosfamide, UCN-01 , vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their respective derivatives or analogs thereof. Several of the above indicated drugs are now administered simultaneously for cancer therapy and, consequently, it is also envisioned that more than one cytostatic and/or cytotoxic drug can be comprised in compositions of the present invention.

As mentioned above, HIF inhibitors render cancer cells more vulnerable to chemotherapy and radiation therapy. Thus, to effectively treat a hyperproliferative disease or disorder, the compounds of the present invention can be co-administered with other active medicinal agents and/or administered in conjunction with other anticancer, antitumor, or antiproliferative disease therapies. In one aspect, the invention provides a method for treating a hyperproliferative disease or disorder comprising administering a compound according to the invention to a patient prior to, during and/or after said patient was subjected to a radiation therapy, a chemotherapy, an immunotherapy, a la- ser/microwave thermotherapy or a gene therapy using antisense DNA and RNA (for examples see Moeller et al., Cancer Cell 2004 5429-441 ).

In a further aspect the invention provides, as already outlined above, the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the therapy, including the treatment or prevention, of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology such as e.g. diabetic retinopathy, ischemic reperfusion injury, ischemic myocardial and limb disease, ischemic stroke, sepsis and septic shock (see, e.g. Liu FQ, et al., Exp Cell Res. 2008 Apr 1 ;314(6): 1327-36); and a disease characterized by pathophysiological hyper- vascularisation, such as e.g. angiogenesis in osteosarcoma (see, e.g.: Yang, Qing- cheng et al., Dier Junyi Daxue Xuebao (2008), 29(5), 504-508), macular degeneration, in particular, age-related macular degeneration and vasoproliferative retinopathy (see e.g. Kim JH, et al., J Cell Mol Med. 2008 Jan 19).

As was already mentioned above, HIF inhibitors, such as the compounds of the invention, are useful to treat inflammatory disease or disorder. For example, it was shown that oxygen-dependent HIF isoforms are strongly upregulated in psoriatic skin (see e.g. Rosenberger C, et al., J Invest Dermatol. 2007 Oct; 127(10):2445-52). Furthermore it was shown that a HIF inhibitor, neovastat, inhibits the airway inflammation in asthma (see e.g., Lee SY, et al., Vascul Pharmacol. 2007 Nov-Dec; 47(5-6):313-8). Furthermore, recent evidence also shows that HIF participates under hypoxic conditions in joint inflammation and destruction in rheumatoid arthritis (see e.g., Ahn, J. K., et al., Rheumatology (Oxford, United Kingdom) (2008), 47(6), 834-839). Thus, in a preferred embodiment of the use of the invention, the inflammatory disease is selected form the group consisting of atherosclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, psoriasis, in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichthyosis; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus ery- thematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea;

scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foli- aceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic skin reaction; and periorale dermatitis. Therefore, a further preferred embodiment of the present invention encompasses a combination of one or more compounds of the present invention and medication in current use for treating such inflammatory diseases or conditions, which can be determined by a person skilled in the art of pharmacological sciences. Such therapeutics for combination can be selected e.g. from a group of anti-inflammatory steroids, antioxidants, therapeutic antibodies or fusion proteins that sequester or bind to certain cytokines or cellular epitopes associated with inflammatory processes, or a dihydrofolate reductase inhibitor like methotrexate.

The compounds of the invention show anti-proliferative effects. Furthermore, HIF inhibitors, such as the compounds of the invention are effective medicaments for the treatment of various cancer diseases (see review article by e.g. Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3 and also review article by N.J. Mabjeesh et al., His- tol. Histopathol (2007), 22:559-572). Thus, also preferred is the use of the invention wherein the hyperproliferative disease is selected from the group consisting of a tumour or cancer disease, precancerosis, dysplasia, histiocytosis, a vascular proliferative disease and a virus-induced proliferative disease. Thus, in one preferred embodiment of the use of the invention the hyperproliferative disease is a tumor or cancer disease selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lympho- cytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, glioma, bone cancer and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal (in particular malignant renal cell carcinoma (RCC)), uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non- small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and pap- illary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endo- theliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, leio- myosarcoma, rhabdomyosarcoma, squamous cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, glioblastoma, papillary adenocarcinomas, cystadenocarcinoma, bronchogenic carcinoma, seminoma, embryonal carcinoma, Wilms' tumor, small cell lung carcinoma, epithelial carcinoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, heman- gioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, glaucoma, hemangioma, heavy chain disease and metastases.

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

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

Estrogen receptor refers to a group of receptors which are activated by the hormone 17β -estradiol (estrogen). Two types of estrogen receptor exist: ER which is a member of the nuclear hormone family of intracellular receptors and the estrogen G protein coupled receptor GPR30 (GPER), which is a G-protein coupled receptor. Es- trogen and the estrogen receptors have been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer and endometrial cancer and other diseases. As the compounds of the invention are capable of inhibiting estrogen receptor-mediated transcriptional activity, they can be used to treat said diseases.

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

In therapeutic use as an antagonist of estrogen receptor signaling, acting through inhibition of cellular replication, the compounds utilized in the use of the invention are administered at the initial dosage of about 0.02 mg/kg to about 20 mg/kg daily. A daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 1 mg/kg being most preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

A compound according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Parenteral administration and particular intravenous administration, preferably by depot injection, is preferred. Depending on the route of ad- ministration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.

Thus, preferably, a compound of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a supposi- tory, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation. Preferably the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebe- sole.

Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid. Typically, such a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. bio- compatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. A compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if com- pared to the free drug and a prolonged more even release of the enclosed drug.

Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chlo- ride may be incorporated in infusion or injection solutions.

Production of sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solu- tions are vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Besides the preferred excipients mentioned already above, also the following excipients can be chosen, without limitation, to be used with the various pharmaceutical forms of a compound of the invention:

a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hy- droxyethyl cellulose, polyvinyl pyrrolidone and the like;

b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates,

c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like. Other suitable excipients can be found in the Handbook of Pharmaceutical Ex- cipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.

It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that the average daily dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 3 g. However, in a preferred use of the present invention a compound of the invention is administered to a subject in need thereof in an amount ranging from 1 .0 to 1000 mg, preferably ranging from 10 to 500 mg preferably ranging from 50 to 200 mg. The duration of therapy and the dosing frequency with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.

As is known in the art, the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous. Typically, a compound of the invention will be administered in ranges of 50 mg to 3 g, preferably 50 mg to 500 mg, if rectal or intragastric administration is used and in ranges of 10 to 500 mg, if parenteral administration is used.

If a person is known to be at risk of developing a disorder treatable with a compound of the invention, a prophylactic administration of the pharmaceutical composition according to the invention may be possible. In these cases, the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diag- nosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or until they are improving.

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.

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 examples and figures 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. SYNTHESIS EXAMPLES

All starting materials used in the examples are either commercially available or can be synthesized by the average skilled person trained in organic chemistry without undue burden following routine laboratory practice as outlined, for example in example 1 .

2,3-Dihydrobenzazine compounds of the formula 1.1 according to the present invention have been prepared for example according to the following approaches:

Additional step:

Similar approaches were used to prepare the compounds of the formula 1.2 starting from 6-bromo-3,4-dihydro-2H-1 ,4-benzo[b][1 ,4]thiazine (8) instead of compound

(1 )-

The compounds of the formula 1.3 and 1.4 can be prepared by selective oxidation of the compounds of the formula 1.2 according to standard procedures as outlined in the following schemes:

The general reaction procedures indicated above are as follows:

General Procedure A. A flask charged with 6-bromo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine hydrochloride (1 ) (1 .0 equiv), 1 ,1 '-bis(diphenylphosphino)ferro- cenepalladium(ll) chloride (=Pd(dppf)Cl2) (0.1 equiv), and the corresponding het- eroaromatic or aromatic boronic acid or boronic ester (1 .2 equiv) in 1 :1 (v/v) tolu- ene/methanol was purged with N2 under vigorous stirring, and 2.0 M aqueous K2CO3 solution (3.5 equiv) were added slowly. The mixture was heated at 88° C for 4 h. After cooling, the mixture was purified by flash column chromatography (silica gel, ethyl acetate/heptane, 1 :5 to 1 :3) to give the compounds (2) (44-82% yield).

General Procedure B. A flask charged with amine compounds (1 ) or (2) (1.0 equiv), the corresponding sulfonyl chloride (1 .1 equiv) and pyridine (10 equiv) in CH2CI2 was stirred at room temperature for 12 h. The reaction mixture was washed with concentrated aqueous NH4CI, subsequently with brine and dried over MgSC . The organic solvent was evaporated and the crude product was purified by preparative HPLC or by flash column chromatography (silica gel, ethyl acetate/heptane) to give the compounds 1.1 or (3) (70% to quantitative yield).

General Procedure C. Thermal Reaction: A reaction tube charged with compound (3) (1 .0 equiv), Pd(dppf)C (0.1 equiv), and the corresponding heteroaromatic or aromatic boronic acid or boronic ester (1 equiv) in methanol was purged with N2 under vigorous stirring and 2.0 M aqueous K2CO3 solution (2.5 equiv) were added slowly. The vessel was sealed and the mixture was heated in a carousel reactor block for 1 h at 85°C. After cooling, the mixture was diluted with CH2CI2, filtered through celite and eluted with CH2CI2. The organic solvent was evaporated and the crude product was purified by preparative HPLC or by flash column chromatography (silica gel, ethyl acetate/heptane,) to give the compound 1.1 (42-90% yield).

General Procedure C. Microwave reaction: A 2-5 ml microwave reaction vessel charged with compound (3) (1.0 equiv), Pd(dppf)C (0.1 equiv), and the corresponding heteroaromatic or aromatic boronic acid or boronic ester (1 equiv) in methanol was purged with N2 under vigorous stirring and 2.0 M aqueous K2CO3 solution (2.5 equiv) were added slowly. The vessel was sealed and the mixture was heated in a microwave oven for 30 min at 90°C (CEM Discover Microwave system, set to P_max=150W). After cooling, the mixture was diluted with CH2CI2, filtered through celite and eluted with CH2CI2. The organic solvent was evaporated and the crude product was purified by preparative HPLC or by flash column chromatography (silica gel, ethyl acetate/heptane,) to give the compounds 1.1 (42-90% yield).

General Procedure D. Bis(pinacolato)diboron (2 equiv), Pd(dppf)C (0.1 equiv), and potassium acetate (4.0 equiv) were added to a flask containing compound (1 ) (1 .0 equiv) in degassed 1 ,4-dioxane. The reaction mixture was heated to 95° C and stirred for 4 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (50 ml), filtered through a short column of silica gel, and further eluted with ethyl acetate. The combined organic solvent was washed with H2O and brine, dried over anhydrous MgSC and evaporated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate/heptane, 1 :3) to yield the boronate esters (4) (50 - 88% yield) as a cream or white-off solid. In a subsequent step, compounds (4) were transformed with a heteroaromatic or aromatic bromide to compounds 1.1 following the general procedures described above.

General procedure E. A compound of the formula 1.2 (1 .0 eq) was dissolved in CH2CI2. 3-Chloroperoxybenzoic acid (1.0 eq) was added at room temperature, and the mixture was stirred for 30 minutes. The progress of the reaction was monitored by LCMS. After completion, the reaction was quenched by addition of H2O, followed by extraction in CH2CI2 (3x). The organic layer was dried with Na2S0₄ and the solvent was removed under reduced pressure. The crude product was further purified by preparative LCMS.

General procedure F. A compound of the formula 1.2 (1 .0 eq) was dissolved in

CH2CI2. 3-Chloroperoxybenzoic acid (2.5 eq) was added at room temperature, and the mixture was stirred for 48 h. The progress of the reaction was monitored by LCMS. After completion, the reaction was quenched by addition of H2O, followed by extraction in CH2CI2 (3x). The organic layer was dried with Na2S0₄ and the solvent was removed under reduced pressure. The crude product was further purified by preparative LCMS.

6-Bromo-3,4-dihydro-2H-1 ,4-benzo[b][1 ,4]thiazine (8) was prepared by the method depicted in the following scheme:

(7) (8)

5-Bromo-2-fluoro nitrobenzene (5) (1 .0 equiv) was dissolved in DMF in a round bottom flask. Thioglycolic acid (1.1 equiv) and K2CO3 (2.5 equiv) were added. The mixture was allowed to stir at room temperature and the progress of the reaction was monitored by thin layer chromatography (TLC). After 16h the reaction was complete and water was added to the reaction mixture. The thus obtained aqueous mixture was washed with CH2CI2 and acidified with diluted hydrochloric acid to pH 1 . The resulting mixture was extracted with ethylacetate. The organic layer was dried over Na2S0₄ and the solvent was removed in vacuo to yield compound (6) in 99% yield as a yellow solid. This was used in the next step without any further purification.

Compound (6) (1 .0 equiv) was dissolved in glacial acetic acid in a round bottom flask and iron powder (4.0 equiv) was added. The mixture was heated under stirring to 70°C for 1 h. After completion of the reaction, the mixture was allowed to cool to room temperature and diluted with water. The aqueous mixture was extracted with ethyl ace- tate. The resulting organic layer was dried over Na2S0₄ and the solvent was removed under reduced pressure. The crude product was dissolved in toluene and the solution was evaporated. This procedure was repeated several times until the acetic acid was removed completely. No further purification was necessary. Compound (7) was obtained in 55% yield as a white, slightly yellow solid.

Compound (7) (1 .0 equiv) was dissolved in dry THF under nitrogen in a round bottom flask. Under vigorous stirring a 1 M solution of BH3^*THF complex (10.0 equiv) in THF was slowly added. Then the mixture was stirred for an additional 3h. After completion of the reaction, monitored by TLC, the reaction was quenched by addition of water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2S0₄ and the solvent was removed under reduced pressure. The crude product was further purified by flash column chromatography (cyclohexane / ethylace- tate 3:1 as eluent) to yield compound (8) as a white solid in 71 % yield.

NMR (DMSO d6): 6.80 (d, 1 H, J= 7.66 Hz), 6.68 (d, 1 H, J= 2.44 Hz), 6.56 (dd, 1 H, J= 7.66 Hz, J= 2.44 Hz), 6.35 (bm, 1 H), 3.5-3.4 (m, 2H), 2.97-2.92 (m, 2H).

Compounds of the formula I, wherein X is O, listed in table I below were prepared using the general procedures A to D described above. Compounds of the formula I, wherein X is S, were prepared using the general procedures A to D described above, starting from 6-bromo-3,4-dihydro-2H-benzo[b][1 ,4]thiazine. Compounds of the formula I, wherein X is SO or SO2, were prepared using the general procedures E or F, respectively, described above, starting from the corresponding benzothiazine-compound 1.2.

Compounds I were analyzed as follows:

Method A: HPLC/MS, using a Waters X-bridge Ci8-column, 5 μηη particle size, 4.6 x 150 mm (diameter x length) at a flow rate of 1 .75 ml/min with a linear gradient (water to methanol, 0.2% formic acid as modifier) from initially 99:1 to 1 :99 over 9.10 min, then held for 1 .80 min. Mass signals were determined using a Waters 3100 Mass Detector.

Method B: HPLC/MS, using a Waters X-bridge Ci8-column, 5 μηη particle size, 4.6 x 150 mm (diameter x length) at a flow rate of 1 .75 ml/min with a linear gradient (water to acetonitrile, 0.2% formic acid as modifier) from initially 99:1 to 1 :99 over 9.10 min, then held for 1 .80 min. Mass signals were determined using a Waters 3100 Mass Detector.

Compounds according to examples 1 to 22 listed in table I were analyzed according to method A. Compounds according to examples 23 to 52 listed in table I were analyzed according to method B.

Table 1

Ex. # R R² X Rt (HPLC) MS

[min]

1 4-methylphenyl 5-cyano-2-thienyl O 9.09 M+1 : 397

2 3-fluoro-4-methylphenyl 4-cyanophenyl O 9.26 M+1 : 409

3 3-fluoro-4-methoxyphenyl 4-cyanophenyl O 8.96 M+1 : 425

4 4-nitrophenyl 4-cyanophenyl O 9.84 M+HCO2H:

466

Ex: Example

Rt: retention time

Compounds of the formula I, listed in table II, below can be prepared using the general procedures described above.

Table II:

BIOLOGY EXAMPLES

1 . General cell culture maintenance and cell proliferation assays

MCF-7 human breast adenocarcinoma cells, Caki-1 and A498 clear cell renal carcinoma cells, and PC-3 prostate adenocarcinoma cells were obtained from ATCC (LGC Promochem). MIA PaCa-2 pancreatic carcinoma cells were purchased from ECACC (HPA Culture Collection). The CellSensor® HRE-bla HCT1 16 cell line (colo- rectal carcinoma) was obtained from Invitrogen. The HeLa cervical adenocarcinoma cell line was obtained from the Chemical Biology Core Facility (EMBL).

Cells were grown under humidified 95% air, 5% CO2 at 37°C in Dulbecco' s modified Eagle's medium (DMEM: MCF-7; HeLa; MIA PaCa-2; PC-3) supplemented with 10% fetal bovine serum (FBS), 100U/ml penicillin and 100μg/ml streptomycin and 2mM L-glutamine. The Caki-1 cell line was maintained under the same atmospheric conditions in McCoy's 5A medium (supplements as above), while the A498 cell line was cultured in Eagle' s Minimum Essential Medium (MEM) with FBS, penicillin/streptomycin, and L-glutamine (as above) and the addition of sodium pyruvate (1 mM). The HCT1 16 cell line was grown under the same atmospheric conditions in McCoy's 5A medium supplemented with 10% FBS and penicillin/streptomycin as above, in addition to blasticidin as a selection marker at a final concentration of 5μg/ml.

Cell proliferation experiments were carried out in 96-well tissue culture plates with seeding of 2000 cells/well in 100μΙ of the relevant medium. Cells were subsequently incubated under the conditions mentioned for 24h prior to addition of compounds.

For the determination of compound EC50 values, 10μΙ compounds at 1 1 X concentrations in 5.5% DMSO were added to the wells at various concentrations yielding a final constant percentage of 0.5% DMSO at the desired 1X compound concentration. As a positive control, cells were treated with 5.5% DMSO. The cells were then incubated for a further 72h prior to the measurement.

To determine the degree of inhibition of cell proliferation, cells were treated with

ATPIite solution according to the manufacturer's instructions (PerkinElmer, ATPIite 1 - step Luminescence ATP Detection Assay System) and luciferase readout measured on an Envision HTS multilabel plate reader (PerkinElmer) in luminescence mode accord- ing to established protocols. Raw data were imported into an ActivityBase database (IDBS, ID Business Solutions) and EC50 values calculated using the IDBS program ActivityBase XE.

Reference: EC50

< "Ι ΟΟηΜ:

100 - 500nM

> 500nM:

Example no. MCF-7 HeLa

1 +++ +++

2 +++ +++

3 +++ +++

4 + +

5 ++ ++

6 +++ +++

7 +++ +++

8 +++ +++

9 +++ +++

10 ++ ++

1 1 +++ +++

12 +++ +++

13 +++ +++

14 +++ +++

15 +++ +++

16 +++ +++

17 +++ +++

18 +++ +++

19 +++ +++

20 +++ +++

21 +++ +++

22 +++ +++

23 +++ +++

24 ++ +++

25 + +

26 +++ +++

27 +++ +++

28 +++ +++ Example no. MCF-7 HeLa

29 +++ +++

30 ++ ++

31 ++ ++

32 ++ -

34 ++ -

35 + -

36 ++ -

37 ++ -

38 ++ -

39 ++ -

40 + -

41 +++ -

42 ++ -

43 ++ -

44 ++ -

45 +++ -

46 +++ -

47 +++ -

48 ++ -

49 ++ -

50 ++ -

51 + -

52 + -

Other tumor cell lines

ER Transfection assay To determine the effect of the compounds on estrogen receptor (ER)-mediated transcriptional activity a transfection assay using the MCF-7 cell line was performed. A luciferase-coupled ERE-tk-/uc construct was obtained from Dr. G. Reid (EMBL).

In brief, MCF-7 cells were maintained as described previously and seeded on the first experimental day at a concentration of 3500 cells/well in 10ΟμΙ medium and incubated under standard conditions for 24h. Following this initial incubation period, transfection was carried out using 5ng of the ERE-tk-/uc construct (per well) and Exgene 500 transfection reagent (Fermentas) in a final buffered solution containing 150mM NaCI and 20mM Tris pH 8.4. The plates were then maintained for 3-4 hours until cell culture conditions in the incubator before compounds were added at 1 1 X concentrations to yield the final desired compound concentrations in 0.5% DMSO (in the same manner as for the proliferation assays described previously).

After an additional 24h incubation period the degree of inhibition of ER-signaling was determined via a luciferase readout. Cells were treated with britelite™ plus solution according to the manufacturer's instructions (PerkinElmer, britelite plus, Ultra-High Sensitivity Luminescence Reporter Gene Assay System) and luciferase levels measured on an Envision HTS multilabel plate reader (PerkinElmer) in luminescence mode according to established protocols. Raw data were imported into an ActivityBase database (IDBS, ID Business Solutions) and IC50 values calculated using the IDBS program ActivityBase XE.

Reference: EC50 < 100nM:

100 - 500nM

> 500nM:

As shown in these experiments, the compounds of the invention are capable of inhibiting estrogen receptor element-mediated transcriptional activity in an ERa - positive cell line. The utility of ER-modulating agents for the treatment of breast, uterine or prostate cancer, as well as metastatic bone disease, is known in the literature.

Park & Jordan (2002) Trends Mol. Med. 8(2): 82-88.

Steiner et al. (2001 ) Urology 57(4 Suppl 1 ): 68-72.

Campisi et al. (1993) Eur. J. Gynaecol. Oncol. 14(6): 479-483.

3. HIF / HRE reporter assay Inhibition of an activated HIF signaling response under chemically-induced hypoxic conditions due to compound treatment was determined using the CellSensor® HRE-bla HCT-1 16 stably transfected reporter cell line from Invitrogen according to the manufacturer's instructions.

Cells were maintained as described previously and seeded into 384-well, clear- bottom plates (Corning 3712) at 15000 cells/well in 32μΙ assay medium (Opti-MEM [Invitrogen], 0.5% FBS, 100U/ml penicillin, 100μg/ml streptomycin, 0.1 mM nonessential amino acids [NEAA], 1 mM sodium pyruvate, 5mM HEPES [pH 7.3]). Follow- ing a 2h incubation period, compounds (4μΙ) were subsequently added to the cells at 10X concentrations in 5% DMSO and incubated under normal conditions for 30min. To induce hypoxic conditions, 4μΙ of a 2mM deferoxamine (DFO) solution was added to the cells followed by 24h incubation under standard assay conditions (as described). Control wells included wells containing only medium (no cells) and wells treated with 0.5% DMSO instead of compound.

Prior to the readout, the Substrate Loading Solution was prepared as described in the manufacturer's protocol and 10μΙ added to each well. Following a further 2h incubation period at room temperature and in the dark, fluorescence was measured at two wavelengths (blue channel: ex. 409nm, em. 460nm; green channel: ex. 409nm, em. 530nm) on a PerkinElmer Envision HTS. For the analysis, the average signal of the cell-free wells at 460nm and 530nm was first subtracted from the blue and green channel data, respectively. The blue/green emission ratios were then calculated for each well, dividing the background-corrected blue emission values by the background- corrected green emission values. IC50 values were determined from these ratios using GraphPad Prism (Prism 5, GraphPad software, Inc.).

Reference: EC50 < 100nM:

100 - 500nM

> 500nM:

Example no. Evaluation

1 +++

2 +++

3 +++

4 ++

5 ++

6 +++

7 +++

8 +++ Example no. Evaluation

9 +++

10 +++

1 1 +++

12 +++

13 +++

14 +++

15 +++

16 +++

17 +++

18 +++

19 +++

20 +++

21 +++

22 +++

23 +++

24 +++

25 +

26 +++

27 +++

28 +++

29 +++

30 ++

31 ++

34 ++

The results of these experiments show that the compounds of the invention are capable of inhibiting hypoxia regulated element-mediated transcriptional activity under hypoxic conditions.

The compounds of this invention have a potency level that is not described for other benchmarks (e.g. the compound PX-478 or an LNA (locked nucleic acid) an- tisense construct, EZN-2968; both entities are currently the only known HIF-inhibitor products in Phase I of clinical development). 4. Caspase-3/7 assay

Activation of caspase-3/7 signal following treatment with test compounds was carried out using a Caspase-Glo® 3/7 kit (Promega). In brief, HeLa cells were seeded at a concentration of 1000 cells/well in 50μΙ medium into 96-well plates and incubated for 24h under the conditions described previously. Compounds at various concentrations were then added to the wells (at all final concentrations 0.5% DMSO) and incubated for a further 24h period. The plates were subsequently removed from the incubator and allowed to equilibrate to room temperature, after which 50μΙ Caspase-Glo re- agent was added to all wells, the plate shaken at 300rpm for 30s, and luminescence measured after a 30min incubation period on an Envision HTS (PerkinElmer).

Reference: EC50 < 100nM:

100 - 500nM

> 500nM:

Following treatment with compounds of the invention, a clear activation of the caspase-3/7 response was observed, indicating that apoptosis is a major factor in the observed decrease in cell proliferation due to the compound mechanisms of action.

Claims

We claim:

1 . 2,3-Dihydrobenzazine compound of the formula (I)

wherein

X is O or S(=0)_n with n being 0, 1 or 2; is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1 , 2 or 3 radicals R^1a which are identical or different; is selected from the group consisting of halogen, cyano, NO2, NH2, OH, SH, Ci-Cio-alkyl, C₂-Cio-alkenyl, C₂-Cio-alkynyl, Ci-C₆-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluori- nated Ci-C₂-alkyl, SF₅, fluorinated Ci-C₂-alkoxy, C(0)R³, NR⁴R⁵, N(OR⁶)R⁷ and C(0)OR⁸, or two radicals R^1a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk-0, wherein Alk is selected from CH₂, CH₂CH₂, CHF and CF₂; is phenyl or C- or N-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1 , 2 or 3 radicals R^2a which are identical or different; is selected from the group consisting of halogen, cyano, N0₂, NH₂, OH, SH, Ci-Cio-alkyl, C₂-Cio-alkenyl, C₂-Cio-alkynyl, Ci-C₆-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluorinated Ci-C₂-alkyl, SF₅, fluorinated Ci-C₂-alkoxy, C(0)R³, NR⁴R⁵, N(OR⁶)R⁷ and C(0)OR⁸, or two radicals R^2a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk'-O, wherein Alk' is selected from CH₂, CH₂CH₂, CHF and CF₂;

R³ is Ci-C₄-alkyl; R⁴ is hydrogen or Ci-C6-alkyl;

R⁵ is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Ci-C4-alkoxy-C2-C4-alkyl or a radical C(0)R^x, wherein R^x is Ci-C₄-alkyl; or

R⁴, R⁵ together with the nitrogen atom, to which they are bound, form an N- bound, 5- or 6-membered saturated nitrogen heterocycle;

R⁶ is hydrogen or Ci-C6-alkyl;

R⁷ is hydrogen or Ci-C6-alkyl;

R⁸ is hydrogen, Ci-C6-alkyl, hydroxy-C2-C6-alkyl or Ci-C₄-alkoxy-C2-C₄-alkyl; the pharmaceutically acceptable salts thereof, and, if one or both of R¹ and R² are a nitrogen containing 5- or 6-membered heteroaryl, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.

The compound according to claim 1 , wherein R¹ is phenyl or a 6-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different.

The compound according to claim 2, wherein R¹ is a radical of the formula Ar1

wherein # indicates the point of attachment to the SO2 group,

K is N or C-R¹¹,

L is N or C-R¹²,

M is N or C-R¹³,

wherein R¹¹, R¹² and R¹³, independently of each other, are hydrogen or have one of the meanings given for R^1a.

The compound according to claim 3, wherein R¹ is selected from radicals of the formulae Ar1 .1 to Ar1 .5:

Ai .4 A .5 wherein # indicates the point of attachment to the SO2 group, and wherein R¹¹, R¹² and R¹³, independently of each other, are hydrogen or have one of the mean ings given for R^1a.

The compound according to claim 3 or 4, wherein

R¹³, if present, are independently of each other selected from the group con sisting of hydrogen, halogen, OH, CN, SH, C1-C4 alkyl, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-alkoxy, Ci-C4-alkylthio, fluorinated Ci-alkyl, fluorinated C alkoxy, NH₂, NR⁴R⁵, hydroxy-Ci-C₄-alkyl and Ci-C₄-alkoxy-Ci-C₄-alkyl; if present, is selected from the group consisting of hydrogen, halogen, OH, SH, CN, N0₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C₄-alkoxy, Ci- C4-alkylthio, fluorinated Ci-C2-alkyl, SF₅, fluorinated Ci-C2-alkoxy, NH2, hy- droxy-Ci-C₄-alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, C(0)R³, NR⁴R⁵ and C(0)OR⁸; or, if K is C-R¹¹ and L is C-R¹², R¹¹ and R¹² together may also form a moiety O-Alk-0, wherein Alk is selected from CH₂, CH2CH2, CHF and CF₂.

The compound according to claim 4, wherein R¹ is a radical of the formulae Ar1 .1 or Ar1 .3.

7. The compound according to claim 6, wherein R¹¹ is selected from the group consisting of hydrogen, halogen, OH, methyl, di- fluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluorometh- oxy; is selected from the group consisting of halogen, OH, SH, CN, NO2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C4-alkoxy, Ci-C4-alkylthio, fluorinated Ci-alkyl, SF₅, fluorinated Ci-alkoxy, NH2, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy- Ci-C₄-alkyl, C(0)R³, and NR⁴R⁵; if K is C-R¹¹ and L is C-R¹², R¹¹ and R¹² together may also form a moiety

O-Alk-0, wherein Alk is selected from CH₂, CH2CH2, CHF and CF₂; and R¹³, if present, is hydrogen.

The compound according to claim 1 , wherein R¹ is a 5-membered C-bound het- eroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R^1a which are identical or different.

9. The compound according to claim 8, wherein R¹ is a radical of the formulae

#

A-D \— A'

\\ // W

or A .E

f^f G G'

A is N or C-R¹⁴,

A is N or C-R¹⁵,

D is N or C-R¹⁶,

E is N or C-R¹⁷,

G is O, S or N-R ⁸,

G' is O, S or N-R¹⁹,

wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷, independently of each other, are hydrogen or have one of the meanings given for R^1a and wherein R¹⁸ and R¹⁹ are selected from the group consisting of hydrogen, cyano, NH2, OH, Ci-Cio-alkyl, C2-Cio-alkenyl, C2- Cio-alkynyl, Ci-C6-alkoxy, hydroxy-C2-C6-alkyl, Ci-C4-alkoxy-C2-C4-alkyl, fluorinated Ci-C₂-alkyl, fluorinated Ci-C₂-alkoxy, C(0)R³, NR⁴R⁵, and C(0)OR⁸. The compound according to claim 9, wherein R¹ is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2M , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2M 0, Ar2M 1 and Ar2M 2:

Ar2.1 Ar2.2 Ar2.3

Ar2.4 Ar2.5 Ar2.6

Ar2.7 Ar2.8

Ar2.10 Ar2.1 1 Ar2.12

Ar2.13 Ar2.14 Ar2.15

Ar2.16 Ar2.17

Ar2M Ar2'.2 Ar2'.3

15

Ar2'.4 Ar2'.5 Ar2'.6

Ar2'.7 Ar2'.8 Ar2'.9

Ar2M 0 Ar2M 1 Ar2M 2 wherein # indicates the point of attachment of R¹ to the SO2 group, wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ have the meanings given in claim 9. 1 1 . The compound according to claim 9 or 10, wherein R¹⁴ if present, is hydrogen;

R¹⁵ if present, is hydrogen;

R¹⁶ if present, is selected from the group consisting of hydrogen, halogen, OH, SH, CN, N0₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C₄-alkoxy, Ci- C4-alkylthio, fluorinated Ci-alkyl, fluorinated Ci-alkoxy, NH2, hydroxy-Ci- C₄-alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, C(0)R³ and NR⁴R⁵;

R¹⁷ if present, is selected from the group consisting of hydrogen, halogen, OH, SH, CN, N0₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C₄-alkoxy, Ci- C4-alkylthio, fluorinated Ci-alkyl, fluorinated Ci-alkoxy, NH2, hydroxy-Ci- C₄-alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, C(0)R³ and NR⁴R⁵;

R¹⁸ if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluorinated Ci-alkyl, Ci-C4-alkoxy-C2-C4- alkyl and hydroxy-C2-C4 alkyl; and

R¹⁹ if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluorinated Ci-alkyl, Ci-C4-alkoxy-C2-C4- alkyl and hydroxy-C2-C4 alkyl.

12. The compound according to claim 1 , wherein R¹ is selected from the group consisting of phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3- trifluoromethoxyphenyl, 4-acetylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-(methylthio)phenyl, 4-mercaptophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- aminophenyl, 4-nitrophenyl, 4-(dimethylamino)phenyl, 3-fluoro-4-methylamino- phenyl, 3-fluoro-4-methylphenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4- fluorophenyl, 4-chloro-3-cyanomethyl, 4-carboxyphenyl, 3,4-dicyanophenyl, 3- methyl-4-cyanophenyl, 3-fluoro-4-cyanophenyl, 3-methoxy-4-cyanophenyl, 3- hydroxy-4-cyanophenyl, 3,5-difluoro-4-cyanophenyl, 4-pentafluorosulfanylphenyl, 3-pyridyl, 4-pyridyl, 5-cyanopyridine-3-yl, 6-isopropylpyridine-3-yl, 5- ethynylpyridine-3-yl, 5-fluoropyridine-3-yl, 5-bromopyridine-3-yl, 5- methoxypyridine-3-yl, 5-trifluoromethoxypyridine-3-yl, 5-methylpyridine-3-yl, 6- ethylpyridine-2-yl, 5-trifluoromethylpyridine-3-yl, 6-aminopyridine-3-yl, 6- cyanopyridine-3-yl, 6-fluoropyridine-3-yl, 6-chloropyridine-3-yl, 6-methylpyridine-3- yl, 6-methylthiopyridine-3-yl, 6-trifluoromethylpyridine-3-yl, 6-methoxypyridine-3-yl, 6-ethoxypyridine-3-yl, 6-trifluoromethoxypyridine-3-yl, 6-dimethylaminopyridine-3- yl, 2-fluoropyridine-4-yl, 2-cyanopyridine-4-yl, 2-methylpyridine-4-yl, 2- methoxypyridine-4-yl, 2-trifluoromethylpyridine-4-yl, 2-trifluoromethoxypyridine-4- yl, 5-cyano-4-methylpyridine-3-yl, 2-cyano-6-methylpyridine-4-yl, 6-cyano-5- hydroxypyridine-3-yl, pyrimidine-5-yl, 2-methylthiopyrimidine-5-yl, 2- trifluoromethoxypyrimidine-5-yl, 5-methoxypyridazin-3-yl, 5-methylpyridazin-3-yl, 5-chloropyridazin-3-yl, 5-cyanopyridazin-3-yl,

furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, 5-hydroxymethylfuran-2-yl, 3- cyanofuran-2-yl, 5-nitrofuran-2-yl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 5-ethyl- 2-thienyl, 5-cyano-2-thienyl, 4-cyano-2-thienyl, 5-methyl-3-thienyl, 5-cyano-3- thienyl, 4-cyano-3-thienyl, 5-hydroxymethyl-3-thienyl, 5-trifluoromethoxy-3-thienyl, 5-ethynyl-2 -thienyl, 4-chloro-5-ethyl-2 -thienyl, 5-cyano-4-fluoro-2 -thienyl, 1 - methylpyrrol-2-yl, 1 -methyl-5-hydroxypyrrol-3-yl, 1 -methyl pyrazol-3-yl, 1 - methylpyrazol-4-yl, 1 -ethylpyrazol-4-yl, 1 -oxopyrazol-4-yl, 1 -methylimidazol-4-yl, 1 -methylimidazol-5-yl, 1 ,2-dimethylimidazol-4-yl, 1 ,2-dimethylimidazol-5-yl, 4- methylthiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 5- methylisothiazol-3-yl, 3-methylisothiazol-5-yl, 5-methylisothiazol-3-yl, 3- cyanoisothiazol-5-yl, 2-methyloxazol-5-yl, oxazol-5-yl, 1 ,2,3-thiadiazol-4-yl, 1 ,2,3- thiadiazol-5-yl, 4-methyl-1 ,2,3-thiadiazol-5-yl, 5-methyl-1 ,2,3-thiadiazol-4-yl, 4- cyano-1 ,2,3-thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,3,4-oxadiazol-2-yl, 5-cyano- 1 ,3,4-thiadiazol-2-yl, 5-cyano-1 ,3,4-oxadiazol-2-yl, 5-methyl-1 ,3,4-oxadiazol-2-yl, 5-methyl-1 ,3,4-thiadiazol-2-yl, 1 ,2,4-[4H]triazol-3-yl, 1 ,2,3,4-tetrazol-5-yl and 2- methyl-1 ,2,3,4-tetrazol-5-yl.

13. The compound according to any of the preceding claims, wherein R² is phenyl or a 6-membered heteroaryl, which carries a CN radical and which may additionally carry 1 or 2 radicals R^2a which are identical or different.

14. The compound according to claim 13, wherein R² is a radical of the formula Ar3

wherein # indicates the point of attachment to the benzazine core of (I),

K' is N or C-R²¹,

L' is N or C-R²²,

M' is N or C-R²³,

Q is N or CH,

P is N or CH, wherein R²¹, R²² and R²³, independently of each other, are hydrogen or have one of the meanings given for R^2a, provided that 1 , 2 or 3 of the variables K', L' or M', are C-CN.

The compound according to claim 14, wherein R² is selected from radicals of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 and Ar3.12,

wherein # indicates the point of attachment to the benzazine core of (I), and wherein R²¹, R²² and R²³, independently of each other, are hydrogen or have one of the meanings given for R^2a provided that one of R²¹, R²² or R²³ is CN.

The compound according to claim 14 or 15, wherein

R²¹, R²³, if present, are independently of each other selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

R²² if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy; provided that one of the radicals R²¹ or R²² or R²³ is CN.

The compound according to claim 15 or 16, wherein R² is a radical Ar3.1 or Ar3.3.

The compound according to claim 16 or 17, wherein R²² is CN and wherein R²¹ and R²³ are independently of each other selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

The compound according to any of claims 1 to 12, wherein R² is 5-membered het- eroaryl, which carries a CN radical and which may additionally carry 1 or 2 radicals R^2a which are identical or different.

The compound according to claim 19, wherein R² is a radical of the formulae Ar4, Ar5 or Ar6

wherein # indicates the point of attachment of R² to the benzazine core of (I), A is N or C-R²⁴,

A' is N or C-R²⁵,

D is N or C-R²⁶, E is N or C-R²⁷,

G is O, S or N-R²⁸,

G' is O, S or N-R²⁹,

wherein R²⁴, R²⁵, R²⁶ and R²⁷, independently of each other, are hydrogen or have one of the meanings given for R^2a, and wherein R²⁸ and R²⁹ are selected from the group consisting of hydrogen, cyano, Nhb, OH, Ci-Cio-alkyl, C2-Cio-alkenyl, C2- Cio-alkynyl, Ci-C6-alkoxy, hydroxy-C2-C6-alkyl, Ci-C4-alkoxy-C2-C4-alkyl, fluori- nated Ci-C₂-alkyl, fluorinated Ci-C₂-alkoxy, C(0)R³, NR⁴R⁵, and C(0)OR⁸ and wherein either A or D or E in the formulae Ar4 and Ar6 is C-CN.

The compound according to claim 20, wherein R² is selected from radicals of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 and Ar6.3

Ar4.7 Ar4.8 Ar4.9

Ar4.10 Ar4.1 1 Ar4.12

Ar4.13 Ar4.14 Ar4.15

Ar5.1 Ar5.2 Ar5.3

Ar5.4 Ar5.5 Ar5.6

Ar5.7 Ar5.8 Ar5.9

Ar6.1 Ar6.2 Ar6.3 wherein # indicates the point of attachment of R² to the benzazine core of (I), wherein R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ have the meanings given in claim 20 and wherein either R²⁴ or R²⁶ or R²⁷ in the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.15, Ar6.1 , Ar6.2 and Ar6.3 is CN.

The compound according to claim 20, wherein R² is selected from the radicals Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 and Ar5.8.

The compound according to claim 20, 21 or 22, wherein

R²⁴ if present, is selected from the group consisting of hydrogen and cyano;

R²⁵ if present, is selected from the group consisting of hydrogen and halogen;

R²⁶ if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

R²⁷ if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

R²⁸ if present, is selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C4-alkoxy, fluorinated Ci-alkyl, fluorinated Ci-alkoxy, Ci-C4-alkoxy-C2-C4-alkyl and hydroxy-C2-C4 alkyl;

R²⁹ if present, is selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C4-alkoxy, fluorinated Ci-alkyl, fluorinated Ci-alkoxy, Ci-C4-alkoxy-C2-C4-alkyl and hydroxy-C2-C4 alkyl.

The compounds according to any of claims 1 to 12, wherein R² is selected from the group consisting of 3-cyanophenyl, 4-cyanophenyl, 4-cyano-3-fluorophenyl, 4- cyano-3-chlorophenyl, 3,4-dicyanophenyl, 3-methyl-4-cyanophenyl, 3-ethyl-4- cyanophenyl, 3-methoxy-4-cyanophenyl, 3-hydroxy-4-cyanophenyl, 3,5-difluoro-4- cyanophenyl, 3-chloro-4-cyanophenyl, 5-cyanopyridine-2-yl, 5-cyanopyridine-3-yl, 6-cyanopyridine-3-yl, 6-cyanopyridine-2-yl, 4-cyanopyridine-2-yl, 2-cyanopyridine- 4-yl, 5-cyano-6-methoxypyridine-3-yl, 6-cyano-5-fluoropyridine-3-yl, 5-cyano-3- fluoro-4-methoxypyridine-2-yl, 5-cyano-4-fluoropyridine-2-yl, 5-cyano-4-methyl- pyridine-2-yl, 2-cyano-6-methylpyridine-4-yl, 6-cyano-5-hydroxypyridine-3-yl, 5- cyanopyrimidine-2-yl, 2-cyanopyrimidine-4-yl, 2-cyanopyrimidine-5-yl, 6-cyano- pyrimidine-4-yl, 5-cyanopyrazin-2-yl, 5-cyano-6-fluoropyrazin-2-yl, 5-cyano- pyridazin-3-yl, 6-cyanopyridazin-3-yl, 6-cyanopyridazin-4-yl, 6-cyano-1 ,2,4-triazin-

3-yl, 6-cyano-5-methoxy-1 ,2,4-triazin-3-yl, 3-cyano-1 ,2,4-triazin-6-yl,

3-cyanofuran-2-yl, 5-cyanofuran-2-yl, 4-cyanofuran-2-yl, 2-cyanofuran-3-yl, 5-cyanofuran-3-yl, 5-cyano-4-fluorofuran-2-yl, 5-cyano-4-chlorofuran-2-yl, 3-cyano-2-thienyl, 5-cyano-2-thienyl, 2-cyano-3-thienyl, 5-cyano-3-thienyl, 4-cyano-2-thienyl, 5-cyano-4-fluoro-2-thienyl, 5-cyano-4-chloro-2-thienyl,

3- cyanopyrrol-1 -yl, 3-cyano-4-methylpyrrol-1 -yl, 4-cyanopyrol-2-yl, 5-cyanopyrrol- 2-yl, 3-cyano-1 -methylpyrrol-2-yl, 1 -methyl-5-cyanopyrrol-2-yl, 1 -methyl-4- cyanopyrrol-2-yl, 5-cyano-4-methyl-pyrrol-2-yl, 1 -methyl-2-cyanopyrrol-3-yl, 5-cyano-pyrrol-3-yl, 1 -methyl-5-cyanopyrrol-3-yl, 2-cyanooxazol-4-yl,

2-cyanooxazol-5-yl, 2-cyanoimidazol-4-yl, 2-cyanoimidazol-5-yl, 2-cyano-1 - methylimidazol-4-yl, 4-cyanoimidazol-1 -yl, 2-cyano-1 -methylimidazol-5-yl, 2-cyanothiazol-4-yl, 2-cyanothiazol-5-yl, 4-cyanooxazol-2-yl, 5-cyanooxazol-2-yl,

4- cyanoimidazol-2-yl, 5-cyanoimidazol-2-yl, 4-cyano-1 -methylimidazol-2-yl,

5- cyano-1 -methylimidazol-2-yl, 5-cyanothiazol-2-yl, 4-cyanothiazol-2-yl,

3-cyanoisoxazol-5-yl, 5-cyanoisoxazol-3-yl, 3-cyanoisothiazol-5-yl,

5-cyanoisothiazol-3-yl, 3-cyanopyrazol-5-yl, 5-cyanopyrazol-3-yl, 3-cyano-1 - methylpyrazol-5-yl, 5-cyano-1 -methylpyrazol-3-yl, 3-cyanopyrazol-1 -yl,

4- cyanopyrazol-1 -yl, 3-cyano-4-chloropyrazol-1 -yl, 3-cyano-4-fluoropyrazol-1 -yl,

5- cyano-1 ,3,4-oxadiazol-2-yl, 5-cyano-1 ,3,4-thiadiazol-2-yl, 5-cyano-1 ,2,4-triazol- 3-yl, 5-cyano-4-methyl-1 ,2,4-triazol-3-yl.

25. The compounds according to any of the preceding claims, wherein X is O.

26. The compounds according to any of the preceding claims, wherein X is S, SO or S0₂.

27. The compounds according to claim 1 , which are selected from

5-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile, 4-(4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(4-nitrophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4- (4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

5- (4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4-(4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5-(4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(6-methylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-ylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile,

5- (4-(4-fluoro-3-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

2-methoxy-4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)benzonitrile, 4-(4-(3-fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)- 2-methoxybenzonitrile,

4-(4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)- 2-methoxybenzonitrile,

4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2-carbonitrile, 4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

2,3-dihydro-4-[(4-methylphenyl)sulfonyl]-6-(3-cyano-2-furyl)-4H-benz-[1 ,4]-oxazin, 4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

4-[4-(4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4-[4-(6-methoxypyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

4-[4-(6-(4-morpholinyl)pyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile, 5-[4-(3-fluoro-4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5-[4-(5-methyl-2-thienyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5-[4-(4-chlorophenyl)sulfonyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene- 2-carbonitrile,

4-[4-(4-methoxyphenyl)sulfonyl-1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

the pharmaceutically acceptable salts thereof, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.

28. The compounds according to claim 1 , which are selected from

2-methoxy-4-(4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-(4-mercaptophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-2- methoxybenzonitrile,

2-methoxy-4-(4-(4-(methylthio)phenylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene- 2-carbonitrile,

4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile, 4-(4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 - methyl-1 H-pyrrole-2-carbonitrile,

4-(4-(4-chloro-3-cyanophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-

1 H-pyrrole-2-carbonitrile,

4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)- 1 H-pyrrole-2-carbonitrile,

2-fluoro-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)benzonitrile,

2-ethyl-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)benzonitrile,

2-methoxy-4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-(6-ethylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

2-chloro-4-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

4-(4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiophene-2- carbonitrile,

4-(4-(6-(dimethylamino)pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 6-yl)thiophene-2-carbonitrile,

4-(4-(6-aminopyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-2- carbonitrile,

4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile, 4- (4-(3-fluoro-4-(methylamino)phenylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)thiazole-2-carbonitrile,

5- (4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile,

5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(4-chloro-5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)-3-methoxypicolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- methyl-1 H-pyrrole-2-carbonitrile,

5- (4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3-fluoro-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-

6- yl)picolinonitrile,

3-methoxy-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)picolinonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan- 2-carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile,

5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-1 H- pyrrole-2-carbonitrile,

5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)furan-2-carbonitrile, 5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiazole-2-carbonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)-3- fluoropicolinonitrile,

5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

5- (4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3-fluoro-5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)picolinonitrile,

3- methoxy-5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-

6- yl)picolinonitrile,

5- (4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole- 2-carbonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

2-methoxy-4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

2-fluoro-4-(4-(6-methoxypyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-

6- yl)benzonitrile,

4-(4-tosyl-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile, 4- (4-(4-(methylthio)phenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H- benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

5- (4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5-(4-(phenylsulfonyl)-1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)thiophene-2-carbonitrile,

5- (4-tosyl-1 -oxido-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-2- carbonitrile,

5-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H- pyrrole-3-carbonitrile,

4-(4-(4-chlorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-2- methoxybenzonitrile,

2-fluoro-4-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)benzonitrile,

4- (4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)furan-2-carbonitrile,

5- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)-1 H-pyrrole-2-carbonitrile, 4-(4-(4-(methylthio)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6- yl)benzonitrile,

5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene-2- carbonitrile,

4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-6-yl)thiophene- 2-carbonitrile, the pharmaceutically acceptable salts thereof, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.

29. The compounds according to claim 1 , which are selected from

2-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)furan-3-carbonitrile,

4-(4-((5-methylthiophen-2-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile, 4-((6-(5-cyanothiophen-2-yl)-2H-benzo[b][1 ,4]oxazin-4(3H)-yl)sulfonyl)benzoic acid,

4- (4-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)benzonitrile,

4-(4-((6-chloropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5- (4-((6-chloropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

4- (4-((6-(methylthio)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)benzonitrile,

5- (4-((4-(pentafluorothio)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile,

6-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)nicotinonitrile,

5- (4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)picolinonitrile,

5-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)pyrimidine-2-carbonitrile, 2-(4-tosyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl)thiazole-5-carbonitrile,

5- (4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-

6- yl)thiophene-2-carbonitrile,

6- yl)picolinonitrile,

6-(4-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-

6-yl)nicotinonitrile,

6- yl)pyrimidine-2-carbonitrile,

6-(4-((6-aminopyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)nicotinonitrile,

5-(4-((6-aminopyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6- yl)thiophene-2-carbonitrile the pharmaceutically acceptable salts thereof, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.

30. The compound as claimed in any one of claims 1 to 29 for use in therapy.

31 . The compound as claimed in any one of claims 1 to 29 for use in therapy of a disease or disorder selected from the group consisting of inflammatory diseases, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation.

32. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 29, optionally together with at least one physiologically acceptable carrier or auxiliary substance.

The pharmaceutical composition as claimed in claim 32, further comprising at least one second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation

A method for treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hypervascularisation, said method comprising administering an effective amount of at least one compound as claimed in any one of claims 1 to 29 to a subject in need thereof.

The method as claimed in claim 34, wherein the disease or disorder is an inflammatory disease which is selected form the group consisting of atherosclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, psoriasis, in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichthyosis; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis

Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic skin reaction; and periorale dermatitis.

36. The method as claimed in claim 34, wherein the disease or disorder is an hyper- proliferative disease which is selected from the group consisting of a tumor or cancer disease, precancerosis, dysplasia, histiocytosis, a vascular proliferative disease and a virus-induced proliferative disease.

37. The method as claimed in claim 34, wherein the disease or disorder is a hyper- proliferative disease which method comprises administering a compound according to any of claims 1 to 29 to a patient prior to, during and/or after said patient was subjected to a radiation therapy, a chemotherapy, an immunotherapy, a la- ser/microwave thermotherapy or a gene therapy using antisense DNA and/or

RNA.

The method as claimed in claim 34, wherein the disease or disorder is a tumor or cancer disease which is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, glioma, bone cancer and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and papillary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lym- phangiosarcoma, lymphangioendotheliosarcoma, synovioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, glioblastoma, papillary adenocarcinomas, cystadenocarcinoma, bronchogenic carcinoma, seminoma, embryonal carcinoma, Wilms' tumor, small cell lung carcinoma, epithelial carcinoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, men- ingioma, neuroblastoma, retinoblastoma, glaucoma, hemangioma, heavy chain disease and metastases.

The use of a compound as claimed in any of claims 1 to 29 in the manufacture of a medicament for therapy of a disorder or disease wherein the disorder or disease is defined as in any one of claims 34 to 38.

40. The compound as claimed in any of claims 1 to 29 for use in therapy of a disorder or disease wherein the disorder or disease is defined as in any one of claims 35 to 38.