TW201120018A - 2,3-dihydrobenzazine compounds for use in therapy - Google Patents

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. 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 R1a which are identical or different; R1a 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 R1a, 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; 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 R2a which are identical or different; R2a 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 R2a, 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; 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 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

201120018 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention provides novel 2,3-dihydroimimina & extracts useful for the treatment of diseases and conditions. These novel compounds inhibit cell proliferation and cell division, and they also inhibit the activation of transcription and signal transduction induced by hypoxia-inducible factor (H j F ) under hypoxic conditions. In one aspect, the compounds of the invention may be used to prepare an agent for treating or preventing a disease or condition selected from the group consisting of: an inflammatory disease, a hyperproliferative disease or condition, an anoxic-related condition, and an over-vascular condition Generated as a characteristic disease. The invention also provides a pharmaceutical composition comprising a compound of the invention and a second therapeutic agent or radiation useful for treating or preventing the above mentioned diseases or conditions. [Prior Art] The normal response of cells to hypoxia is mediated by an anoxic signaling pathway. This response is important for a number of physiological functions including, for example, tumorigenesis and metastasis, apoptosis resistance, induction of neovascularization, and metabolism. For a comprehensive review of hypoxic signaling, see, for example, Qingd〇ng

Ke and Max Costa, Molecular Pharmacology (2006), Vol. 70, No. 5. It has been observed that hypoxia leads to, for example, transcription factors (hypoxia-inducible factor, HIF) in tumors, most particularly HIF-1 (increase in the inclusion of heterodimeric complexes of X and HIF-Ιβ) with other cofactors. Together, it compensates for the reduced availability of oxygen and nutrients in this fast-growing tissue type. Under anaerobic conditions, the homeostasis of Hip-1α is unbalanced due to reduced degradation, thereby enabling the passage of hypoxia response elements (HRE). The signal transmission is enhanced and leads to a number of survival and growth factors. 151494.doc 201120018 is now increasing. Hypoxic conditions are also found in non-tumor tissues. For example, retinopathy is a general term that refers to the non-inflammatory of the retina of the eye. Sexual injury 4 conditions are most commonly caused by hypoxia caused by insufficient blood supply. People with diabetes are especially at risk of retinopathy. Oxygen deficiency in the retina of diabetic patients leads to clear condensation along the retina and inside the filling eye. Growth of fragile new blood vessels in colloidal vitreous fluid. If not treated in time, these new blood vessels may bleed, blurring the vision and destroying the retina. Causes partial retinal detachment. These new blood vessels can also grow into the anterior chamber of the eye and cause neovascular glaucoma. Recently, the inhibition of HJF-i activity has also been used as evidence to prevent inflammation. The role of megatuber and neutrophil activation and infiltration into disease-invading tissues (see, for example, "Drug Discovery, Vol. 2, 2, 3 years, 1 month"). For the reasons outlined above, compounds that inhibit HIF function are useful agents for the treatment or prevention of diseases or conditions selected from the group consisting of inflammatory diseases, hyperproliferative diseases or conditions, hypoxic-related diseases. Diseases characterized by overproduction of blood vessels. Due to the importance of HIF-1 in tumorigenesis, progression and metastasis, considerable effort has been devoted to identifying HIF_丨 inhibitors that can be used in cancer therapy. A number of small molecules have been reported. RNA constructs (eg, siRNA) can exhibit inhibition of the HIF-1 pathway, eg, Kung AL et al, cancer Cell (2004), Vol. 6, p. 33 et seq; Rapjsarda a et al, Cancer Res. 2002) ‘Volume 62’, page 4316 and subsequent pages; Tan C. et al., 151494.doc 201120018

Cancer Res. (2005), vol. 65, p. 605 et s; Mabjeesh NJ et al., Cancer Cell, (2003), vol. 3, p. 363 and subsequent pages; Kong X et al. Mol Cell Biol (2006), vol. 26, p. 2019 and subsequent pages; Kong D et al., Cancer Res. (2005), vol. 65, p. 9047 and subsequent pages; Chau N. et al. , Cancer Res. (2005), vol. 65, p. 4918 and subsequent pages; Welsh S et al., Mol Cancer Ther (2004), vol. 3, p. 233 and subsequent pages. However, these compounds generally have other activities in addition to the HIF-1 inhibitory activity, and most of these compounds lack the desired pharmacokinetic or toxic properties required for the agent. In addition, some compounds have the disadvantage of not being orally administered, 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-indole, fluorene-bis-(2-aeroethyl)amino]phenylpropionate bismuth-oxide dihydrochloride, It is also known as technetium-478, which can be used to modulate the level of HIF-la under normoxic conditions or under hypoxic conditions. WO 2006/05 0734 discloses LNA oligonucleotides suitable for down-regulating HIF-la expression. WO 2006/066846 discloses a inhibition of HIF-1 activation by inhibiting the interaction of HIF-1 with the agonist p3 00 of HIF-1 expression. Determine the compound. WO 2007/025 169 discloses certain octal compounds having an N-(arylsulfonyl)amino fluorenyl group at the 6 position. These compounds are mentioned as HIF-1 inhibitors. 151494.doc 201120018 WO 2007/130037 proposes that a bidentate zinc chelate which inhibits HIF-1 can be used for the treatment of cancer or tumors. WO 2008/004798 discloses phenoxyacetanilide or ... pyridylguanamine and 2-(phenoxymercapto)azepine as HIF-1 inhibitors. The scientific literature mentioned above emphasizes the strong medical need for novel therapeutic agents that provide more effective treatment for different proliferative and inflammatory diseases or conditions, hypoxic-related conditions, and diseases characterized by over-angiogenesis. WO 2004/056820 discloses 2,3-dihydroimiline compounds having a (azoline-2-one-3) group methylene group at the 6 position. It is mentioned that such compounds are suitable for the treatment of conditions which are responsive to lipoinositol-3 -kinase inhibition, including certain inflammatory diseases and certain cancer diseases. In particular, US 2007/191603 discloses a 2,3-dihydro" cultivating compound having an arylaminocarbonyl group at the 6 position. It is mentioned that these compounds are suitable for the treatment of conditions which are inhibited by the palmitase transfer enzyme in response to liver visceral toxicity, including hyperglycemia and glucose intolerance. WO 2009/035997 discloses a compound of formula A:

Wherein A is, for example, CO, CONH or S02, Y is a system of (CH2)p, wherein p = 1, 2 or 3, Z is Ο, S, SO or S02, and R is an alkyl group, a cycloalkyl group, optionally substituted An aryl group or an optionally substituted heterocyclic group, r2, r3 is hydrogen or alkyl, and R4 is selected from coor5; CONR5R6; aryl, as the case may be 151494.doc 201120018 1 : 2 or 3 Substituted from a group of dentate, Κ6_Hyun, Ci々 alkoxy, CF3 or 〇CF3; and a heterocyclic group, optionally, 2, 3 or 3 selected from the group consisting of halogen 'Cl_C6_, Ci_C6•Alkoxy group, C3_Cs_cycloalkyl group is substituted with a substituted aryl group or an optionally substituted heterocyclic group, (3) or a group of 〇cf3. These compounds bind to the cannabinoid receptor cm or CB2 on the surface of mammalian cells, thereby modulating the cell.AMp concentration. Thus, the compounds are indicated to be useful in the treatment of conditions associated with cannabinoid receptors, including the treatment of pain, pain, skin disorders, inflammatory diseases, neurodegenerative disorders, neuroinflammatory or psychiatric disorders, pulmonary disorders, ocular disorders, heart Vascular disorders, gastrointestinal disorders, and certain cancer disorders. SUMMARY OF THE INVENTION The present invention provides novel compounds capable of preventing or treating a disease or condition. The data presented herein establishes that the compounds of the invention are surprisingly potent inhibitors of the following events: (1) activation of HIF-mediated transcription under hypoxic conditions, and (ii) cell proliferation. In a first aspect, the invention relates to a 2,3-dihydromi-mole compound having the structure of formula (1):

(I) X-system or S(=0)n' where η is 〇, 1 or 2; R is a phenyl or C-bonded monocyclic 5-member or a member heteroaryl, of which phenyl 151494.doc 201120018 3 / 5 or 6 member heteroaryl unsubstituted or with 1, 2 or 3 identical or different groups Rla; free of the following group of groups: halogen, cyano, N 〇 2, 2 〇H, SH, Cl-Cl. -alkyl, c2-c10-thinyl, c2-Cl〇-blockyl, Cl-C6-homoyloxy, C1_C6_院thio, hydroxy_c]-c6, Ki_c4•desyloxy_c _c4_alkyl, fluorinated c]·. Elementary SFs, fluorinated C丨-c2-alkoxy, c(〇)R3, V, n(or6)r, c(〇)〇r8, or a combination Two groups Ria to adjacent anatomical atoms may also form a bridging moiety R/R3 R4 R5 wherein Aik is selected from the group consisting of CH2, CH2CH2, CHF and CF2; "C or N combined monocyclic 5-membered or 6-membered heteroaryl Wherein the phenyl and monocyclic 5 or 6 membered heteroaryl groups bear a CN group and may additionally carry 1 '2 or 3 identical or different groups r2, R2a selected from the group consisting of: , cyano, N〇2, NH2, OH, SH, CVC, -alkyl, c2_Ci〇_dense, c2_C丨.-alkynyl, CVCV alkoxy, c丨·c6_alkylthio, Hydroxy C]-C6-alkyl, C丨_c4-alkoxy_Ci_C4_alkyl, fluorinated Ci_C2 alkyl, SF5, fluorinated c丨<2 alkoxy, c(〇)r3, NR4R5 , N(0R6)R7 and C(9)(10)8, or two groups Rh bonded to adjacent carbon atoms may also form a bridging moiety 〇_Alk, · 〇, wherein Alk' is selected from the group consisting of: CH2CH2, CHF and cf2; -匕-alkyl; hydrogen or CVC6-alkyl; system ^(:6·Hyun, fluorenyl C2-c6-hospital, Ci_C4_院oxy_C2_ 15I494.doc -10· 201120018 c4-alkane a group or group C(0)RX, wherein Rx is a Cl_c4_alkyl group; or R4 R6 R7 R8 R, together with the nitrogen atom to which it is bonded, forms a N-bonded 5- or 6-membered saturated nitrogen heterocycle; hydrogen or CVC6 - hospital base; hydrogen or C 〗 - C6-alkyl; hydroxy-cvc: 6-alkyl or cvcv hospital oxygen, C!-C6-hospital C2-C4-alkyl; The salt to be accepted, and if one or both of R]&R2 is a nitrogen-containing 5 or 6-membered heteroaryl group, the N-oxide and a pharmaceutically acceptable salt of the N-oxide. The present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or (mR2 or both nitrogen-containing 5 or 6 membered heteroaryl) N_oxide or such oxime oxidation The use of therapies, in particular for the treatment of diseases or diseases selected from the group consisting of: inflammatory diseases, hyperproliferative diseases or conditions, hypoxic-related conditions, and pathophysiological overproduction Characteristic disease. In another aspect, the invention is related to a pharmaceutical composition comprising at least one compound of formula I, or at least one of pharmaceutically acceptable extracts, at least one of 匕3, a salt of saponin, or (if one or one of R1 and R2 is nitrogen-containing 5员或物夕Μ 基 )) its 1"1-oxide or the Ν-oxidation pre-pg dredging, brother and at least one species can be used for treatment or prevention selected from the group consisting of squat, j. The second therapeutic agent group. Major diseases, excessive colonization a ^ 3S 4: ^ . Diseases or conditions, hypoxia-related conditions and diseases characterized by pathophysiological vascular hyperactivity ± ii ^ ; Condition The drug is a carrier or auxiliary substance (excipient). 151494.doc 201120018 In the re-existing aspect, the present invention relates to a method for treating or preventing a disease or condition selected from the group consisting of inflammatory diseases, hyperproliferative diseases or conditions, hypoxic-related conditions, and pathology. A disease characterized by over-generation of physiological blood vessels' method comprising administering to an individual in need thereof an effective amount of at least one compound of the formula 1, or a pharmaceutically acceptable salt thereof, or (if the sum of R1 and R2) A nitrogen-based or 6-membered heteroaryl) N-oxide or a pharmaceutically acceptable salt thereof, optionally in combination with a second therapeutic agent useful for treating or preventing the disease or condition. [Embodiment] It is to be understood that the terminology used herein is for the purpose of describing the particular embodiments and is not intended to limit the scope of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Preferably, the term "r A multilingual glossary of biotechnological terms: (IUPAC Recommendati〇ns)", Leuenberger, HGW, Nagel, B. and Klbl, H. Ed. (1995), Helvetica Chimica Acta, CH- Defined in 4010 Basel, Switzerland. Throughout the specification and the accompanying claims, unless the context requires otherwise, the words "comprise" and variations (for example, "comprises" and "comprising") shall be understood to mean An integer or step or group of integers or groups of steps, but does not exclude any other integer or step or group of integers or groups of steps. 151494.doc 12 201120018 Several documents are cited throughout the text of this manual. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturers, etc.), (herein or in the following) are incorporated by reference. In this article. It is to be understood that the disclosure is not intended to be a prior If the compound of formula (1) consisting of the right oxime can be arranged in different spaces (for example if it has - or more asymmetric centers, polysubstituted rings or double bonds) or as different tautomers, the invention is also directed to Isomeric mixtures (especially racemates), diastereomeric mixtures and tautomeric mixtures, however, preferably each of the compounds of formula (1) and/or its salts and/or its n-oxides are substantially pure Enantiomers (enantiomerically pure), diastereomers and tautomers. The racemate obtained can be resolved into the isomers in a physical or chemical manner by a method 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 (10) type tartaric acid == acid, diphenylmethyl tartaric acid, mandelic acid, malic acid, various optically active camphors (iv), for example, phthalic acid. It is purely advantageous to carry out the enantiomeric resolution by means of a burning column of a right optically active resolving agent (for example, dinitrobenzyl phenylglycolic acid); suitable for the liquid of the eluent A mixture of propanol/acetonitrile. Diastereomeric fractions can also be carried out by means of ', 笙, 4+ mountain chromatography or fractional crystallization. The method also provides a compound of formula (I) which is active by using an optically active starting material. The present invention is also directed to a "pharmaceutically acceptable salt" of a compound of formula (1), 151494.doc • 13· 201120018, especially an acid addition salt with a physiologically tolerable acid (ie, a pharmaceutically acceptable acid) Suitable examples of suitable physiologically tolerable organic and inorganic acids include, but are not limited to, hydrochloric acid; hydrobromic acid; phosphoric acid; sulfuric acid; alkylsulfonic acids such as sulfonic acid; aromatic sulfonic acids, such as benzenesulfonate Acids and toluenesulfonic 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 acetic acid Salt, alginic acid, ascorbic acid, aspartic acid, citric acid, butyric acid, camphoric acid, citric acid, clavulanic acid, cyclopentyl propionic acid, gluconic acid, citric acid, acetic acid, propionic acid, new Valeric acid, valeric acid, caproic acid, heptanoic acid, oleic acid, palmitic acid, pantothenic acid, pectic acid, stearic acid, hexylresorcinic acid, hydroxynaphthoic acid, nialic acid and viscous acid. Other available acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research]' Vol. 10, page 224 and subsequent pages 'Birkhauser Verlag, Basel and Stuttgart, 1966 and Berge, S. Μ. et al., "Pharmaceutical Salts" , Journal of Pharmaceutical Science, 1977, 66, 1-19 e. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, Benzene sulfonate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate and camsylate ), carbonate, vapor, citrate, clavulanate, cyclopentate propionate, digluconate, dihydrochloride, lauryl sulfate, ethylenediaminetetraacetate, ethanedisulfonate Acid salt, eto acid salt, esylate and ethanesulfonate, decanoate, fumaric acid 15I494.doc 14 201120018 salt, glucoheptonate (gluceptate and glucoheptonate), gluconate, glutamine Salt, glycerol phosphate, hydroxyethyl phthalate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrogen Molybdate, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isethionate, lactate, lactate, laurate, Lauryl sulfate, malate, maleate, malonate, mandelate, mesylate and methanesulfonate, methyl sulfate, acid salt, 2-naphthalene sulfonate, Naphthalene sulfonate, nicotinate, nitrate, N-decyl glucosamine ammonium salt, oleate, oxalate, pamoate (embyanate) Extracted acid salt, pantothenate, pectate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionic acid Salt 'salicylate, stearate, sulfate, hypoacetate, succinate, citrate, tartrate, 8-alcoholate, sulfonate, triethyl iodine Compounds, phosphonates, valerates, and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities which allow the compounds to be converted to base or acid addition salts. Further, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include an alkali metal salt (for example, a sodium salt or a potassium salt), an alkaline earth metal salt (for example, a calcium salt or a magnesium salt); Salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium, and amine cations formed using counter anions such as: tooth ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitric acid Root ion, alkyl sulfonate ion and aryl sulfonate ion). 151494.doc 201120018 The neutral form of these compounds can be regenerated by contacting the salt with the test or acid and isolating the parent compound by conventional means. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, although such salts are otherwise equivalent to the parent form of the compound for the purposes of the present invention. The present invention is also directed to a compound-like oxide of the formula (1), provided that the compound contains a basic nitrogen atom, for example, a nitrogen atom of an ice-aromatic group which may be present in the ... and/or the ruler 2. Examples of the N-heteroaromatic aromatic group in which nitrogen may be present in the form of an N-oxide include _ group, aryl group, fluorenyl group, and hydrazine. Chalyl, pyrazolyl 'imidazolyl, oxazolyl, oxadiazolyl, triazolyl and the like. In addition to the salt form, the cerium oxide, and the salt of the N-oxide, the present invention also provides a compound in the form of a prodrug. The compounds of the compounds described herein are susceptible to undergoing chemical changes under physiological conditions to provide a compound of the compound of formula (1). The compound has a pharmacologically active or non-pharmacologically active compound' in the administration of the prodrug to the patient. Thereafter, it is converted to the compound of the invention by chemical modification of physiological effects in vivo (e.g., hydrolysis, metabolism, and the like). Further, the prodrug can be converted to the compound of the invention in an ex vivo environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch container with a suitable enzyme, the prodrug can be slowly converted to the inventive compound. The suitability and techniques associated with the manufacture and use of prodrugs are well known to those skilled in the art. A comprehensive discussion of the drugs involved in esters can be found

Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988); and Bundgaard, Design of Prodrugs, Elsevier (1985). Masked 151494.doc .16- 201120018 Examples of acidic anions include various esters such as alkyl (eg, decyl, ethyl), cycloalkyl (eg, cyclohexyl), aralkyl (eg, benzyl, p. _Methoxybenzyl) and alkylcarbonyloxyalkyl (for example, pentyloxymethyl). An amine that has been masked as a derivative substituted with an arylcarbonyloxyindenyl group can be cleaved by an esterase in vivo to release free drug and formaldehyde (Bimgaard J_ Med. Chem. 2503 (1989)). In addition, once used Oxymethane masks 3 drugs that have an I-NH group (eg, π m d sit, yttrium, β 丨 及, and the like) (Bundgaard, Design pr〇drugs, Elsevier (1985)). Hydroxyl masking to esters and ethers. EP 0 039 05 1 (Sloan and Little '^ on the day of the year n) reveals Mannich base homochlorohydrazone prodrugs, their preparation and use. Certain compounds of the invention may The presence of β in the form of an unsolvated form and the solvate of the solvate (including hydrated forms) is generally the solvate form equivalent to the unsolvated form and is intended to be encompassed within the scope of the invention. Certain compounds of the invention It may exist in a polymorphic or amorphous form. Generally, all physical forms are equivalent to the intended use of the invention and are intended to be encompassed within the scope of the invention. One or more atoms: An atomic isotope of a non-natural proportion. An isotopic variation of a formulation of the invention or a pharmaceutically acceptable salt thereof is defined as at least one atom replaced by an atom having the same atomic number but an atomic weight different from the atomic mass normally found in nature. Examples of isotopes which may be included in the reagent and its pharmaceutically acceptable salts include gas, carbon, nitrogen, oxygen, dish, sulfur, and chlorine: isotope, for example, 屮, 3Η, 13 (:, 14< :, 15ν, ΐ7〇, 18〇, 151494.doc • 17- 201120018 PS, F and 36C]. The reagent and its pharmaceutically acceptable salt: a variant of a morpheme, for example, such as m, etc. Radiation: Isotope, which can be used for drug and/or substrate and carbon-i4 (ie, % isotope is easy to prepare and detectable, and is particularly good for use with isotopes (such as atmosphere, which means that it is replaced by a stronger generation). Poetry can provide certain therapeutic advantages, for example, a reduction in the length of the living body, and thus may be preferred in some cases:: a monthly agent and an isotope of the pharmaceutically acceptable salt of the present invention Variants can usually be borrowed Conventional procedures are prepared using suitable isotopic variations of suitable reagents. All isotopic variations of the compounds and compositions of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. The following definitions of terms are provided: The term "heteroaryl", "heteroaryl", "alkenyl", "alkyl", "alkyl", and the like are used in the description of the remainder of the present invention. "In the general text (4) #巾, in some cases, it will indicate the preferred meaning of these terms. The organic part mentioned in the definition of the above variables _ such as the term dentate _ is listed separately The collective name of each group member. The prefix Cn_Cm indicates, in each case, the number of possible carbon atoms in the group. If two or more groups are selected independently of each other, the term "independently" means that the groups may be the same or different. The term "halogen" means, in each case, fluorine, fill, gas or iodine, especially fluorine, gas or bromine. The term "CrC" is a straight-chain or branched alkyl group having 4 to 10 carbon atoms, preferably 1 to 151,494.doc to 18, 2011,200,18 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl 'isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 2-methyl Butyl, 3-methylbutyl, 2,2-dimercaptopropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 12-dimethylpropyl, 1-methyl Pentyl, 2-methylpentyl, 3-decylpentyl, 4-decylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, hydrazine, 3_2 Nonylbutyl, 2,2-dimercaptobutyl, 2,3-didecylbutyl, 3,3-didecylbutyl, 1-ethylbutyl, 2-ethylbutyl, ι , ι, 2 · trimethyl propyl, trimethyl propyl, 1-ethyl-1-methyl propyl, 1 · ethyl 2 - decyl propyl, heptyl, octyl, decyl and癸基. The term "fluorinated C"-C2 alkyl" means as defined above having one or two carbon atoms and wherein at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms are replaced by fluorine. alkyl. Examples of such groups include fluoromethyl, di-methyl 'difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1. 2,2-tetraseethyl and 1,1,2,2,2-pentafluoro 1 ethyl. The term "pentafluorothio" refers to the group SF5. The term "hydroxy-CrC6-alkyl" denotes a straight or branched chain having from 1 to 6, especially from 1 to 4 carbon atoms (=trans-C1-C4 alkyl) and wherein one hydrogen atom is replaced by a hydroxy group. Alkyl' is exemplified by hydroxymethyl, hydrazine hydroxyethyl, 2-hydrylethyl, 3-hydroxypropyl, hydroxy-isopropyl, b-hydroxybutyl or 2-hydroxybutyl. The term "hydroxy-CrC6-alkyl" denotes having 2 to 6, especially 2 to 4, carbon atoms (=trans-based-CrC4 alkyl) and wherein H@ hydrogen atom (which is preferably not located at (^) from a hydroxyl group) Replacement of a straight or branched alkyl group, such as 2_ylidylethyl or 151494.doc -19- 201120018 3-hydroxypropyl. The term "Cl" refers to a hydroxy-C2-C6.alkyl group to which The remainder of the carbon atom. The term "Ci-C6. alkoxy" means a straight or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms bonded to the remainder of the molecule via an oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, 2-butyloxy, isobutyloxy, tert-butyloxy Base, pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy, 3-decylbutyloxy, 2,2-dimethylpropyloxy, oxime-ethyl Propyloxy, hexyloxy, 1,1-dimercaptopropyloxy, 1,2-dimethylpropyloxy, methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2_2 Methyl butyloxy, 1,3-dimethylbutyloxy, 2,2-dimercaptobutyloxy, 2,3-dimethylbutyloxy, 3,3-didecyl Butyloxy, 丨-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy, 12,^-trimethylpropyloxy, 1- Ethyl-1-methylpropyloxy and ethyl-2-methylpropyloxy. The term "fluorinated q-C2-alkoxy" means having one or two carbon atoms and at least one of which is hydrogen. An alkoxy oxime in which an atom, for example, hydrazine, 2, 3, 4 or 5 hydrogen atoms is replaced by fluorine. Examples of such a group include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyl. Oxy, 2,2·difluoroethoxy, 2,2,2•trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy and nnh pentafluoroethoxy. -C4-alkoxy-CVC4.alkyl" means a straight or branched alkyl group having from 1 to 4 carbon atoms and wherein one hydrogen atom is replaced by a Cl_C4 alkoxy group, such as methoxymethyl, B Oxymethyl, propoxymethyl &, b methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 151494.doc 201120018 2-A Oxypropyl a group, a 2, ethoxypropyl group, a 3 methoxy propyl group or a 3 ethoxy propyl group. C! C4_the hospitaloxy group _C2_C4_hospital group means having 2 to 4 carbon atoms and a linear or branched alkyl group in which one hydrogen atom (which is preferably not located at C1) is replaced by a c^-c:4 alkoxy group, for example, 2-methoxyethyl, 2-ethoxylated Base, 2-methoxypropyl, 2-ethoxypropyl, 3-methoxypropyl or 3-ethoxypropyl. The term "C1" means C]_C4_alkoxy (: 2_€: 4_alkyl is bonded to the carbon atom of the rest of the molecule. The term "C^C6.alkylthio" means a straight or branched alkyl group having 1 to 6 carbon atoms attached to the skeleton via a sulfur atom (_S-) (as described above). Sf "CVCnr fluorenyl" means having 2 to 4, 6, 8 or 1 carbon atoms and having one or more (for example 2 or 3) carbon-carbon double bonds, preferably 1 carbon carbon, at any position. a linear or branched hydrocarbon group of a double bond, such as an ethylene group 'dilyl (2-propyl-l-yl), 1-propan-1-yl, 2-propan-2-yl, anthracene Base propyl (2.-methylpropan-2-ylidene-1-yl), 2-buten-1-yl, 3-butene-I-based, 2-pent-1-yl, 3-pentyl Alken-1-yl, 4-penta-1-yl, methylbutane-2 dilute, 2-ethylpropan-2-ylidene-1-yl, hexyl, heptenyl or octyl . The term "C2-C1Q alkynyl" means having 2 to 4, 6, 8 or 1 carbon atoms and having one or more (for example 2 or 3) carbon-carbon triple bonds, preferably 1 carbon, at any position. a linear or branched hydrocarbon group of a carbon triple bond, such as a b-propynyl group, a 2-propynyl group, a 1 butynyl group, a 2-butynyl group, a 3 butyl group, a thiol-2- Propynyl, 丨-pentynyl, 2·pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2_曱基_3_butynyl, 3-methyl-1·butanyl, 1,1-dimercapto-2-propynyl, ι_ethyl_2·propyl 151494.doc -21 - 201120018 Alkynyl alkynyl alkynyl 1-hexynyl, 2-hexynyl, 3·hexyl, benzyl, 4-hexynyl, 5-hexyl-1-indenyl-2-pentyl _Methyl-3-pentynyl, 1-methyl-4-pentan-2-indolyl-3-pentyl, 2-methylj. A A pentynyl, 3-mercapto-1-pentyl 3-methyl-4-pentyl group, 4-methyl-1,1-methyl-2-butynyl, 1,1·oxa-1·pentynyl, 4-methyl-2-pentylmethyl-3 -butynyl, 1,2, diindolyl_3_butynyl, 2,2. dimethyl-3, butyl, 33-dimethyl-butynyl, 1-ethyl-2-butyl Base, ethyl, alkynyl and 1-ethyl-1-indolyl 2 && A alkynyl, 2-ethyl-3-butyl or decynyl. decynyl, octynyl, decyne "heteroaryl (he-)" (also known as heteroaryl (h - does not contain carbon atoms but also contains 2, 3 or 4 miscellaneous numbers selected from N, 0 and S as a negative ring a cyclic 5- or 6-membered heterocyclic group. The C-bonded heteroaryl group means a heteroaromatic group bonded via a carbon ring atom, and the n-bonded heteroaryl group means a heteroaromatic group bonded via a nitrogen ring atom. Examples of a 5-member or a member heteroaromatic group include a pyridyl group, that is, a 2, 3, or 4-π ratio β group; a pyrimidine group, that is, a 2-, 4- or 5-pyrimidine group;噃基;健β|基基', ie 3- or 4-pyridazinyl; thienyl, ie 2- or 3-thienyl; furyl, ie 2- or 3-furyl; pyrrolyl, ie 1-, 2- or 3-pyrrolyl; oxazolyl, ie 2-, 3- or 5-oxazolyl; isoxazolyl, ie 3-, 4- or 5-isoxazolyl; thiazolyl, ie 2- , 3- or 5-thiazolyl; isothiazolyl' is 3-, 4- or 5-isothiazolyl; pyrazolyl, ie 1-, 3-, 4- or 5-pyrazolyl; imidazolyl, ie 1-, 2-, 4- Or 5-imidazolyl; oxadiazolyl, for example 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]oxadiazolyl; thiadiazolyl, for example 2_ or 5-151494.doc •22· 201120018 [1,3,4 Diterpenoid, 4_ or 5·π, 2, disal, 3 or diazolyl; Sitting base, for example, 1Η_, 2Η—, η 4 JH-1, 2,3-triazole-4_, 2H-triple-3·group, 1H_, melon, and trisodium: and ^, ie 1H- or 2H-tetrazolyl. The term "N-bonded 5-member or 6-membered saturated nitrogen heterocycle" means having a nitrogen atom as a ring member (which is attached to the rest of the molecule) and optionally one or more, for example 1 or 2 straight He has a heterocyclic atom (for example, 〇, § or N) as a member of the ring and has a total of 5 or 6 saturated heterocyclic groups ringed into M atoms. Examples of "N-bonded 5-member or 6-member saturated nitrogen heterocycle" are butyl group, hexahydropyridine small group, hexahydropyrazine group, 4-methylhexaazine, morpholine 4-yl 'thiomorpholine _4_ group, oxazolidine small group... oxazolidine _3 · yl thiophene-3-yl' especially bites small base, hexahydro. It is a small base, *methylhexahydropyrazin-1-yl, hexahydropyridine-丨-yl and morpholine_4-yl. Specific or preferred meanings of 3 R, R2a, R3, r4, R R, R and R8 are intended to illustrate the specific embodiment of the compounds of the present invention. It will be well understood by those skilled in the art that any specific or preferred meaning of any of these variables can be combined with a general definition or a specific or preferred meaning of any other variable, such as a specific or preferred embodiment of R1. Any derogatory meaning may be combined with any particular or preferred meaning of R2. According to a first embodiment, the invention relates to a compound of the formula I of the X system, a salt of the isolated N-salt and an N-oxide thereof. These compounds are also hereinafter referred to as dihydrobenzoxazine or a compound of formula 1.1. According to a second embodiment, the present invention is directed to a compound of formula I of the X system S, a salt of its muscle N-oxide and N-oxide. These compounds are hereinafter referred to as dihydrobenzothiazine or a compound of formula 1.2 by giving the variables X, ri, ru 151494.doc • 23- 201120018. According to a third embodiment, the invention relates to a salt of the formula s = 〇, a salt thereof, an N-oxide thereof and a cerium oxide. These compounds are also hereinafter referred to as dihydrobenzothiazine oxides or compounds of formula 13. According to a fourth embodiment, the present invention relates to a salt of the formula I of the X system S(=〇) 2, a salt thereof, an N-oxide and a salt of an N-oxide. These compounds are also referred to hereinafter as dihydrobenzothiazine dioxide or a compound of formula 14. A preferred embodiment is the first embodiment, a compound of formula 1.1.

R2

o=s=o li R1 (I4) According to a particular embodiment, the invention relates to a salt of a compound of the formula I, jj 2, I 3^ 1.4, a salt thereof, an N-oxide thereof and an oxide of the same, wherein R1^ A phenyl group which is unsubstituted or carries 1, 2 or 3 identical or different groups Ria. Among these compounds, a carbon ring atom in the ortho position relative to the sulfonyl group is preferably a group Rh. Preferably, one of the groups (if present) is in the para position of the sulfonyl group. According to another particular embodiment, the invention is related to the formula J, J. i, 12, 151494.doc • 24 - 201120018 = a salt of a compound, a salt thereof, an N-oxide thereof and an N-oxide, wherein R1 糸-substituted or carries i, 2 or 3 identical or different groups of r heteroaryl. Among these compounds, it is preferred that - or a plurality of nitrogen ring atoms are not adjacent to the moiety. Among these compounds, it is preferred that the carbon ring atom does not carry a group 0 with respect to the ortho position. Preferably, one of the groups; R (present in the right) is in the para position relative to the sulfonyl group. According to still another particular embodiment, the invention relates to a compound of the formula mu and 1.4, a salt thereof, an N-oxide thereof and a salt of ν.Oxide, which is a C-bonded 5-membered heteroaryl group which is unsubstituted or With a group of different or different R R. In the case of 兮* stem JL·A.iL/_μ equalization &, it is preferred that the carbon ring atom in the ortho position relative to the sulfonyl moiety has no group Rla. In such embodiments, the group Rla, if present, has the above meaning and is preferably selected from the group consisting of (IV) UH; CN; N〇2; Ci_C4 alkyl, especially methyl, ethyl or isopropyl; C2-C4 alkenyl 'In particular vinyl; C2_C4 alkynyl, especially ethyl hexyl; C1·04-decyloxy, "methoxy or ethoxy; C1.C4. sulphur-based" especially thiol or ethylthio; IKCA - affiliary, especially difluoromethyl or trifluoromethyl; SF5; KbCi_c2 alkoxy, especially difluoro; oxy or trifluoromethoxy; NH2; hydroxy-Ci_C4.alkyl, especially hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; Ci_C4_alkoxy·q-Cf alkyl, especially methoxymethyl, ethoxymethyl|, dimethoxyethyl or 2-methoxy a group; C(0)R3, especially an ethylidene or a propyl group; NR4R5, especially a mercaptoamino group or a dimercaptoamine group; and c(〇)〇R8, especially a methoxycarbonyl group, an ethoxycarbonyl group or The carboxyl group, or two groups 1113 bonded to adjacent carbon atoms, may also form part of the group 〇_Alk_〇, which is such that Alk is selected from c 151494.doc -25- 201120018 CH2CH2, CHF and CF2. The group R, if present, is in particular selected from the group consisting of halogens, in particular fluorine or gas; CN (= cyano); N 〇 2 (nitro); OH; SH; (VCV fluorenyl, especially fluorenyl, Ethyl or isopropyl; Ci_C4_ alkoxy', especially decyloxy or ethoxy; NH2; NR4R5, especially NH(CH3) or N(CH3)2; fluorinated C丨-hospital, especially difluoromethyl Or a trifluoromethyl group, SFs; a fluorinated Cr alkoxy group, especially a difluoromethoxy group or a trifluoromethoxy group or two groups R1 a bonded to an adjacent carbon atom may together form a partial group. -Alk_0 'where Aik is selected from CH2, CH2CH2, CHF and CF2. The R丨 in formula I, 1.1, 1.2, 1_3 or Ι4 is unsubstituted or carries i, 2 or 3 identical or different A compound of the compound of the invention of the phenyl or 6-membered heteroaryl group of the group Ria is preferably a compound of the formula: [Mj 2, 13 or 14;

AM wherein # represents an attachment point to the S02 group, κ system N or C-R11, L system N or C-R12, lanthanide N or C-R13, wherein R", R12 and R13 are independently of each other hydrogen or One of the meanings of Rla given, one of the preferred meanings. R1 of the formula ϊ, Ι·1, 1.2, 1.3 or 1.4 is unsubstituted or has one, two or three phenyl or 6-membered heteroaryl groups of the same or different group Rla 151494 .doc -26· 201120018, R2 in [2, 1.3 or Ι·4 is selected from the group of R1 selected from the formula Arl.l and the compound of the compound 'the preferred formula i, the formula j Arl.l a compound to the Arl.5 group, a compound of the Arl.3 group··

Arl .2

Arl·4 Arl.5 wherein # represents an attachment point to the S〇2 group and wherein the ..., the ruler and the ruler are independently of each other hydrogen or one of the meanings of the given 2Ru is particularly preferred. In the compounds of formula I, 1.1, 1.2, 1.3 or 1.4 of the Ri formula Arl, AH, Arl. 2 ' Arl 3, Arl 4 or octa 5 groups, specific embodiments of the invention relate to the variables R11, Ri2 and R 3 (if present) individually or especially in combination with a compound having the following meaning: R, R (if present) are independently selected from the group consisting of: 虱'halogen, Ο Η, CN; SH; C!-C4 Affiliation, especially fluorenyl, ethyl isopropyl; CrC4 alkenyl, especially vinyl; c^C4 alkynyl, especially ethynyl; Ci-C4-alkoxy, especially methoxy or ethoxy; Ci_c4 _Alkyl sulfide 151494.doc -27- 201120018 base, especially methylthio or ethylthio; fluorinated c]-alkyl, especially difluoromethyl or trifluoromethyl; fluorinated Ci-alkoxy, especially two Fluoromethoxy or trifluoromethoxy; NH2; NR4R5, such as NHCH3 or n(ch3)2; trans-CVC4-alkyl, especially hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; Ci_C4 · Alkoxy-Ci-C Alkyl', especially methoxymethyl, ethoxymethyl, hydrazine-methoxyethyl or methoxyethyl; R, if present, is selected from the group consisting of hydrogen; halogen; 〇H ; SH ; CN ; N 〇 2 ; CVC 4 alkyl, especially methyl, ethyl or isopropyl; cvc: 4 alkenyl, especially vinyl; C 2 -C 4 alkynyl, especially ethynyl; Ci · C4-alkoxy a group, especially an oxime or ethoxy group; a Ci_C4_alkylthio group, especially a methylthio group or an ethylthio group; a fluorinated G-C2-alkyl group, especially a difluoromethyl group or a trifluoromethyl group; SF5; C--C2-alkoxy, especially difluoromethoxy or trifluoromethoxy; NH2; hydroxy-q-CV alkyl, especially hydroxymethyl, hydrazine hydroxyethyl or 2-ylethyl; Ci -CV alkoxy-CrC4-alkyl, especially decyloxymethyl, ethoxymethyl, 1-methoxyethyl or 2-decyloxyethyl; c(〇)R3', especially ethyl hydrazino Or a propyl group; nr4r5, especially a methylamino or didecylamino group; and C(0)0R8, especially a methoxycarbonyl or ethoxycarbonyl group. R12, if present, is especially selected from halogens, especially fluorine or Gas; CN (= aryl group); N02 (confirmation); 〇H; SH; C丨-C4-alkyl, especially methyl Ethyl or isopropyl; Ci-C4.alkoxy, especially methoxy or ethoxy; Nh2; NR4R5, especially NH(CH3) or n(ch3)2; fluorinated Ci-alkyl, especially Mercapto or di-It methyl, SF5, normalized C!-alkoxy, especially dimethoxy or trifluoromethoxy, or 'if K is C-R" and L is C-RI2, then R&quot And R12 can also form 151494.doc -28- 201120018 a part of the group O-Alk-O, wherein Aik is selected from ch2 'CH2CH2, CHF and CF2. A preferred embodiment of the invention in a compound of formula I, 1.1, 1.2, 1.3 or Ι·4 of the R ' Ar 1 ' Arl. 1, Arl . 2, Ar 1.3, Ar 1.4 or Arl .5 group With respect to the variables R11, R12 and R13 (if present), respectively, or in particular combinations of compounds having the following meanings: R11 is selected from the group consisting of hydrogen 'halogen, hydrazine, fluorenyl, di-methylmethyl, trifluoromethyl , 曱oxy, difluoromethoxy and trifluoromethoxy; R·12 is selected from the group consisting of halogen; hydrazine; SH; CN; Ν02; C1-C4 alkyl, especially methyl, ethyl Or isopropyl; C2_C4 alkenyl, especially vinyl; CrC4 alkynyl, especially ethynyl; Ci_C4_alkoxy, especially methoxy or ethoxy; q-C4-alkylthio, especially methylthio or B Sulfhydryl; fluorinated ^:, -alkyl, especially difluoroindolyl or trifluoromethyl; sh; fluorinated Ci alkoxy, especially difluoromethoxy or trifluoromethoxy; NH2; hydroxyl-c丨_C4_alkyl, especially hydroxymethyl, hydroxyethyl or 2-hydroxyethyl; Ci C4_alkoxy-Cl_C4_alkyl, especially methoxy fluorenyl, ethoxymethyl, 1- Ethoxyethyl or 2-methoxyethyl; c( R3, especially acetyl or propyl amide; NRR, especially methylamino or dimethylamino, or, if K is C-RHiLsc_ri2, ..., and ... can also form a mouth P knife group together 〇-Alk_〇' wherein Alk is selected from the group consisting of cH2, ch2CH2, CHF and CF2; and R13, if present, is hydrogen. R51 of the formula IU, L2, U or 1.4 is unsubstituted or has a C-membered 2 or 3 beryl or a different group of C-bonded 5-membered heteroaryl I51494.doc •29· 201120018 Among the compounds, the preferred formula is i ΑΓ 2 or Ar 2 , the compound of the group: LI, 1.2 ' 1.3 or R 1 in 1.4

(Αγ2) (α“2) where # represents the attachment point of the R1 and S〇2 groups, 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 system Ο, S or N-R18, G' system Ο, S or N-R19, wherein κ Ά π and independently of each other are nitrogen or have one of the meanings given, and 9 series hydrogen; cyano; NH2; 〇h CVCn-alkyl, especially C _C4_alkyl, especially methyl, ethyl or iso-yl; c2-c10-alkenyl' especially C2_C4-alkenyl, especially Or a C-C10-alkynyl group, especially a C2_C4-alkynyl group, especially an ethynyl group or a 3-propyl group; a q-C6.alkoxy group, especially a Ci_C4_alkoxy group, especially a methoxy group Or ethoxy; hydroxy-C2_C6_alkyl, especially hydroxy-C2_C4_alkyl, especially 2-ethoxyethyl; C^C4·alkoxy_C2_C4_alkyl, especially methoxyethyl or 2-methoxyethyl; fluorinated Cl_C2_alkyl, especially fluorinated Ci-alkyl; fluorinated ^-匚2.alkoxy, especially fluorinated c-widely alkoxy, especially difluoromethoxy or Difluorodecyloxy 'C(0)R3 'in particular ethyl hydrazino or propyl hydrazide; nr4r5, especially 151494.doc -30· 201120018 戈::~A Amino group; and c(0)0r8, especially a methoxy or ethoxy group. ΐ二二?, 1,3 or "R1 is unsubstituted or has 1 or 2 Or a compound of the present invention in which 3 groups of the same or different n groups 11 are red-bonded with a 5-membered heteroaryl group. Preferably, the formula is ^^, 1 ^ [3 or R1 of 1.4 is selected from the formula Ar2.1, Ar2 .2, Ai·, 2 ^ . Λ

Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7,

Ar2.8 % Ar2.9 ^ Ar9 in λ 〇 "

Ar2.10, Ar2.ll, Ar2.12, Ar2.13,

Ar2,14, Αγ2_15, Ar2 16, Ar2 17, Ar218, Ar2.19,

Ar2, .l, Ar2i.2, Ar2, .3, Ar2, 4, Ar2, 5, Ar2, 6, Ar2, 7,

Ar2 "8 Ar2 ·9, Αι·2'·1〇, Ar2'_ii and Ar2' 12 group compounds, especially preferred R is selected from the formula Ar2 l, Ar2 2, 八^^2 and Ar2, 2 Group of compounds: F #

, 17, 18

Ar2,

Ar2.2 R Ar2.3

Ar2.4

Ar2_5

Ar2.6 151494.doc • 31 - 201120018

Ar2.7 Ar2.8

Ar2.9

Ar2.10 Ar2.11 Ar2.12

Ar2.13 Ar2.14 Ar2.15

Ar2.16 Ar2.17 Ar2.18 Ar2.19

Ar2'.l Ar2'.2 Ar2,.3 151494.doc -32- 201120018 #

4·· 1R

5 1 R # o

4-- 1R

.N

5 1R s

5 1

Ar2’.4 Ar2'.5 Ar2,.6

Ar2,.7 Ar2'.8 Ar2,.9 # #

R

N. λ o

R

N. λ

Ar2,.10 Ar2'.ll Ar2'.12 wherein # represents the attachment point of the R1 and S02 groups, wherein R14, R15, R16, R17, R18 and R19 have the meanings given above. In R1, it is selected from the group consisting of Ar2.1, Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2_7, Ar2.8, Ar2.9, Ar2.10, Ar2.11, Ar2_12, Ar2 .13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2, .l, Ar2'.2, Ar2, .3, Ar2'.4, Ar2'. 5. Ar2, 6, Ar2, .7, Ar2'.8, Ar2, _9, Ar2, .10, Ar2'.ll and VIII.12 groups of formula 1, 1.1, 1.2, 1.3 or 1.4 Specific embodiments of the invention relate to the variables R14, R15, R16, R17, R18 and R19, if present, individually or in particular to a compound having the following meaning: I5l494.doc -33- 201120018 R (if present) hydrogen R (present to the right) is hydrogen; R16 (if present) is selected from the group consisting of: hydrogen; halogen, especially fluorine or gas; 〇H; SH; CN; N02; (VC4 alkyl, especially methyl, ethyl Or isopropyl; CrC4 alkenyl, especially vinyl; C2_c4 alkynyl, especially ethynyl; q-C4-alkoxy, especially methoxy or ethoxy; Ci_C4_alkylthio, especially methylthio or B Thio group; fluorinated Ci_C2_alkyl group, especially difluoromethyl or difluoromethyl; SFs; fluorinated C]-C2_alkoxy, especially difluorodecyloxy Or difluoromethoxyl; NH2; hydroxy-Ci_C4_alkyl, especially hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; Cl_C4_alkoxy_Ci_C4-alkyl, especially decyloxymethyl , ethoxymethyl, 丨 曱 methoxyethyl or 2 methoxyethyl ' C (0) R 3 'in particular ethenyl or propyl fluorenyl; and NR 4 R 5 , especially methylamino or dimethylamine R17, if present, is selected from the group consisting of hydrogen; halogen, especially fluorine or gas; OH; SH; CN; N02; Cl-C4 alkyl, especially methyl, ethyl or isopropyl; a group, especially a vinyl group; a C2_C4 alkynyl group, especially an ethynyl group; a Gc: 4-alkoxy group, especially a methoxy or ethoxy group; a C|_C4_alkylthio group, especially a methylthio group or an ethylthio group; Ci_C2_alkyl, especially difluoromethyl or difluoroindolyl; SFs; fluorinated CrC2-alkoxy, especially difluoromethoxy or difluorodecyloxy, NH2; hydroxy-C1-C4-alkyl, Especially hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; Cl_C4_alkoxy_Ci_C4_alkyl, especially methoxymethyl, ethoxymethyl, 丨-methoxyethyl or 2 _methoxyethyl, C(0)R, especially ethyl or propyl; and nr4r5 In particular, methyl group or dimethylamino. 151494.doc -34· 201120018 R18 (if present) is selected from the group consisting of: hydrogen; cn; base: especially methyl, ethyl or isopropyl; c2-c4 alkenyl, especially vinyl 'G-C4 a 'in particular ethynyl group; a proficient C, a pyridyl group, especially a difluoromethyl or a trimethyl group; a hydroxy-C2 alkyl group, especially a 2-hydroxyethyl group;

Ci-CV is a 4-mercapto group, especially a 1-methoxyethyl group or a 2-methoxyethyl group, and R18 is especially hydrogen or methyl.

R (present in the right) is selected from the group consisting of: hydrogen; CN group, especially fluorenyl, acetaminophen ▲ L- or isopropyl, c2-c4 alkenyl, especially vinyl terphenyl, especially ethynyl ; gasification c widely burned base or trimethyl methyl ncvw base, especially with base ethyl = ethyl. R19 is especially hydrogen or methyl. An example of a methoxy group R is exemplified. Table A - out which is a specific implementation of the invention Table A: Meaning of R1

151494.doc •35· 201120018 # R1 12 4-Hydroxyphenyl 13 4-epoxyphenyl 14 4-(indolyl)phenyl 15 4-Mylphenyl 16 2-decylphenyl 17 3-cyano Phenyl 18 4-cyanophenyl 19 4-aminophenyl 20 4-nitrophenyl 21 4-(dimethylamino)phenyl 22 3-a-4-methylamino-phenyl 23 3-fluoro-4-methylphenyl 24 3-fluoro-4-methoxyphenyl 25 3-mercapto-4-ylphenyl 26 4_ gas-3-ylthiol 27 4-carboxyphenyl 28 3,4-Dicyanophenyl 29 3-decyl-4-cyanophenyl 30 3-fluoro-4-cyanophenyl 31 3-methoxy-4-cyanophenyl 32 3-hydroxy 4-Mercaptophenyl 33 3,5·difluoro-4-cyanophenyl 34 4-pentafluorothiol 35 2·0 ratio biting group 36 3-pyridyl 37 4-. Bipyridyl 38 5-gas σ ratio bit-2-yl 39 5-carbyl quinone 0-yl-2-yl 40 5-cyano group. Bipyridin-2-yl 41 5-ethylidene ratio bite_2_yl 42 5·fluorenyl 0 to biti-2-yl 43 5-methoxypyridin-2-yl 44 5-trifluoromethoxy 》Bistidin-2-yl-36- 151494.doc 201120018 # R1 45 5-Trifluoromethylpyridin-2-yl 46 5-Ethylpyridin-2-yl 47 5-Shoshyl σ-Phenyl-2-yl 48 5-cyano. Bipyridin-3-yl 49 5·B fast base ° bite-3-yl 50 5-inverse than bite-3-yl 51 5-> stinky than bite-3-yl 52 5-decyloxy&quot Bibi-3-yl 53 5-trifluorodecyloxypyridin-3-yl 54 5-methylpyridin-3-yl 55 5-trifluoromethylpyridin-3-yl 56 6-cyanopyridinium -3-yl 57 6-fluoroα is more than -3-yl 58 6-chloro-to-bit-3-yl 59 6-methylpyridin-3-yl 60 6-ethyl °°°·3-base 61 6-Trifluoromethylpyridin-3-yl 62 6-methoxypyridin-3-yl 63 6-ethoxyl ratio -3-yl 64 6-fluorenylthio. More than biting 3-yl 65 6-dimur methoxyl ratio bite-3·yl 66 6-fluoropyridin-2-yl 67 6- disordered base atb bit-2-yl 68 6-fluorenyl ° bite ~ 2·yl 69 6-ethyl D butyl-2-yl 70 6-(dimethylamino)pyridin-2-yl 71 6-ethylpyridylpyridin-2-yl 72 6-trifluoromethylpyridine- 2-Based 73 6-decyloxy σ-Bite-2-yl 74 6-Trifluoromethoxypyridin-2-yl 75 2-Gas ratio bite-3·Base 76 2-Azide-pyrene ratio bite-3 -yl 77 2-decylpyridin-3-yl-37- 151494.doc 201120018 # R1 78 2-methoxyl ° than biting-3-yl 79 2-trii-l-oxyl 17-biting-3-yl 80 2-Trifluoromethylpyridin-3-yl 81 6-aminopyridin-3-yl 82 6-dimethylamino π ratio acetyl-3-yl 83 3-fluoropyridin-2-yl 84 3 · gas base . Specific biti-2-yl 85 3-decylpyridin-2-yl 86 3-methoxypyridin-2-yl 87 3-trifluoromethylpyridin-2-yl 88 3-trifluorodecyloxy acridine 2-yl 89 4-fluoropyridin-2-yl 90 4- gas-based ratio bite · 2 · group 91 4-fluorenyl ° ratio bit-2-yl 92 4-decyloxypyridin-2-yl 93 4- Trifluoromethylpyridin-2-yl 94 4-trifluoromethoxy. Bipyridin-2-yl 95 6-isopropylpyridin-3-yl 96 3- gas D ratio biti-4-yl 97 3-carbyl ratio biti-4-yl 98 3-methylpyridin-4-yl 99 3-decyloxypyridin-4-yl 100 3-trifluoromethylpyridin-4-yl 101 3-trifluoromethoxy"bipyridin-4-yl 102 2-fluoroteptyl-4-yl 103 2 · gas base ° bite-4-yl 104 2-mercapto 0 than bite-4-yl 105 2-decyloxy ° pyridine-4-yl 106 2-trifluoromethyl. Bipyridin-4-yl 107 2-trifluoromethoxypyridin-4-yl 108 5- gas-6-fluorenyl ° butyl-2-yl 109 5-fluoro-6-decyloxy-2-yl 110 4,6-Dimethyl 0 to 0^-2-yl-38- 151494.doc 201120018 # R1 111 4-Actyl-6-methoxyl °D-3·Base 112 4-Mercapto-6 -Methoxy acridine-3-yl 113 5-amino-3-ox-4-oxooxyl ratio bite-2·yl 114 5-carbyl-4-fluoro D ratio bite-2·group 115 5 -Cyano-4-methylacridin-3-yl 116 2-lacyl-6-methyl 0-bite-4·yl 117 6-alkyl-5-transester D ratio -3-yl 118 σ Bite-2-yl 119 Mouth bite-5-yl 120 Pyridine-4-yl 121 5-cyanopyrimidin-2-yl 122 6-Attachyl aceto-4-yl 123 2-hydroxy-4-fluorenyl Pyrimidine-5-yl 124 5-ethynylpyrimidin-2-yl 125 4,6-diamidinopyrimidin-2-yl126 4-ox-5-methoxypyrimidin-2-yl 127 2-indolethio Bite-5-yl 128 2-trifluoromethoxypyrimidin-5-yl 129 5-methyl-pyrazine-2-yl 130 5 · aryl group ° ° Qin-2-yl 131 5-cyano-6 -Fluorine ratio °Qin-2-yl 132 5-decyloxypyridazin-3-yl 133 6-Gaoxazin-3-yl 134 6-Cyano-5-methoxy-1,2,4- Triazin-2-yl 135 σ fut-2-yl 136 furan-3-yl 137 5-methylfur -2-yl 138 5_ethyl ate ° ̄-2-yl 139 5-hydroxydecylfuran-2-yl 140 2-mercaptofuran-3-yl 141 3-cyanofuran-2-yl 142 5- Exact base 2 -yl 143 2,5-dimethylfuran-3-yl·39· 151494.doc 201120018 # Ri 144 2-thienyl 145 3-decyl 146 5-methyl-2-α Serenyl 147 5-ethyl-2-11 thiophene 148 3-methyl-2-thienyl 149 2-mercapto-3-d-sepyl 150 5-mercapto-3-thienyl 151 4- Mercapto-3-thienyl 152 5-cyano-2-thienyl 153 4-oxyl-2-11 secantyl 154 ' 3-cyano-2-thienyl 155 2-cyano-3-thienyl 156 5-Alkyl-3-°3⁄4 phenyl 157 4-cyano-3-thienyl 158 5-hydroxymethyl-3-thienyl 159 4·Three methoxy-3·°Sepyl 160 5 -ethynyl-2-thienyl 161 5-oxo_4-fluoro-2-nonyl 162 4-ox-5-ethyl-2-nonyl 163 2,5-dimethyl-3-thiophene Base 164 1-methylpyrrol-2-yl 165 1-mercapto-5-carbyl 0 bromo-3-yl 166 1-decylpyrazol-3-yl 167 1-decylpyrazol-4-yl 168 1-Ethylpyrazol-4-yl169 1,3-didecylpyrazol-4-yl 170 1,5-dimethylpyrazol-4-yl 171 1-sided oxy-° ratio ° sitting- 4- 172 1-meridazolidin-4-yl 173 1-methylimidazol-5-yl 174 1,2-dimercapto imidazole-4-yl 175 U-dimercaptoimidazole-5-yl 176 4-methylthiazole -2-yl•40- 151494.doc 201120018 # R1 177 2,4-Dimercaptothiazol-5-yl 178 2-carbyl-4-methyl ° 嗤-5-yl 179 isothiazol-3-yl 180 isothiazol-4-yl 181 isothiazole _5-yl 182 4-methylisothiazol-3-yl 183 5-methylisothiazol-3-yl 184 3-methylisothiazol-4-yl 185 3 -mercaptoisothiazol-5-yl 186 4-methylisothiazol-5-yl 187 5-methylisothiazol-4-yl 188 3-cyanoisothiazol-5-yl 189 4-cyanoisothiazole- 5-ylyl 190 5-cyanoisothiazol-4-yl 191 3,5-dimethylisothiazol-4-yl 192 4·methyl-5-trifluorodecylisothiazol-3-yl 193 2-indole Oxazol-5-yl 194 oxazol-5-yl 195 3,5-dimethylisoxazole-4-yl 196 1,2,3-thiadiazol-4-yl 197 1,2,3- Thiazol-5-yl 198 4-mercapto-1,2,3-thiadiazol-5-yl199 5-methyl-1,2,3-thiadiazol-4-yl 200 5-chaotic -1,3,4·α塞二° sit-2-yl 201 4-cyano-1,2,3-thiadiazol-5-yl 202 1,3,4-thiadiazol-2-yl 203 1,3,4-oxadiazol-2-yl204 5-methyl -1,3,4-oxadiazol-2-yl 205 5-aryl-1,3,4-° dioxin. Sodium-2-yl 206 1,2,4-triazol-4-yl 207 1,2,4-[4Η]triazol-3-yl 208 1,2,3,4-tetrazol-5-yl 209 1,2,3,4-tetrazol-1-yl•41 - 151494.doc 201120018 # _ R1 210 2·Methyl-1,2,3,4-tetra. Sit-5- some 211 benzo·1,4-dioxane-6-yl 212 benzo-1,3-dioxan am -------------- according to a specific Illustrative, R 2 -phenyl or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl have a CN group ' and may additionally carry i, 2 or 3, especially 1 Or two identical or different groups R2a, according to a particular embodiment, the invention relates to salts of the formulae j", 12, 13 and 5, salts of the N-oxides and N-oxides thereof, Wherein R 2 is a phenyl group bearing a CN group and may additionally carry one, two or three, in particular one or two identical or different radicals ya. It is preferred that the carbon ring atoms in the ortho position relative to the attachment point of the cultivating core of (I) have no group R2a. Preferably, the CN group is positioned opposite the attachment point to the imming core of (1). In particular, the phenyl group bears a CN group and may additionally carry one or two identical or different groups R2a. According to another particular embodiment, the invention relates to the formulas, 12, i3 and 1.4. a salt of its salt, its N_oxides and oxides, of which the anatomical group of the genus 2 has its own group and can have an additional number of 2, 3 or 3, especially 1 Or 2 identical or different groups R2a. In particular, the 6-membered heteroaryl has a CN group and may additionally carry i groups R2a. It is preferred that the compounds or the nitrogen ring atoms are not located adjacent to the attachment point of the (I) taste core. The compound towels are preferably one having no group R2a with respect to the carbon ring atom in the ortho position to the attachment point of the core of (I). Preferably, the CN group is in the para position relative to the attachment point to the taste core of (1). According to yet another particular embodiment, the present invention is directed to a workman, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker, a worker a salt thereof, a salt thereof, an N-oxide and an oxide thereof, wherein the r2 is a C-bonded 5-membered heteroaryl group having a (:1^ group and may have an additional one, two or three In particular, one or two identical or different groups ya. Among these compounds, it is preferred that the carbon ring atom in the ortho position relative to the sulfonyl moiety has no group R2a. The aryl group bears a CN group and may additionally carry one group R2a. In these embodiments, the group R, if present, has the above meaning and is preferably selected from the group consisting of lignin; OH; SH; CN; N〇 2; c]_c4, especially fluorenyl, ethyl or isopropyl; CrC4 alkenyl, especially vinyl; c2_c4 alkynyl, especially ethynyl; Ci-C4-alkoxy, especially decyloxy or ethoxy Alkylthio, especially thiol or ethylthio; fluorinated Ci_c2_alkyl, especially difluoromethyl or difluoroindolyl; SF5; fluorinated C-C2-alkoxy, especially Difluoromethoxy or difluoromethoxy; NH2; hydroxy-Ci-C4.alkyl, especially hydroxyindenyl, 1-hydroxyethyl or 2-hydroxyethyl; q-CV alkoxyalkyl, especially Methoxymethyl, ethoxymethyl, i•methoxy Or 2 methoxyethyl; C(0)R3, especially ethyl hydrazino or propyl fluorenyl; NR4R5, especially methylamino or decylamino; and C(0)0R8, especially methoxy The group, the ethoxycarbonyl group, or the two groups R2a bonded to an adjacent carbon atom may also form a partial group O-Alk-O, wherein Aik is selected from the group consisting of CH2, CH2CH2, CHF and CF2. The group R2a, if present, is especially selected from the group consisting of: halogen 'especially fluorine or chlorine; CN(=cyano); N〇2(nitro); 〇H; SH; C,-C4-alkyl' Especially fluorenyl, ethyl or isopropyl; c] _c4_alkoxy, especially methoxy or ethoxy; NH2; NR4R5, especially NH(CH3) or N(CH3)2; fluorinated CV alkyl, Especially difluoromethyl or trifluoromethyl; sf5; 151494.doc •43· 201120018 Fluorinated c丨-morphyloxy, yoshi _ 凡凡, monofluoromethoxy or trifluoromethoxy, or The two groups R2a to the adjacent carbon atoms may also form part of the group together...

Aik-0 'where Alk is selected from CH2, CH2CH2, CHF and preferably, R2a is selected from the group consisting of hydrogen, sulfonium, OH, CN, methyl, methoxy, bis, base, three Gas methyl, dimethoxy and oxy. a preferred compound of the formula 1-1, 1.2, "or a compound of the invention in which the r2 is unsubstituted or has a (10), two or three identical or different groups ... or a heteroaryl group. A compound of the formula 2, which is a compound of the formula 2:

(Ar3) where # denotes the attachment point of the imming core with (I), 'system' or C-R21, L' system or C-R22, 'system' or C-R23, Q system or CH, Ρ System or CH, wherein R2丨, R22 and R23 are, independently of each other, a hydroquinone having the meaning given to CN. The conditional variable π, L' or Μ' in the soil or both is C-. The R2 in the formula I, 1.1, 1.2, 1.3 or 1.4 is unsubstituted or has 1 or 3 identical or different The base of the base 2!1 of the phenyl or 6 Chang her # 〜贝杂方基的发发151494.doc -44 - 201120018 The best compound in the compound I, Ι·1, 1.2, Ι·3 Or R2 in I_4 is selected from the group consisting of Ar3.1, Ar3.2 'Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7,

A compound of the Ar3.8, Ar3.9, Ar3.10, Ar3.11 and Ar3.12 groups, particularly preferably a compound selected from the group consisting of the Ar3.l and Ar3.3 groups:

Ar3.1 Ar3.2 Ar3.3

Ar3.4 Ar3.5

Ar3.6 #

R21^^N^^R Ar3.7 # 23

.twenty three

Ar3.10 Ar3.11

Ar3_12 151494.doc .45 201120018 where # is not attached to the imino core of (i), and wherein rZ1, R22 and R are independently of each other hydrogen or have one of the given meanings of RZa, conditional basis One of the groups R2 and R^r23 is CN. In the group Αγ3", Αγ32,

In Ar3.3, Ar3.4, Ar3.5, Ar3.6 and Ar3.ll, R22 is preferably CN, and R21 and, if present, R23 are not CN. In the R2 system, Ar3.1, Ar3.2, Ar3.3, Ar3.4, Ar3.5 'Αϊ·3.6, Ar3.7 Ar3.8, Ar3.9, Ar3.1〇, Ar3.11 or Ar3. Of the compounds of formula 1, LI, 1.2, 1.3 or 1.4 of the group 12, preferred embodiments of the invention are directed to the variants R, R22 and R23, if present, individually or in particular combinations of compounds having the following meanings, the conditions being One of the groups R2!, R22 or R23 is CN. R21, if present, is selected from the group consisting of hydrogen; halogen; 0H; CN; Ci_C4 alkyl, especially methyl, ethyl or isopropyl; Cl_C4_alkoxy, especially methoxy or ethoxy; hc:4. Thio group, especially methylthio or ethylthio; fluorinated Ci-C2.alkyl, especially difluoroindolyl or trifluoromethyl; fluorinated Ci_C2_alkoxy, especially difluoromethoxy or trifluoro Methoxy; hydroxy_C _C4_alkyl, especially hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; &Cl_C4_alkoxy_Ci_c4 alkyl, especially methoxy fluorenyl, B Oxymethyl, methoxyethyl or 2-methoxyethyl. R (if present) is selected from the group consisting of hydrogen; halogen; 〇H; CN; CVC4 alkyl, especially methyl, ethyl or isopropyl; Cl_C4.alkoxy, especially methoxy or ethoxy; hc:4- Alkylthio, especially thiol or ethylthio; fluorinated Ci_C2_alkyl, especially difluoroindolyl or trifluoromethyl; fluorinated Ci_C2_alkoxy, especially gas oxy or difluoromethoxy ; through the group -Ci-C4*·alkyl group, especially transmethyl, hydrazine-yl-ethyl or 2-hydroxyethyl; & Cl-C4_alkoxy-C]_c4-burning 151494.doc • 46· 201120018 The base 'especially methoxymethyl, ethoxymethyl, 1-methoxyethyl or 2-methoxyethyl. R23, if present, is selected from the group consisting of hydrogen; halogen; OH; CN; CVC4 alkyl, especially decyl, ethyl or isopropyl; Cl-C4-alkoxy, especially decyl or ethoxy; a group, especially a methylthio or ethylidene; a fluorinated Ci_C2_alkyl group, especially a difluoromethyl or trifluoromethyl group; a fluorinated Ci_c2_alkoxy group, especially a difluoromethoxy group or a trifluoromethoxy group; a hydroxy-Cl_c4-alkyl group, especially a hydroxy fluorenyl group, a hydroxyethyl group or a 2-hydroxyethyl group; and a fluorenyl-fluorenyl-alkoxy-CrCr alkyl group, especially a methoxy fluorenyl group, an ethoxylated fluorenyl group , 丨 methoxyethyl or 2- methoxyethyl. In the R system, Ar3.1, Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6,

Preferably, the invention is better in the formula I' Ι·1, Ι·2, 1.3 or 1.4 of Ar3.7, Ar3.8, Ar3.9, Ar3.10, 八1>3_11 or 八!*3.12 group The examples relate to the variables R, r and the ruler 23 (if present), respectively, or in particular combinations of compounds having the following meanings, one or both of the conditions R^, Ruler 22 or R23 being CN: R21 (if present) Choose from the following groups: hydrogen, dentate, 〇H, cn, methyl, methoxy, tridity, trimethyl, tris-methoxy and trifluoromethoxy; R22 (if present) Is selected from the group consisting of hydrogen, halogen, OH, methyl, decyloxy, difluorodecyl, trifluoromethyl, difluorodecyloxy, and bis-oxooxy; and R23 (if present) is selected Free group of the following: hydrogen, dentate, OH, methyl, decyloxy, di-H methyl, trifluoromethyl, dimethoxymethoxy 151494.doc • 47· 201120018 and trifluoromethoxy. In the R2 system, Ar3.1, Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6 or

Among the compounds of formula I, 1.1, 1.2, 1.3 or 1.4 of the Ar3.11 group, specific examples of the invention are those in which the variables R21, R22 and R23, if present, are individually or in particular combined with the following meanings: R21 From hydrogen; dentate; OH; CVC4 alkyl, especially methyl, ethyl or isopropyl; q-cv alkoxy, especially methoxy or ethoxy; Ci_C4_thiol' especially thiol or Ethylthio; fluorinated C]-alkyl, especially di-methyl or di-methyl, fluorinated Cr alkoxy, especially difluoro-methoxy or ternary methoxy; hydroxy-CrC4-alkyl , especially hydroxyindenyl, hydroxyethyl or 2-ylethyl, and G-C4-alkoxy-CVC4.alkyl, especially methoxymethyl, ethoxymethyl, 1-decyloxy Ethyl or 2-decyloxyethyl. R22 is CN. R23, if present, is selected from the group consisting of hydrogen; halogen; hydrazine H; alkyl, especially methyl, ethyl or isopropyl; C^-C: 4-alkoxy, especially methoxy or ethyl; C -C4-alkylthio, especially thiol or ethylthio; fluorinated alkyl, especially difluoromethyl or trifluoromethyl; fluorinated Cl-alkoxy, especially difluoromethoxy or dicha An oxy group, via a phenyl group, especially via a fluorenyl group, a κ hydroxyethyl group or a 2-hydroxyethyl group; &Cl_C4_alkoxy-Ci_C4 alkyl group, especially a methoxymethyl group, an ethoxymethyl group, an anthracene _Methoxyethyl or 2-methoxyethyl. In the R system, Ar3.1, Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6 or

In the formula I, Ι·ι, 12, ι·3 or ι·4 of the Ar3.11 group, a particular embodiment of the invention relates to the variables R2», r22&r23 (if present), or in particular 151494. Doc •48· 201120018 Combine compounds having the following meanings: R21 is selected from the group consisting of hydrogen, halogen, hydrazine H, hydrazino, methoxy, difluorodecyl, trifluoromethyl-difluoromethoxy and Trifluorodecyloxy. R22 is CN. 2 3 R (if present) is selected from the group consisting of hydrogen, halogen, hydrazine H, methyl, methoxy, difluorodecyl, trifluoromethyl, difluorohanoxy and trifluoromethoxy. R2 in formula I, 1.1, 1.2, 1.3 or 1.4 has a CN group and may additionally carry 1, 2 or 3 groups of the same or different group 2& Among the compounds of the present invention, preferred are compounds of the formula R1, 丨2, I" or R4 of the formula R4, αγ5 or Ar6 groups: #

Ar4 Ar5 Ar6 where # denotes the attachment point of R2 and (I) the p-well core, 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 〇, S or N-R28, G' is 0, S or N-R29, wherein R, R25, R26 and R27 are each independently hydrogen or have one of the meanings given, And wherein R28 and R29 are selected from the group consisting of hydrogen; cyano; NH2; OH, C^Cjo-alkyl, especially alkyl, especially fluorenyl, ethyl or iso-151494.doc-49·201120018 propyl; C2_C1()·ene a radical, especially a C 2 —C 4 —alkenyl group, especially a vinyl or 3-propenyl group; a C 2 —C 1 (··· alkynyl group, in particular a C 2 —C 4 —alkynyl group, in particular an ethynyl group or a 3-propynyl group; a CrC 6 —alkoxy group, in particular a Cl_C 4 —alkane Oxyl, especially decyloxy or ethoxy; hydroxy-CrC6-alkyl, especially hydroxy-C2_C4_alkyl, especially 2- ethoxyethyl; C^-C:4·alkoxy-CyC:4- Alkyl, especially methoxyindenyl, ethoxymethyl, 1-methoxyethyl or 2-methoxyethyl; fluorinated C2_alkyl, especially fluorinated alkyl; fluorinated Ci_c2_alkoxy, especially cesium fluoride, -alkoxy' especially difluoromethoxy or trifluoromethoxy; c(o)R3, especially Mercapto or propenyl; NR4R5, especially methylamino or dimethylamino; and C(0)0R8, especially methoxycarbonyl or ethoxycarbonyl. In the formula Αγ4 and Ar6, one of the ring members A or D or E is C-CN. R2 in the formula I, 1.1, 1.2, 1.3 or 1.4 is a 5-membered heteroaryl group having a cn group and additionally having one, two or three identical or different groups R2a. Among the compounds of the present invention, R2 of the formula I, J 1, 2, 1.3 or 1.4 is preferably selected from the group consisting of the formulas Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6. , Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.11, Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1, Ar5.2, Ar5.3, Ar5 .4, Ar5.5, Ar5.6, Ar5.7, Αγ5·8, Ar5.9, Ar6.1, Ar6.2 and

The compound of the Ar6.3 group, particularly preferred, is selected from the group consisting of Ar4, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1, Ar5 2, Ar5 3, Ar5 7 and Ar5. 8 group of compounds: 151494.doc -50- 201120018

Ar4.1 Ar4.2 Ar4.3

Ar4.4 Ar4.5 Ar4.6

Ar4.7 Ar4.8 Ar4.9

Ar4.12 26

Ar4.10

Ar4.11

N-N

#^〇^CN

Ar4.13

151494.doc -51 - 201120018

4- 2 R #

5 2 R

Xs N c

N c , 5

Ar5.1 Ar5.2 Ar5.3

Ar5.4 Ar5.5 Ar5.6

Ar5.7 Ar5.8 Ar5.9

5 2 R ,7

27

N丨#

Ar6.1 Ar6.2 Ar6.3 where # represents the attachment point of the imming core of R2 and (I), wherein R24, R25, R26, R27, R28 and R29 have the meanings given above, and wherein Ar4.1, Ar4.2, Ar4.3, Ar4_4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.11, Ar4.12, Ar4.15, 151494.doc -52- 201120018

Any of R24 or R26 or R27 in Ar6.1, Ar6.2 and Ar6.3 is CN. In R2, it is selected from the group consisting of Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Αγ4·7, Ar4.8, Ar4.9, Ar4.10, Ar4.11, 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_l In the compounds of formula 1, 1.1, 1.2, 1.3 or 1.4 of the Ar6.2 and VIII ".3 groups, a particular embodiment of the invention relates to the variables R24, R25, R26, R27, R28 and R29 (if present). Or a combination of compounds having 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, especially fluorine or chlorine; CN(=cyano); N〇2(nitro); 〇H; SH; CVC4-alkyl, especially methyl, ethyl or isopropyl; Cl_c4_alkoxy, Especially oxime or ethoxy; nh2; Nr4r5, especially nh(CH3) or N(CH3)2; fluorinated Ci_, especially difluoromethyl or trifluoromethyl; fluorinated Cl_alkoxy, Especially difluoromethoxy or trifluoromethoxy. Choose from the following groups: hydrogen; halogen, especially fluorine or gas; ) 'N〇2 (true); 〇H; SH; CVC4-alkyl, especially 曱: ethyl or isopropyl; Ci-C4-alkoxy, especially decyloxy or ethoxy, especially NH (CH3) ) or n(ch3)2; fluorinated Cl_alkyl', especially difluoromethyl, its eleven kilograms of methyl methoxy, a certain methyl group; defeated. "Alkoxy, especially two chaotic or trifluoroanthracene R. R is selected from the group consisting of: hydrogen, C!-C4, especially methyl, 151494.doc-53-201120018 ethyl or isopropyl; c2_c4 alkenyl' especially ethylidene; C2_C4 block, especially ethynyl; Cl-c4_ alkoxy, especially methoxy or ethoxy; fluorinated c, _ alkyl, especially dimethyl or tridecyl; gasification C]-burning An oxy group, especially a di-morphic methoxy or trifluoromethoxy group; a thiol group, especially a 2-ethyl group, and a CVC 4-morphyl-c2-c4. thiol group, especially i methoxy R29 is selected from the group consisting of hydrogen; Ci_C4 alkyl, especially methyl, ethyl or isopropyl; (iv) alkenyl, especially vinyl; C2-C4 alkynyl , especially ethynyl; C丨·C4•alkoxy', especially methoxy or ethoxy; fluorinated C]·Hyun In particular - methyl or difluoromethyl; fluorinated C plant alkoxy, especially difluorodecyloxy or trifluoromethoxy; hydroxy _c2 decyl, especially 2-hydroxyethyl, and C - C4-alkoxy-CrC4-alkyl, especially methoxyethyl or 2-decyloxyethyl. In R2, it is selected from the group consisting of Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, AH.6, Ar4.7, AH.8, Ar4.9, Αΐ·4·10, Ar4.ll , Αι·4.12

Ar4.13, Ar4.14, Αγ4.15, Ar5.1, Ar5.2, Ar5.3, Αγ5·4,

Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1, Ar6.2 and

Among the compounds of the formulas of L6, 1.2, 1.3 or 1.4 of the Ar6,3 group, the specific embodiments of the invention have the following meanings with respect to the variables r24, r25, r26, r27, r28 and r29 (if present), respectively or in particular combinations. Compound: R24 is hydrogen. R25 is hydrogen. Choose from the following groups: hydrogen, halogen (especially fluorine or gas), 〇H, CN, sulfhydryl, methoxy, dimethyl, trimethyl, tuned 151494.doc -54· 201120018 oxygen And trifluoromethoxy. R27 is selected from the group consisting of hydrogen, halogen (especially fluorine or gas), OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy . R28 is hydrogen or an alkyl group, especially hydrogen or methyl. R29 is hydrogen or a Ci-G alkyl group, especially hydrogen or methyl. Examples of the group R2 are given in Table B below, which is a specific embodiment of the invention. Table B: Meaning of R2 R2 1 3-cyanophenyl 2 4-cyanophenyl 3 4-aryl-3-denylphenyl 4 4-cyano-3-phenylphenyl 5 3,4-dicyanic Phenyl 6 3-methyl-4-cyanophenyl 7 3-ethyl-4-cyanophenyl 8 3-decyloxy-4-cyanophenyl 9 3-hydroxy-4-cyanobenzene Base 10 3,5-difluoro-4-cyanophenyl 11-cyano-pyridin-2-yl 12 5-cyanoindole-3-yl 13 6-enyl group °^^-3 Base 14 6- disorder base ratio °^~2_yl 15 4-cyano-pyridin-2-yl 16 2-cyanoacridin-4-yl 17 5-cyano-6.methoxy. Bipyridin-3-yl 18 6·nitro-5-methoxyl ratio -3-yl 19 6-ranyl-5-fluoro-pyrifos-3-yl 20 5-cyano-4-fluoroindole Pyridin-2-yl 151494.doc -55- 201120018 R2 21 5-decyl-4-methyl'•pyridin-2-yl 22 2-mercapto-6-fluorenyl. Bipyridin-4-yl 23 6-enyl-5-ylpyridinyl-3-yl-24 5-cyanopyrimidin-2-yl 25 2-decylpyrimidin-4-yl 26 2-mercaptopyrimidine 5-yl 27 6-cyanopyrimidin-4-yl 28 5-carbyl ° ° Qin-2-yl 29 5-carbyl-6-fluoro D ratio D-Qin-2-yl 30 5-carbyl hydrazine -3·基3 6-Alityl-3-yl 32 6-Alityl-4-yl 33 6-Gas-1,2,4-diin-3-yl 34 6-Gas- 5-methoxy-1,2,4-tri. Qin-3-yl 35 3-aeroyl-1,2,4-disuccinyl-6-yl 36 3-cyanofuran-2-yl 37 5-decylfuran-2-yl 38 4-cyanofuran -2-yl 39 2-gas-based bite--3_yl group 40 5-fluorofuran-3-yl 41 5_carbyl-4-deprived 11 south-2-yl 42 5-cyano-4- gas Furan-2-yl 43 3-cyano-2-thienyl 44 5_carbyl-2-11 thiophene 45 2-carbyl-3-σsecenyl 46 5-cyano-3-thienyl 47 4-cyano-2-thienyl 48 5-aeroyl-4·fluoro-2-°secenyl 49 5-aeroyl-4·gas-2-septenyl 50 2-a gas-based ratio 嘻-1 - group 51 3 · gas group ° ratio 0 -1 - group 52 3-cyano-4-methyl.咯r-l-yl 53 4-alkyl group ratio 17 each-2-yl-56- 151494.doc 201120018 R2 54 5-azyl group piroxi-2-yl 55 3-ranyl-1-yl group 0 Big-2-yl 56 1-methyl-5-cyano "pyrrol-2-yl 57 1-methyl-4-cyanopyrrol-2-yl 58 5-carbyl-4-methyl ratio L--2-yl 59 1-methyl-2-cyano. Benzyl-3-yl 60 5-ranyl-pyrrol-3·yl 61 1-indolyl-5-enylylpyroxy-3-yl 62 2-cyanoimidazole-4-yl 63 2-cyano Imidazol-5-yl 64 2-cyano-1-methylimidazol-4-yl 65 4-cyanoimidazol-1-yl 66 2-cyano-1-indolizyl-5-yl 67 4-cyano 5-imidazol-2-yl 68 5-cyanoimidazol-2-yl 69 4-cyano-1-indenyl imidazole-2·yl 70 5-cyano-1·nonyl imidazol-2-yl 71 5-cyano Thiothazole-2-yl 72 4-cyanothiazol-2-yl 73 2-cyanothiazol-4-yl 74 2-cyanothiazol-5-yl 75 2-cyanooxazole-4-yl 76 2- Cyanooxazole-5-yl 77 4-decyloxazol-2-yl 78 5 -murenyl-2-yl 79 3-cyanoisoxazole-5-yl 80 5-cyanoisoxazole 3-yl 81 3-cyanoisothiazol-5-yl 82 5-cyanoisothiazol-3-yl 83 3-cyano. Biazole-5-yl 84 5-cyano. Bisazo-3-yl 85 3-mercapto-1-indolylpyrazole-5-yl 86 5·yl-1-yl group °°--3-yl-57- 151494.doc 201120018 R2 87 3 - gas-based oxazol-1-yl 88 4-mercaptopyrazol-1-yl 89 3-carbyl-4·gas*» than *1 gui · 1 · base 90 3-alkali _4. Than sitting _ 1^^ 91 5-nitro-1,3,4-che-dijun-2-some 92 5-fluoro-1,3,4·oxadiazole-2-some 93 5-air- 1,2,4-Triazol-3-yl 94 5-Alkyl-4-methyl-1,2,4-c-Jun-3- One of the basic embodiments of the invention is related to Formula I, 1.1, L2 1.3 and 1.4 compounds, salts thereof, salts of the N-oxides and N-oxides thereof, wherein the Ri group is a group and wherein the r2 group is an Ar3 group, especially the formula Ar3", Ar32, Αγ3.3 > Ar3. 4 'Ar3.5 'Ar3.6 > Ar3.7 'Ar3.8 'Ar3.9 ' Αγ3·10, 八^-^ or Ar3 12 group, especially the formula Ar3" or 3 group. Another particular embodiment of the invention relates to a salt of a compound of formula I, j 1, j 2 , I 3 and 14 , a salt thereof, an N-oxide thereof and a salt of the same, wherein r 1 is a group of the formula Arl and wherein R2 is a type of Ar4, αΓ5 or Ar6 group, especially

Ar4.1, Ar4.2, Ar4, 3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.1, Ar4.ll, 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 group, especially the formula Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1, Ar5_2, Ar5.3, Ar5.7 or Ar5.8 Group. A further specific embodiment of the invention relates to a compound of formula I, j 1, 丨2, I 3 and I, a salt thereof, an N-oxide thereof and an N-oxide, wherein the Ri system

An Ar2 or Ar2. group and wherein the R2 is a Αγ3 group, especially the formula Ar3.1,

Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, 151494.doc -58- 201120018 Αι*3·9, ΑΓ3·1〇, Ar3 u or Ar3 12 group, especially a formula of Ar3" or Ar3.3. A further specific embodiment of the invention relates to a compound of formula I, Ι1, 1.2' 1.3 and 1.4, a salt thereof, a cerium-oxide and a cerium-oxide salt thereof, wherein the R1 formula is an Ar2 or Ar2' group. And wherein the R2 system is a type of Ar4, Ar5 or Ar6 group

Ar4.1, Ar4.2, Ar4.3, Ar4_4, Ar4.5, Ar4.6, Ar4.7, Ar4, 8, Ar4.9, Ar4.10, Ar4.11, Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1, Ar5.2, Αι·5.3, Ar5.4, Ar5.5,

Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar61, Ar6 2 or Ar6 3 groups 'in particular, Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5 1 , Αγ5·2, Αι·5·3, Ar5.7 or Ar5.8 groups. A further specific embodiment of the invention relates to a salt of a compound of the formula I, LI, j 2, and 4, a salt thereof, an N-oxide thereof and a cerium oxide, wherein the r1 is of the formula Arl.l to Arl.5 a group, in particular an Arl.l or Arl.3 group, and wherein the Rule 2 is an Ar3 group, especially the formulas Ar3.1, Ar3.2, Ar3.3, Ar3 4, Ar3.5, Ar3.6, Ar3 .7, Ar3.8 'Ar3.9, Ar3.1〇, Ar3.u* Ar3.12 group 'in particular the formula Ar3.1 or Ar3.3 group. A further specific embodiment of the invention relates to a compound of formula I, 1:1, j 2, j^, and 4, a salt thereof, an N-oxide thereof, and an N-oxide salt, wherein R1 is a formula of Arl. a group of Arl. 5, especially an Arl.l or Arl.3 group, and wherein the rule 2 is of the Ar4, Ar5 or Ar6 group, especially the formula Ar4.i, Ar4 2, AH 3,

Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4 10, Ar4.11, Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5 1, Ar5.2, Ar5.3, Ar5_4, Ar5.5, Ar5_6, Ar5.7, Ar5 8, 151494.doc • 59- 201120018

Ar5.9, Ar6.1, Ar6.2 or Ar6.3 groups, especially sAr41, Ar4 2

Ar4.3, Ar4.4, Ar4.5, Ar5.1, Ar5.2, Ar5.3, Ar5.7 or

Ar5.8 group. A further specific embodiment of the invention relates to a compound of the formula I, j 1, j 2, 1.3 and 14 , a salt thereof, an N-oxide thereof and a salt of an N-oxide, wherein Ri is selected from the group consisting of the formula Ar2.1, Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.11, Ar2.12, Ar2.13, Ar2. 14. Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.l, Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'. 6, Ar2'.7,

Ar2'.8, Ar2'_9, Ar2'.10, Ar2'.ll and Ar2,.12 groups, especially selected from the group consisting of the formulas Ar2.1, Ar2.2, Ar2'.l and Ar2'.2, And wherein R2 is a group of Ar3 groups, especially the formulas Ar3 j, Ar3 2, Ar3 3, Ar3 4, Ar3 5,

The Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.11 or Ar3.12 group 'is especially a Group of Ar3.1 or Ar3.3. A further specific embodiment of the invention relates to a salt of the formula 1, 1.1, 1.2, 1.3 and 1.4, a salt thereof, an N-oxide thereof and a salt of an n-oxide, wherein ri is selected from the group consisting of the formula Ar2.1, Ar2 .2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2, 9, Ar2.1, Ar2.ll, 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'.l〇, Ar2,.ll and Ar2'.12 groups, especially selected from the formulas Ar2.1, Ar2.2, Ar2'.l And an Ar2,.2 group, and wherein R2 is a group of Ar4, Ar5 or Ar6, especially Αγ4", Ar4.2, Ar4.3,

Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, 151494.doc •60- 201120018

Ar4.11, 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 groups, especially the formulas Ar4.1, Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1, Ar5.2, Ar5.3, Ar5.7 or

Ar5.8 group. A further specific embodiment of the invention relates to a compound of the formula I, I, 2, 1.3 and I · 4 , a salt thereof, an N-oxide thereof and a salt of an N-oxide, wherein the Ri system

Arl.l or Arl.3 group, and wherein R2 is Ar3.1, Ar3.2, Ar3.3,

Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10,

The Ar3.11 or Ar3.12 group' is especially a group of the formula Ar3.1 or Ar3.3. A further specific embodiment of the invention relates to a compound of formula I, 1:1, 丨2, i4, a salt thereof, an N-oxide thereof and a salt of an N-oxide, wherein the Ri system

Arl.l or Arl.3 group 'and where R2 is Ar4.1, Ar4.2, Ar4.3' Α γ 4.4, Ar4.5, Ar5.1, Α γ 5.2, Ar 5.3, Ar 5.7 Or Ar5.8 group. Yet another specific embodiment of the invention pertains to Formula I, ! 1. A compound of 丨2, I4, a salt thereof, an N-oxide thereof and a salt of an N-oxide, wherein R is selected from the group consisting of the formulas Ar2.1, Ar2.2, AC.1 and Ar2, .2, And wherein the rule 2 is an Ar3 group, especially a group of Ar3.1 and Ar3.3. A further specific embodiment of the invention relates to a compound of formula I, L1, 2, j4, a salt thereof, an N-oxide thereof and a salt of an N-oxide, wherein R1 is selected from the group consisting of the formulas Ar2.1, Ar2_2, Ar2' .l and Ar2, .2 groups, and wherein the r2 system

Ar4.1, Ar4.2, Ar4_3, Ar4.4, Ar4_5, Ar5.1, Ar5 2, Αγ5·3, Ar5.7 or Ar5.8 groups. 151494.doc •61 · 201120018 For the group c(9)R3, the following meanings are specific examples of r3: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The group C(0)R3 is selected from the group consisting of an ethenyl group or a propyl group. For the group NRV, the following meaning is the specific meaning of r4: C4_alkyl group, especially hydrogen, methyl, ethyl, n-propyl, isopropyl or n-; The following meanings are specific examples of R5: • Institute base, especially methyl, ethyl, n-propyl, isopropyl or n-butyl. In other embodiments, R, R, together with the nitrogen atom to which they are combined, form a n-binding member or 6 members.

A saturated nitrogen heterocycle such as pyrrolidinyl, morpholinyl, thiomorpholinyl, hexahydropyrazin-1-yl or 4-methylhexahydropyrazine-indole. In particular, the group NW is selected from the group consisting of methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, N-methyl_n_ Ethylamino, N-methyl oxime isopropylamino, N-methyl*propylamino, pyrrolidine small, morpholin-4-yl, thiomorpho-4-yl, six gas Pyrazine small group and methylhexahydropyrazine-1-yl. For the group N(〇R6)R7, the following meanings are specific examples of r6: hydrogen or q-cv alkyl, especially hydrogen, methyl, ethyl, n-propylisopropyl or n-butyl. Specific examples of R7 are: hydrogen or Ci_c4_alkyl, especially hydrazine, methyl, ethyl, n-propyl, isopropyl or n-butyl. For the group C(0)0R8, the following is a specific embodiment of R8: a. c4-alkyl, especially methyl, ethyl, n-propyl 'isopropyl, n-butyl, isobutyl or second Butyl. Specifically, the group C(〇)〇R8 is selected from the group consisting of an anthraceneoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group or a third butoxycarbonyl group. 151494. Doc -62· 201120018 For the group C(〇)RX ‘ the following meaning is a specific embodiment of Rx: Ci_C4.  The alkyl group is especially methyl, ethyl, n-propyl, isopropyl, n-butyliso-diyl or tert-butyl. Specifically, the group c(〇)RX is selected from the group consisting of an ethyl group or a propyl group. Examples of suitable compounds of the invention are the compounds of formula (1) given in the following tables, % to 188, 189 to 282 and 283 to 376, pharmaceutically acceptable salts thereof, and N-oxides thereof. And a pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable compound of the formula (1) wherein X is hydrazine and R 2 is 3-cyanophenyl, and wherein R 1 has the meaning given in rows 1 to 212 of Table A. One (Compound 1-1 to 1-212); Table 2 The compound of the formula (1) wherein X is oxime and R2 is 4-cyanophenyl, and wherein R1 has the meaning given in the rows 1 to 212 of Table A. (Compounds 1-213 to Ι·424); Table 3 Compounds of formula (1) wherein X is hydrazine and R2 is 4-cyano-3-fluorophenyl, and wherein R1 has the formula given in rows 1 to 212 One of the meanings (compounds 1-425 to 1-636); Table 4 Compounds of formula (I) wherein X is oxime and R2 is 4-cyano-3-phenylphenyl, and wherein R1 has Table A to One of the meanings given in row 212 (compounds 1-637 to 1-848); Table 5 Compounds of formula (I) wherein X is oxime and R2 is 3,4-dicyanophenyl, and wherein R1 has a table One of the meanings given in lines 1 to 212 (compounds 1-849 to 1-860); ⑴ compound of Formula 6, where X is 0 and R2 is 3-methyl-4-cyano-benzene-based 151,494. Doc • 63 - 201120018 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Base ' and where R! has one of the meanings given in rows 1 to 212 of Table A (compounds 1-161 to 1- a compound of formula (I) wherein X is hydrazine and R 2 is 3-ethyl-4-cyanophenyl ' and wherein R 1 has one of the meanings given in rows 1 to 212 (compound M 273 to 1-1484); a compound of formula (I) wherein X is hydrazine and R 2 is 3-methoxy-4-cyanophenyl ' and wherein Ri has one of the meanings given in rows 1 to 212 of Table A ( Compound 1-1485 to 1-1696); a compound of formula (I) wherein X is hydrazine and R 2 is 3-hydroxy-4-cyanophenyl ' and wherein R 1 has the meaning given in rows 1 to 212 of Table A One of the compounds (Compounds 1-1697 to 1-1908); the compound of the formula (I) wherein X is oxime and R 2 is 3,5-difluorocyanophenyl' and wherein R1 has the contents of Tables 1 to 212 One of the meanings given (compounds 1-1909 to 1-2120); a compound of formula (I) wherein X is 〇 and R 2 is 5 cyanopyridine-2-yl, and wherein R 1 has the same The meaning given (compounds 1-2121 to 1-2332); the compound of formula (I) where X is 〇 and R2 5. Cyanopyridine-3-yl, and wherein R1 has the meaning given in rows 1 to 212 of Table A (compounds 1-2333 to 1-2544); a compound of formula (I) wherein X is 〇 and R2 Is a 6-aminopyridine _3_ group, and wherein R1 has the meaning given in the rows 1 to 212 of Table A (compounds 1-2545 to 1-2756); the compound of formula (I) wherein X is 〇 And R2 is 6·cyanopyridine-2-yl, 151494. Doc-64-201120018 and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-2757 to 1-2968); Table 15 Compounds of formula (I) wherein X is Ο and R2 is 4 -cyano"bipyridin-2-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-2969 to 1-3180); Table 16 Compounds of formula (1) wherein X is And R2 is 2-cyanopyridin-4-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-3181 to 1-3392); Table 17 is a compound of formula (1) wherein X is an anthracene and R 2 is 5-cyano-6-fluorenylpyridin-3-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds I-3393 to 1-36〇) 4); Compound of formula (1) wherein X is hydrazine and R2 is 6-cyano-5-methoxypyridin-3-yl, and wherein R1 has the meaning given in rows 1 to 212 of Table a. (Compounds 1-3605 to 1-3816); Table 19 Compounds of formula (1) wherein X is hydrazine and R2 is 6-cyano-5-fluoro-pyridin-3-yl, and wherein R1 has Tables 1 to 212 One of the meanings given in the row (Compound 1-3817 to 1-4028); Table 20 Formula (1) Compound 'where X is oxime and R2 is 5-cyano-4- Fluorine is more than pyridine-2-yl, and R1 has Table Eight! One of the meanings given in row 212 (compounds 1-4029 to 1-4240); Table 21 Compounds of formula (1) wherein X is oxime and R2 is 5-cyano-4-methylpyridin-2-yl' Wherein R1 has one of the meanings given in rows 1 to 212 (compounds 1-4241 to 1-4452); Table 22 is a compound of formula (1) wherein X is hydrazine and R2 is 2-cyano-6-methyl Pyridine - 151494. Doc-65- 201120018 Table 23 Table 24 4-Based, and wherein R1 has one of the meanings given in rows 1 to 212 of Table a (Compounds 1-4453 to 1-4664); Compound of Formula (1) 'where X is 〇 And R 2 is 6-cyano·5_hydroxypyridin-3-yl' and wherein R 1 has one of the meanings given in rows 1 to 212 of Table a (compounds 1-4665 to 1-4876); a compound 'wherein X is hydrazine and R 2 is a 5-cyanopyrimidine-2-yl group, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-4877 to 1-5088); 25 A compound of the formula (1) wherein X is oxime and R 2 is 2-cyanopyrimidine and wherein R 1 has the compound 1-5089 to 1-5300 given in rows 1 to 212 of Table A; meaning - Ut TABLE 26 Compounds of formula (1) wherein X is hydrazine and R 2 is 2-cyanopyrimidine, and wherein R1 has the meanings given in rows 1 to 212 of Table A, 1-5301 to 1-5512) (Formula 27) The compound of formula (1) wherein X is oxime and R2 is 6-cyanopyrimidine and wherein R1 has the compounds 1-5513 to 1-5724 given in rows 1 to 212 of Table A; a compound of the formula (1), wherein the X system is ruthenium and the R 2 system is 5-cyanopyrene, and R1 has the compounds 1-5725 to 1-5936 which are given in the first row and the second row of Table A; Table 29 is a compound of the formula (1) wherein X is oxime and R2 is 5-cyano-6_fluoro.嗓 ' ' and wherein R has the meaning given in rows 1 to 212 of Table A (compounds 1-5837 to 1-6148); Table 30 Compounds of formula (1) wherein X is 0 and R 2 is 5-cyano -哒嚷151494. Doc •66· 201120018 and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-6149 to 1-6360); Table 31 Compounds of formula (I) wherein X is Ο and R 2 is 6 a cyano-pyridazine _3_ group, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-6361 to 1-6572); Table 32 Compounds of formula (I) wherein X And R2 is 6-cyano-oxime_4_yl, and wherein R has the meaning given in rows 1 to 212 of Table A (Compounds 1-6573 to 1-6784); Table 33 Formula ( I) a compound wherein X is Ο and R 2 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 (Compound 1 -6785 to 1-6996); Table 34 Compounds of formula (1) wherein X is hydrazine and R2 is 6-cyano-5-methoxy-1,2'4-di-Chent-3-yl' and wherein 111 One of the meanings given in rows 1 to 212 of Table 8 (Compounds 1-6997 to 1-7208); Table 35 Compounds of formula (I) wherein X is oxime and R2 is 3-cyano-1,2,4 - tris-6-yl' and wherein R1 has one of the meanings given in rows 1 to 21 of Table A (compounds 1-7209 to 1-7420); Table 36 Compounds of formula (1) wherein X is hydrazone R2 is 3-cyanofuran-2-yl, and wherein R1 has one of the meanings given in rows i through 212 of Table VIII (compounds 1-7421 to 1-7632); Table 37 is a compound of formula (I) wherein X is 〇 and R 2 is 4-cyanofuran-2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-7633 to 1-7844); Table 38 Compound of formula (1) , wherein X is Ο and R 2 is 5-cyanofuran-2-yl, 151494. Doc -67- 201120018 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (Compounds 1-7845 to 1-8056); A compound of formula (I) wherein X is hydrazine and R2 is 2-cyanofuran-3-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compound Ι·8057 to 1-8268) a compound of formula (I) wherein X is hydrazine and R 2 is 5-cyanofuran-3-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 (compound 1-8269 to 1) a compound of formula (I) wherein X is hydrazine and R 2 is 5-cyano-4-fluorofuran-2-yl' and wherein R 1 has one of the meanings given in rows 1 to 212 of Table A ( Compound 1-8481 to 1-8692); a compound of the formula (I) wherein X is hydrazine and R2 is 5-cyano-4-furfuran-2-yl, and wherein R1 has the number of rows 1 to 212 of Table A One of the meanings given (compounds 1-8693 to 1-8904); a compound of formula (1) wherein X is oxime and R2 is 3-cyano-2-thienyl, and wherein R1 has the same as in rows 1 to 212 of Table A. One of the meanings given (compounds 1-8905 to 1-9116); the compound of formula (1) wherein X is oxime and R2 is 4-cyano-2 a -thienyl group, and wherein R1 has one of the meanings given in the ninth to the second row of Table VIII (compounds 1-9117 to 1-9328); the compound of the formula (1) wherein X is 〇 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 1-9329 to 1-9540); a compound of formula (1) wherein X is 〇 and R 2 is 2-cyano _3-Thienyl, 151494. Doc • 68 - 201120018 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 and where R1 has one of the meanings given in rows 1 to 21 of Table A (Compound 1-9541 to 1-9752) A compound of the formula (1), wherein X is hydrazine and R 2 is 5-cyano-3-thienyl, and wherein R 1 has one of the meanings given in rows 1 to 21 of Table A (compounds 1-9753 to 1-9964) a compound of formula (1) wherein X is hydrazine and R 2 is 5-cyano-4-fluoro-2-thienyl' and wherein Ri has one of the meanings given in rows 1 to 212 of Table A (compound 1-9965) To 1-10176); a compound of formula (1) wherein X is hydrazine and R 2 is 5-cyano-4- ox-2-thienyl' and wherein R 1 has one of the meanings given in rows 1 to 212 of Table A ( Compound 1-10177 to 1-10388); a compound of formula (1) wherein X is hydrazine and R 2 is 2-cyanopyrrolidin-1-yl, and wherein R 1 has one of the meanings given in rows 1 to 2 12 of Table A (Compound 1-10388 to 1-10600); a compound of the formula (1) wherein X is hydrazine and R 2 is 3-cyanopyrrolidin-1-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of Table A (Compound 1-10601 to M0812); a compound of the formula (1) wherein X is oxime and R2 is 3-cyano 4-methyl-pyridinium-l-yl' and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compounds 1-10813 to 1-11024) compounds of formula (I) wherein X is And R2 is 4-cyano-pyrrol-2-yl, and wherein R1 has one of the meanings given in rows 1 to 21 of Table A (compounds 1-11025 to M1236); a compound of formula (1) wherein X 〇 and R2 is 5-cyano-pyrrol-2-yl, 151494. Doc -69· 201120018 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (Compounds 1-1 1237 to 1-11448) A compound of formula (1) wherein X is hydrazine and R 2 is 3-cyano-1-methyl-pyro-2-yl' and wherein it has one of the meanings given in rows 1 to 212 of Table a (Compound 1- 11449 to 1-1 1660); a compound of the formula (I) wherein X is oxime and "system" - methyl-5-cyano is more than indol-2-yl" and wherein it has the one given in rows 1 to 212 of Table a One of the meanings (compounds 1-11661 to 1-11872); a compound of formula (1) wherein X is 〇 and 尺 2 is 丨 曱 曱 -4 -4- cyano-pyridin-2-yl' and wherein Ri has a One of the meanings given in rows 1 to 212 (compounds I-11873 to I-12084); a compound of formula (1) wherein X is hydrazine and R2 is 5-cyano-4-methyl-pyrrol-2-yl' And wherein Ri has one of the meanings given in rows 1 to 212 of the table a (compounds 1-12085 to 1-12296); a compound of the formula (1), wherein the X is indole and the methyl group is 2-2-cyano-0. -3-yl' and wherein Ri has one of the meanings given in Tables VIII! to 212 (compounds 1-12297 to 1-12508); I) compounds, where X is square. And R2 is 5-cyano-pyrrole_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); X is 〇 and "system _-5_cyanopyrrole-3-yl" and wherein Ri has one of the meanings given in rows 1 to 212 of Table a (compounds 1-12721 to 1-12932); (I) a compound wherein X is 0 and the rule 2 is 2-cyanoimidazole-4, 151,494. Doc •70· 201120018 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 formula (I) wherein X is Ο and R 2 is 2 a cyanoimidazole-5-yl group, 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 formula (I) wherein X is hydrazine 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); (I) a compound wherein X is hydrazine and R2 is 4-cyano-imidazol-1-yl, and wherein R1 has one of the meanings given in rows 1 to 21 of Table A (compound 1-13569 to 1- Table 66 Compounds of formula (I) wherein X is in the formula and R2 is 2-cyano-1-indenyl-imidazole-5-yl, and wherein R is given in rows 1 to 212 of Table A. One of the meanings (compounds 1-13781 to 1-139992); Table 67 Compounds of formula (1) wherein X is oxime and R2 is 4-cyano-imidazole-2., and wherein R1 has in rows 1 to 212 of Table A. One of the meanings given (compounds 1-13993 to 1-14204); Table 68 Compounds of formula (I) wherein X is 〇 and R2 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 formula (I) wherein X Is 0 and R2 is 4-cyano-1-indenyl imidazole-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); a compound of formula (I) wherein X is hydrazine and R 2 is 5-cyano-1-methylimidazole - 151494. Doc -71 - 201120018 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 2-Base' and wherein R1 has one of the meanings given in rows 1 to 212 of Table a (Compound 1-14629 to 1) a compound of the formula (I) which is X-based and R2 is 5-cyanothiazol-2-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (Compound 1- 14841 to 1-15052); a compound of the formula (I) wherein X is hydrazine and R2 is 4-cyanothiazol-2-yl, and wherein R1 has one of the meanings given in rows 1 to 212 of Table A (compound) 1-1 5053 to 1-15264); a compound of formula (I) wherein X is hydrazine and R 2 is 2-cyanothiazol-4-yl, and wherein R 1 has the meaning given in rows 1 to 212 of Table A. A (compound 1-15265 to 1-15476); a compound of formula (I) wherein X is hydrazine and R2 is 2-cyanothiazol-5-yl, and wherein R1 is given in rows 1 to 212 of Table A One of the meanings (compounds 1-15477 to 1-15688); a compound of formula (I) wherein X is hydrazine and R2 is 2-cyanooxazol-4-yl, and wherein R1 has in rows 1 to 212 of Table A. One of the meanings given (compounds 1-15689 to 1-15900); a compound of formula (I) wherein X is hydrazine and R2 2-cyanooxazole-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); a compound of formula (1) wherein X is Ο 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 1-16113 to 1-16324); a compound of formula (1) wherein X is R2 is 5-cyanooxazol-2-yl, 151494. Doc •72· 201120018 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 is a compound of formula (1) wherein X is ruthenium and R 2 is 3 cyanide Isoxazole-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 Formula (I) Compound 'where X is 〇 And R2 is 5-cyanoisoxazole-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 Compound of Formula (1) Wherein X is 〇 and R 2 is 3-cyanoisothiazol-5-yl' and wherein Ri has one of the meanings given in rows 1 to 212 of Table A (compounds 1-169961 to 1-17172); (1) a compound wherein X is hydrazine 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 formula (I) wherein X is in the formula 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 Compound of formula (1) wherein X is oxime and R2 is 5-cyanocarbazole-3- And wherein R1 has one of the meanings given in Tables VIII to 212 (compounds 1-17597 to 1-17808); Table 85 Compounds of formula (I) wherein X is 〇 and R 2 is 3-cyano- 1-methyl. Bisazo-5-yl' and wherein R1 has one of the meanings given in rows 1 to 212 (compounds 1-17809 to 1-18020); Table 86 Compounds of formula (1) wherein X is 〇 and R2 is 5 -Cyano-1-methylpyrazole - 151494. Doc -73- 201120018 Table 87 Table 88 Table 89 Table 90 Table 91 Table 92 Table 93 Table 94 3_Base' and where R1 has one of the meanings given in rows 1 to 212 of Table A (Compound 1-18021 to 1 A compound of the formula (1), wherein the X is indole and the R 2 is 3-cyano-pyrazol-1-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of Table A (compound 1-18233) To 1-18444); a compound of formula (1) wherein X is hydrazine and R 2 is 4-cyano-pyrazol-1-yl, and wherein it has one of the meanings given in rows 1 to 212 of Table A (Compound 1- 18445 to 1-18656); a compound of formula (1) wherein X is hydrazine and R 2 is 3-cyano-4 clopyrazol-1-yl' and wherein R 1 has the meaning given in rows 1 to 212 of the formula A (compound 1-18657 to 1-18868); a compound of the formula (I) wherein X is an anthracene and a stalk 2 is a 3-cyano-4-oxo 0-oxazol-yl group and wherein R1 has Tables A to 212 One of the meanings given in the row (compounds 1-18869 to 1-19080); the compound of formula (1) wherein X is oxime and R2 is 5-cyano-4,3,4-oxadiox-2-yl' Wherein Ri has one of the meanings given in rows 1 to 212 of Table 8 (compounds 1-19081 to 1-19292); the compound of formula (1) X is 〇 and is based on % cyano·丨), ‘thiadi. Sodium-2-yl' and wherein Ri has one of the meanings given in rows 1 to 212 of Table a (Compounds 1-19293 to 1-195〇4); a compound of formula (I) wherein X is 〇 and R2 is 5-cyano^,2,4-triazole-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); a compound of formula (1), Among them, the χ system and the rule 2 are 5 _ cyano _ 4- fluorenyl 151494. Doc -74 · 201120018 1,2,4-Triazol-3-yl, and wherein the ruthenium has one of the meanings given in rows 1 to 212 of Table 8 (compounds 1-17917 to 1-19928). Tables 95 to 188: Compounds of the formula (1) corresponding to the compounds of Tables 1 to 94 (Compound 1 19929 to 39856) which have been replaced by x = s. Tables 189 to 282. Compounds of formula (I) corresponding to the compounds of Tables 1 to 94 (compounds UQg% to 59784) which have been replaced by x = s χ. Tables 283 to 376: Compounds of the formula (1) corresponding to the compounds of Tables 1 to 94 (compounds _59785 to I-79712) whose χ = 替换 has been replaced by x = s 〇 2 . Further preferred examples of the compounds of the invention are the compounds listed below - their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of such N-oxides: 5-(4-toluene Continued g blue base · 3,4-dihydro-2H-benzo[b][l,4] ° evil. Qin-6-yl) sinter-2-carbonitrile, 4-(4-(3-fluoro 4-methylphenylindenyl)-3,4-dihydro-211-benzo[13][1,4].oxazin-6-yl) nitrite, 4-(4-(3- Fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2-indolyl[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(4) -nitrophenylsulfonyl)_3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(4-aminophenyl) (3) 4-dihydro-2H-benzo[b][l,4]oxan-6-yl)benzonitrile, 151494. Doc •75· 201120018 4-(4-(4-Methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzyl Nitrile, 4-(4-indolesulfonyl-3,4-diaza-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 5- (4-(3- Fluoro-4-mercaptophenylsulfonyl)·3,4-dihydro-2H-benzo[b][l,4]oxo-Q--6-yl)°Cet-2-A Guess, 5 -(4-(3-Fluoro-4.methoxyphenyl)sulfonyl)-3,4-diindole-2H-benzo[b][l,4]oxazin-6-yl)thiophene-2- Nitrile, 4-(4-(6-methoxyindolepyridinyl-3-ylsulfonyl)_3,4_diaza_2H_benzoi,4] ° 恶-6-yl) nitrite , 5- (4_(6-decyloxy. butyl-3-yl), 3,4-dihydro-2H-benzo[b][l,4] °, ° °-6-6隹 曱-2-曱 guess, 5-(4-(6-methylηpyridin-3-ylsulfonyl)_3 4 dihydro-2H benzo[b][14] oxa-6-yl ) porphin-2-carbonitrile, 5 (4(4(monomethylamino))-based hydrazino)_3,4_dihydro-2h_benzo[1)][1,4]° -6-yl) ° cephene-2-carbonitrile, 4-(4-(4-(monomethylamino)phenylsulfonyl)-34 dihydro benzo[b][l,4]oxazine -6-yl)benzonitrile, 5-(4-(2,3-dihydrobenzo[b][1,4]dioxanylenesulfonylsulfonate醯3)_3,4_ diar-argon-2H-benzo[b;][l,4]oxazin-6-yl)thiophene-2-indene nitrile, 5-(4-(4-1-3-methyl) Phenyl hydrazino)_3,4_diazo 2H_benzoxazine-6-yl)thiophene-2-carbonitrile, 2-methoxy-4-(4-indolyl benzoin-3,4 -Dihydro·2H_benzo[b][1,4]. 恶 _ 6·基) 节猜, 151494. Doc • 76 - 201120018 4-(4-(3-Fluoro-4-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][ 1,4]oxan-6- ))-methoxy-knot' 4-(4-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l, 4] Oxazine-6-yl)-2-methoxybenzonitrile, 4-(4-toluenesulfonyl-3,4-dihydro-2H-benzo[b][l,4]oxazine- 6-yl)thiophene-2-carbonitrile, 4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxan -6-yl) ° thiophene-2-achay> 2,3-dihydro-4-[(4-methylphenyl)sulfonyl]-6-(3-cyano-2-furanyl) -4H-benzo[1,4]-oxazine, 4-(4-nonylbenzenesulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazine-6- Benzymidonitrile, 4-[4-(4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)benzyl Nitrile, 4-[4-(6-methoxy~pyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl )benzonitrile, 4-[4-(6-(4-morpholinyl).pyridin-3-yl)sulfonyl-3,4-dihydro-2H-benzo[b][l,4] Thiazin-6-yl)benzonitrile, 5-[4-(3-fluoro-4-methoxyphenyl)sulfonyl-3,4-dihydro-2H-benzo[b][l,4 Αα嗓·· 6 -基)σ SERINO-2 - Acha' 5-[4-(5-methyl-2-thienyl)sulfonyl-3,4-dihydro-2-indole-benzo[b][l,4]thiazide- 6-yl)π-cephen-2-yl-[5-[4-(4-chlorophenyl)sulfonyl-3,4-dihydro-2-indole-benzo[b][l,4]thiazine -6-yl)thiophene-2-indene nitrile, 151494. Doc -77- 201120018 4-[4-(4-Methoxyphenyl)sulfonyl-indole_oxy-ion (〇xid〇)_3,4•dihydro_ 2H-benzo[b][l, 4]thiazin-6-yl)benzonitrile, 4-[4-(4-methoxyphenyl)sulfonyldioxyl (di〇xid〇)_3,4-dihydro-2H-benzo [b][l,4]. Pyrrazine-6-yl)benzonitrile. Further preferred examples of the compounds of the invention are the compounds listed below, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of such n-vapors: 2-(4-toluene)醯-based-3,4-dihydro-2H-benzo[b][i,4]oxazin-6-yl)fura-3-A guess, 4-(4-((4-ethyl) Phenyl)sulfonyl)_3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl) nitrite, 4-(4-((5-methylthiophene-2) -yl)sulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl) nitrite, 4-((6-(5-cyanothiophene)- 2-yl)-2H-benzo[b][14]oxazine_4(3H)-yl)sulfonyl)benzoic acid, 4-(1-((2,3-dihydro)[b] [1,4]dioxine_6-yl)sulfonyl)-3,4-dihydro-211-benzo[13][1,4]°oxo-6-yl)benzonitrile , 4-(4-((6-chloro.bipyridin-3-yl)-indolyl)·3,4-dihydro-2H-benzo[b][l,4].oxazin-6-yl Benzonitrile, 5-(4-((6-a)pyridin-3-yl)sulfonyl)-3,4-diargon-2H-benzo[b][l,4]oxazin-6 -yl)thiophene-2-carbonitrile, 151494. Doc • 78· 1 _(4-((6-(indolyl))pyridin-3-yl)indolyl)_3,4_dihydro-2H-benzo[b][l,4] Pyridin-6-yl)benzonitrile, 5-(4-((4-(pentafluorothio)phenyl)sulfonyl)-3,4-dihydro-2H_benzo[J][200][l,4 ] ° 恶 -6-yl) η phenophene _2 carbonitrile, 4- (4_((6-methyl pyridine-3-yl) sulfonyl)_3,4_ dihydro 2 Η · stupid [ b][l,4]oxazin-6-yl)benzonitrile, 6-(4-indolylsulfonyl-3, dihydrogen-2H_benzo[b][1,4]oxazine-6 Nicotinyl nicotinol ' ' 5-(4-toluenesulfonyl-3,4_dihydro-2H-bromo[b][14]oxazin-6-yl)pyridine-2-carbonitrile, 5-_( 4·Indolylsulfonyl _3,4_dihydro-2H_ benzo[b][1,4]oxazine-6-yl)pyrimidine-2-carbonitrile, 2-(4-toluenesulfonyl) _3 4_Dihydro 2H_ benzoxazine _6 oxazole-5-indolecarbonitrile, 4·(4-((2,3-dihydrobenzo[b][1,4]dioxane) Hexene-6-sulfonyl)-3,4-dihydro-211-benzo[15][1,4]oxazin-6-yl)11cetin-2-carbonitrile, 5-(4) -((6-(dimethylamino).pyridyl_3_yl)sulfonyl)_3,4_dihydro-2h_benzo[b][l,4]oxazin-6-yl)thiophene -2-carbonitrile, 5-(4-((6-(dimethylamino).pyridin-3-yl)sulfonyl)_3, 4_Dihydro_2h_benzo[b][l,4]oxazin-6-yl)acridin-2-carbonitrile, 6-(4-((6-(dimethylamino)) hydrazine -3-yl) 醯3,4_dihydro-2h_benzo[b][l,4]oxazin-6-yl)nicotinonitrile, 5-(4-((6-(methyl)) Amino). 比3,4-dihydro·2η_benzo[b][l,4]oxazin-6-yl)pyrimidine-2-carbonitrile, 6- ( 4-((6-Amino. Ratio: D--3-yl)sulfonyl)_3,4-dihydro-2-indole benzo[匕][1,4]°Evil °Q-6-yl) Nitrile, 5-(4-((6-amino group) than _3_yl) continuation) _3,4_dihydro-2H-stupid and 151494. Doc -79- 201120018 [b][l,4]oxazin-6-yl)thiophene-2-indolecarbonitrile. Further preferred examples of the compounds of the invention are the compounds listed below, their pharmaceutically acceptable salts, their cerium oxides and the pharmaceutically acceptable salts of such N-oxides: 2-methoxy -4-(4-(4-(trifluoromethyl)phenylsulfonyl)·3,4-dihydro-2-indole·bumi[b][l,4]oxazin-6-yl)benzonitrile , 4-(4-(4-Hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2-oxooxybenzyl Nitrile, 2-methoxy-4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6- Benzymidonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6·yl)-2 · 曱oxybenzonitrile, 4-(4-(4-carbylphenyl)-3,4-dioxane-2H-benzo[b][l,4]°Evil "•秦-6_ 2-oxooxybenzonitrile, 2-methoxy-4-(4-(4-(methylthio)phenylsulfonyl)-3,4-dihydro-2H-stupid[b ][l,4]oxazin-6-yl) nitrite, 4-(4-(4-ethylphenylindolyl)-3,4-dihydro-2H-benzo[b][l, 4]oxazin-6-yl)-2-decyloxybenzonitrile, 2-methoxy-4-(4-(4-(trifluoromethoxy)phenylsulfonyldihydro-2H-benzene And [b][l,4]oxazine -6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl Thiophene-2-indene nitrile, 4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Pyrazin-6-yl)thiophene-2-carbonitrile, 151494. Doc -80- 201120018 4-(4-(4-Ethylphenylsulfonyl)·3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiophene- 2-carbonitrile, 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzoindole, oxazin-6-yl)thiophene-2-carbonitrile, 4- (4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-1Η-pyrrole-2-carbonitrile, 4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-1-methyl- 1H-pyrrole-2-carbonitrile' 4-(4-(4-chloro-3-cyanophenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Pyrida-6-yl)-1Η-pyrrole-2-fcarbonitrile ' 4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[ b][l,4]oxazin-6-yl)-1Η-pyrrole-2-carbonitrile '2-fluoro-4-(4-(5-nonylthiophen-2-ylsulfonyl)-3, 4-Dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 2-ethyl-4-(4-(5-nonylthiophen-2-ylsulfonyl) -3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(6-isopropyl)pyridin-3-ylsulfonate Mercapto)-3,4-dihydro-2H-benzopyrene, 4] ° 嗓 _ 6 -yl) ° thiophene-2 - Acha, 2-methoxy-4-(4-(5 -methylthiophene- 2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(5-methylthiophene-2) -sulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(5-ethylthiophen-2- 3-sulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2-methoxybenzonitrile, 151494. Doc -81 - 201120018 4-(4-(5-Ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H- benzo[b][l,4] oxa-6-yl )-2-fluorobenzonitrile, 4-(4-(6-ethylacridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxan -6-yl)B-cephen-2-pyrene>> 2-chloro-4-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[ b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(.pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][ l,4]oxazin-6-yl)thiophene-2-indrene, 4-(4-(6-(dimethylamino)"bipyridin-3-ylsulfonyl)-3,4- Dihydro-2H-indigo[b][l,4]oxazin-6-yl)thiophene-2-indolecarbonitrile, 4-(4-(6-amino)pyridin-3-ylsulfonyl) -3,4-dihydro-2H-benzo[b][l,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 -Di-argon-2H-benzo[b][l,4]oxazin-6-yl)thiazole-2-carbonitrile, 4-(4-(4-(dimethylamino)phenylsulfonyl) )-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiazole-2-carbonitrile, 4-(4-(3-fluoro-4-(methyl) Amino)phenylsulfonate -3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiazole-2-carbonitrile, 5-(4-(5-methyl-fuca-2) -based sulfhydryl)-3,4-dihydro-2H-benzo[b][l,4] °oxazin-6-yl)-1Η-pyrrole-2-carbonitrile' 5-(4-( 5-methylfuran-2-yl cans)-3,4-diargon-211-benzo[13][1,4]oxazin-6-yl)thiazole-2-carbonitrile' 151494. Doc •82- 201120018 5-(4-(5-Methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][ 1,4] oxa ° Qin-6 ))β夫喃-2-甲猜' 5-(4-(5-fluorenylfuran-2-ylsulfonyl)-3,4-dihydro-2Η-benzo[b][l,4] Oxime-6-yl)π-cephen-2-pyrene, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2-indole-benzo[b ][l,4]Evil V" - °Q-6-yl) 0-bite-2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4- Dihydro-2H-benzo[b][l,4]oxazin-6-yl)-3-fluoro. Specific bite-2-carbonitrile, 5-(4-(4-murine-5-ethyl°cephen-2-yl),-3,4-dimur-2H-benzo[b][l , 4]oxazin-6-yl)-3-methoxy"pyridin-2-indene nitrile, 5-(4. -(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxo-6-yl)-3-methyl-1Η -.嘻-2 - A guess, 5-(4-(5-mercaptothiophen-2-ylsulfonyl)-3,4-dihydro-2Η-benzo[b][l,4]oxan- 6-base). ratio.定-2-甲猜' 3-Fluoro-5-(4-(5-nonylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Oxazine-6-yl)pyridine-2-carbonitrile, 3-methoxy-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzene And [b][l,4]oxazin-6-yl)pyridine (2-carbonitrile, 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxan-6-yl)°fu-2-pyrene-5-(4-(5-ethylthiophen-2-ylsulfonyl)-3, 4-Dihydro-2H-benzo[b][l,4]oxo 11 Qin-6-yl)11-cephen-2-pyrene 5-(4-(5-ethylthiophen-2-ylsulfonate) Mercapto)-3,4-dihydro-2H-benzo[b][1,4]oxan-6-yl)α夫喃-2-甲猜' 151494. Doc -83- 201120018 5-(4-(5-Ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxañ-6 Base) ° 嗤 嗤-2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Evil 0 Qin _ 6 -yl)-1 Η -0 鸣 · · - 2 - Acha, 5-(4-(5-nonylthiophen-2-ylsulfonyl)-3,4-dihydro-2Η- Benzo[b][l,4]caco-6-yl)D-cephen-2-pyrene 5 5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4- Dihydro-2H-benzo[b][l,4]ox. Qin-6-yl)η夫喝-2-甲猜' 5-(4-(5-methylthiophen-2-ylsulfonyl) )-3,4-dioxa-6-yl). Plug.曱-曱 nitrile, hydrogen-2Η-benzo[b][l,4]oxo 5-(4-(5-methylnonphen-2-yl)--3,4-di-qin -6 -yl)-1Η -σBiluo-2 -曱猜' Hydrogen-2H-benzo[b][l,4]oxo 5-(4-(5-ethyl σ pentan-2-yl continued Stuffed base) -3,4-di-Qin-6-yl). Specific bite-2-carbonitrile, argon-2H-benzo[b][l,4]oxo 5-(4-(5-ethyl.freath-2-yl)--3,4-di ° Qin-6-yl)-3-fluoro. ratio.定,-2 -甲猜' Hydrogen-2H-benzo[b][l,4]oxo 5-(4-(5-ethyl sigma-2-yrene)-3,4-di -6-yl)-3-methoxyl ° ° -2- _ _ 'hydrogen-2H-benzo[b][l,4] oxa 5-(4-(5-ethylfuran-2 - sulfamoyl)-3,4-diin-6-yl). Phenyl-2-carbonitrile, hydrogen-2H-benzo[b][l,4]oxo 5-(4-(5-methyl-bit.South-2-yl)--3,4-di Pyridin-6-yl)pyridine-2-carbonitrile, hydrogen-2H-benzo[b][l,4]oxo-3-milk-5-(4-(5-methyloxafuran-2-yl) continued Brewing base)-3,4 -digas-2 Η -本乙[b][l,4]oxazin-6-pyridin-2-indene nitrile, 151494. Doc -84- 201120018 3 -decyloxy- 5-(4-(5-methyld-f-am-2-yl)-, 3-dihydro-2 Η-benzo[b][l , 4]oxazin-6-yl)pyridine-2-carbonitrile, 5 (4 (5-ethyl-Of-2)-based yellow wine--3,4-diazo- 2H-benzo[b ][i,4]嗓°秦-6-基)>» Plug. 2--2-carbonitrile, 4-(4-(3-fluoro-4-methoxyphenyl)-3,4-dihydro-2Η-benzo[b][l,4]thiazine- 6-yl) nitrite, 4-(4-(4-aminophenylsulfonyl)_3,4-dihydro-2H-benzo[b][ 1,4]thiazin-6-yl)benzyl Nitrile, 2-methoxy-4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazol-6-yl)benzonitrile, 2-fluoro-4-(4-(6-methoxy D-pyridyl_3_ylsulfonyl)_3,4-dihydro-2H-indigo[b][l,4]thiazine-6- Benzymidonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H•benzo[b][14]thiazide·^ base gas nitrite, 4-( 4-(4-Carboxyphenylsulfonyl)oxynionic group _3,4_dihydro-2H_benzo[b][l,4]thiazin-6-yl)-2.methoxyl Nitrile, 2-gas-4·(4-methyl sulfonyl sulfonyloxy) dihydro-2H_ benzo[b][l,4]thiazine-6-yl)benzonitrile, 4_(4· (3_Fluoromethoxyphenylsulfonyl M,l-dioxyindol-3,4-dihydro-2H-benzo[b][i,4]thiazin-6-yl)benzonitrile, 4-(4-methyl sulfonyl hydrazinyl hydrazinyl hydrazinyl hydrazone hydrazone hydrazone hydrazone hydrazone hydrazone hydrazide 4-(4-(4-(4-()) 4-(4-(4-(4-) 4-aminophenyl phenolate)_u_dioxy ionyl 3,4·diaza-2Η·stup [b][l,4]thiazide Pyrazine _6_yl)benzonitrile, 151494. Doc • 85· 201120018 4- (4-(4-(Methylthio)phenylsulfonyl)-1,1-dioxyindol-3,4-dihydro-2H-benzo[b][l , 4] thiazol-6-yl)benzonitrile, 5-(4-(4-decyloxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Thiophene-Qin-6-kisone-2-caryo' 5-(4-(phenylsulfonyl)-1,1-dioxyindol-3,4-dihydro-2H-benzo[b ][l,4]thiazin-6-yl)thiophene-2-carbonitrile, 5-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[ b][l,4]thiazol-6-yl)11 thiophene-2-methyl-' 4-(4-(4-aminophenylsulfonyldioxy)-3,4-dihydro- 2H-benzo[b][l,4]thiazin-6-yl)thiophene-2-indolecarbonitrile, 4-(4-(phenylsulfonyl)-1-oxoionyl-3,4-di Hydrogen-2H·benzo[b][l,4] **塞°秦_ 6 -yl)α夫D南-2 -甲猜' 5- (4-toluenesulfonyl-1-oxyl group _ 3,4_Dihydro-2H-benzo[b][i,4]thiazin-6-yl)-1Η-pyrrole-2-carbonitrile' 5-(4-(4-aminophenyl can) -3,4-dihydro-2H-benzo[b][1,4]non-6-yl)-1Η-pyrrole-3-carbonitrile, 5-(4-toluenesulfonyl-3 ,4-dihydro-2H-benzo[b][l,4]thiazine_6j)_1H_ 0Bilu-2-A guess, 4-(4-(4-phenylphenyl) Mercapto)-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)-2-methoxybenzonitrile; 2-fluoro1-4-(4-toluene) Brewing base-3,4-一风-211-本和[1)][1,4] 00秦_6_ base) benzonitrile; 4-(4-(phenylsulfonyl)-3,4 -Dihydro-2H-benzo[b][l,4]thiazin-6-yl)furan-2-method, 151494. Doc -86- 201120018 5-(4-Toluenesulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)-1Η-pyrrole-2-carbonitrile ; 4- (4-(4-(indolylthio)phenylsulfonyl)-3,4-dihydro-2H·benzo[b][ 1,4]thiazol-6-yl) ; 5-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)thiophene-2-carbonitrile; (4-(4-Aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)°Cet-2-曱. The compounds of the invention were named according to the IUPAC standard using the Struct=Name software from Cambridgesoft's ChemDraw Ultra version 10. The compound I of the present invention is prepared in a manner similar to the methods known in the literature. X-type oxygen or sulfur of the compound of formula I can be, for example, as depicted in Reaction Schemes 1, 2 and 3, not from 6-halogen-3,4-dihydro-2H-benzo[b][l,4]oxazine, respectively. Preparation of II and 6-halogen-3,4-monohydro-2H-benzo[b][l,4]thiazine II or a salt thereof. Reaction Figure 1:

15I494.doc -87· (i) (V) 201120018 Reaction Figure 3: R2Hal_ (VII)

R

"Check (BRaRb) 2 οι) "Pdj

(Vla)〇2S,Ri R2Hal' (I) "Pd" In the reaction diagrams „ , , 闽丄, 2 and 3, 'R1 and R2 have the above meanings. ab# hydroxy 戋C r _ ,1 义 4·alkoxy a group (for example, a methoxy group or an ethoxy group), or a moiety which forms a partial group with an oxime, wherein R is a group of B.12-diyl, 1,122-hydroxyl-1,2-diyl, and C. 4,3-diyl, 2,2-dimercaptopropyl L3-diyl or ^I3.trimethylpropane-1,3-diyl. Hal and Hal, each independently of gas, 'odor or iodine, Preferably, it is bromine or gas. "Pd" means a Pd(0) catalyst or a Pd(0) precursor, which is optionally combined with a suitable ligand. "Alkali" means a suitable basic compound which contributes to the formation of sulfonamide. According to the first step of the reaction scheme 1, the compound Η compound or its salt (for example, acid addition) is treated in the presence of a palladium catalyst using a drying compound Ιπ in a known manner under Suzuki c〇upling conditions. Salts, for example with salts of hydrohalic acids, 'obtain compound IV intermediates. This reaction is usually carried out in the presence of a base and a palladium catalyst as described, for example, in the experimental literature or in the experimental part of the present application: Synth. Commun. 'Vol. u, p. 513 (1981); acc. Chem. Res., Vol. 15, pp. 78.184 (1982); chem. Rev., 151494.doc -88- 201120018, Vol. 95, pp. 2457-2483 (1995); Organic Letters, Volume 6 (16), 2808 Page (2004); "Metal catalyzed cross coupling reactions", 2nd edition, Wiley, VCH 2005 (edited by De Meijere, Diederich); "Handbook of organopalladium chemistry for organic synthesis" (Edited by Negishi), Wiley, Interscience, New York, 2002; "Handbook of functional ed organometallics" (edited by P. Knochel), Wiley, VCH, 2005. Suitable catalyst system 三 (triphenylphosphine) palladium (0); bis (triphenylphosphine) gasified palladium (II); bis (acetonitrile) gasification palladium (II); [1,1,-double (two Phenylphosphino)ferrocene]_ chlorinated (II)/dioxane (1:1) complex; bis[bis-(], 2_diphenylphosphino)ethane]palladium ( 0); bis[bis-(1,2-diphenylphosphino)butane]_palladium (π); B I le (II) 'weathering (n); and acetic acid (II)/three - a mixture of phthalocyanine or a phosphine with a Pd salt or a phosphine with a Pd_ complex, such as dibenzylideneacetone-palladium and di-tert-butylphosphine (or its tetrafluoroborate) , anthracene cyclohexylphosphine; or a Pd_triphenylphosphine catalyst system in combination with a polymer. Suitable alkalis are usually inorganic compounds such as alkali metal and alkaline earth metal oxides such as oxidized H, sodium oxide, oxidized and oxidized towns; metal and soil metal sulphide such as carbonic acid, sodium carbonate, carbonic acid unloading, carbonic acid Extinguish the anaerobic acid and the metal gt hydrogen salt, such as sodium bicarbonate; metal and alkaline earth metal alkoxides such as sodium decoxide, sodium ethoxide, potassium ethoxide and potassium butoxide; and organic bases, for example Tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine and N-methylhexahydro. Than bite. ratio. Determining, substituting a pyridyl (for example, ccmidine, a dimercapto and a bismuthylamine group), and a cyclic amine, preferably potassium carbonate. 151494.doc •89· 201120018 The reaction is usually carried out in an inert organic solvent. Suitable solvents are aliphatics such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and p-nonylbenzene; For example, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, anisole and tetrahydrofuran and dimethoxyethane; alkanols, such as Ci-C0-alkanols, such as methanol, ethanol Or a mixture of such solvents, particularly preferably an ether (for example, dioxane) or a stupid/methanol mixture. According to the second step of the reaction scheme 1, according to the organic chemical standard method and as in the experimental part of the present application The intermediate of the compound IV is reacted with a sulfonium gas oxime. 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, For example, benzene, o-, m-, and p-quinone; halogenated hydrocarbons, such as two Methane, chloroform and gas benzene; ethers, such as diethyl ether, diisopropyl ether, tert-butyl fluorenyl, dioxin, benzopyrene, tetrahydrofuran. Compound IV intermediates and compounds v The reaction is usually carried out in the presence of an auxiliary base, suitably a base inorganic base such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate; and an organic base such as a trialkylamine such as triethylamine or such ratio a pyridine compound such as pyridine, monodecyl pyridine, 4 dimethylamino pyridine, etc. The auxiliary base is usually used in an amount of at least the molar amount, based on the amine compound IV. Unless otherwise stated, the above reaction is usually in the solvent. It is carried out at a temperature between room temperature and the boiling point of the solvent used. Alternatively, microwaves (which have proven effective) can be used to introduce the activation energy required for the reaction into the reaction mixture, in particular in the case of eucalyptus coupling ( For the reaction using microwaves, see 151494.doc -90· 201120018

Tetrahedron 2001, 57, pp. 9199 and subsequent pages, and pages 9225 and subsequent pages, and in the usual manner, "Microwaves in Organic Synthesis", Andr6 Loupy (ed.), Wiley-VCH 2002). Those skilled in the art will appreciate that the first step of Reaction Scheme 2 can be carried out under conditions as described for the second step of Reaction Scheme 1. Similarly, the second step of Reaction Scheme 2 can be carried out under the conditions as described for the first step of Reaction Scheme 1. Reactions Figures 1 and 2 may be advantageous as including the additional steps shown in Figure 3. According to the reaction scheme 3, the compound II is first converted into an aryl butterfly compound Ila under Suzuki coupling conditions. This conversion can be carried out, for example, as described above for the first step of Reaction Scheme 1. Preferably, the <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&&&& Subsequent reaction of compound IIa to compound I can be carried out by reacting compound na with a suitable heteroaromatic or aromatic halide VII as described in Scheme 1 to give the compound iv intermediate and obtaining The compound iv intermediate is reacted with a sulfonium chloride v; or the compound IIa is reacted with a suitable sulfonium gas v as shown in the reaction scheme 2 to obtain a compound Via intermediate, and then the obtained compound VIa intermediate is obtained. The aryl vanadium halide R2Hal' (compound VII) is reacted in the eucalyptus coupling condition. The starting materials of formula II required for the preparation of compound I have been known from the literature or are commercially available or can be prepared by one of ordinary skill in the art of organic chemistry without undue work in accordance with conventional laboratory procedures. Sun Compound III and Ilia are available for sale, or you can pick up "Sigh", Science of

Synthesis, Volume 6, Thieme, 2005 to prepare β 151494.doc -91 - 201120018 If it is true that chlorine v cannot be purchased commercially, follow conventional procedures in accordance with procedures known in the industry without excessive work. Operational specifications are obtained. The compound of formula I wherein X is s=o can be obtained by using a suitable amount of an oxidizing agent (specifically, 'inorganic or organic peroxide or hydroperoxide, such as peroxyacid, such as 3-p-peroxybenzoic acid or Prepared by treating compound X with sulfur by treatment with a single amount of an alkali metal periodate or a hydroperoxide as the monoperoxy phthalate or hydroperoxide. The compound of formula I of the X series S〇2 can be used, for example, by using a suitable amount of an oxidizing agent (specifically, an inorganic or organic peroxide or a hydroperoxide such as a peroxyacid such as 3-p-peroxybenzoic acid or It is prepared by treating a compound of formula I of X-series S or SO with monoperoxyphthalic acid or a suitable amount of an alkali metal periodate or hydroperoxide. The N-oxides of the compounds of formula I can be used, for example, by the use of oxidizing agents (specifically, inorganic or organic peroxides or hydroperoxides such as hydrogen peroxide or peroxycarboxylic acids such as peroxyacetic acid, peroxygen Benzoic acid or m-chloroperoxybenzoic acid) is prepared by treating a compound of formula I.

In addition to the guidance provided in the general procedures below, alternative synthetic transformations that can be used in the synthesis of intermediates involved in the synthesis of compounds of formula J and in the synthesis of compounds of formula I are known or familiar to those skilled in the art. Can be easily obtained. A collection of synthetic transformations can be found in the compilation, for example: J

March. Advanced Organic Chemistry, 4th edition; John Wiley:

New York (1992); RC Larock. Comprehensive Organic Transformations, 2nd edition; Wiley-VCH: New York (1999); FA Carey; RJ Sundberg. Advanced Organic Chemistry » 2nd edition; Plenum Press: New York (1984); TW Greene; P. 151494.doc -92- 201120018 GM Wuts. Protective Groups in Organic Synthesis, 3rd edition; John Wiley: New York (1999); L. S. Hegedus.

Transition Metals in the Synthesis of Complex Organic Molecules, 2nd Edition; University Science Books: Mill Valley, CA (1994); LA Paquette, ed., Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994); A. R · Katritzky; 0· Meth-Cohn; Edited by C. W. Rees, Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995); G. Wilkinson; F. G A. Stone; EW Abel Editor, Comprehensive Organometallic Chemistry Pergamon Press: Oxford, UK (1982); BM Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press: Oxford, UK (1991); AR Katritzky; CW Rees Editor, Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK ( 1984); AR Katritzky; CW Rees; EF V. Scriven, Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK (1996); C. Hansch; P. G. Sammes; JB Taylor Editor, Comprehensive

Medicinal Chemistry: Pergamon Press: Oxford, UK (1990). In addition, regular reviews of synthetic methods 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 151494.doc -93 - 201120018

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 Methodender Organischen Chemie (Houben-Weyl); Thieme: Stuttgart, Germany. In addition, synthetically transformed databases include Chemical Abstracts, which can be searched using CAS OnLine or SciFinder; Handbuch der Organischen Chemie (Beilstein), which can use SpotFire search; and REACCS. As shown in the examples below, advantageous properties of the compounds of the invention include the ability to effectively inhibit cell proliferation and activity as HIF inhibitors. For example, it has been shown that the compounds of the invention inhibit the activation of HIF-mediated transcription under hypoxic conditions. Thus, the compounds of the invention may be used to prepare agents for the treatment of conditions characterized by pathological physiological HIF signaling. Those skilled in the medical, biological, and/or pharmacological arts can utilize conventional methods to determine whether a condition is characterized by undesirable HIF signaling. Tissues affected by these diseases will overexpress genes that are induced by activation of the HIF response element (HRE). HIF-1 functions by binding to a HIF response element (HRE) in a promoter that normally contains the NCGTG sequence. The genes affected by HIF activity regulated by such promoters are well known to those skilled in the art and are also described in several reviews (see, eg, Gregg L. Semenza, Nature Reviews, October 2003, Vol. 3). Figure 3). In animal studies, HIF-1 overexpression is associated with increased tumor growth, increased angiogenesis, metastasis, and fibrosis (eg, renal fibrosis) (see: Semenza, G, Drug Discovery Today, Vol. 12, pp. 19/20) Period, 151494.doc -94- 201120018 October 2007; Kimura, Kunik〇 et al., Americari J〇urnal 〇f

Physiology (2008), 295 (4, Pt. 2), F1〇23 Fl〇29; and comments can be found in N_J. Mabjeesh et al., Hist〇1 Hist〇path〇1 (2〇〇7) 22:559-572 ). Fibrosis forms or exhibits excessive fibrous connective tissue in an organ or tissue. Recently, the inhibition of certainty can also play a role in the prevention of inflammation, in view of the important role of HIF_丨 in macrophage and neutrophil activation and infiltration into disease-invading tissues (see for example

Giaccia et al., Drug Discovery, Vol. 2, October 2003). For the reasons described above, the compounds of the invention are useful in the treatment of inflammatory diseases, hyperproliferative diseases or conditions, hypoxic-associated conditions, and diseases characterized by pathologically occurring blood cell overproduction. Thus, as another aspect, the invention comprises a pharmaceutical composition comprising at least one compound of the invention and at least one physiologically acceptable carrier or auxiliary substance. In still another aspect, the invention provides a therapeutic composition comprising, in addition to a compound of the invention, at least one other active compound that is useful in the treatment of a disease or condition as described above. Such therapeutic compositions are useful because the therapeutic efficacy of the compounds of the invention can be enhanced by the presence of the at least one other pharmaceutically active compound, and vice versa. For example, it has been shown that inhibition of HIFla activity via antisense gene therapy enhances the therapeutic efficacy of doxorubicin against hepatocellular carcinoma (see Liu, Fengjun et al., Canca).

Science (2008), 99(10), 2055-2061). In still another aspect, the present invention relates to a pharmaceutical composition comprising the present stagnation sigma and a second therapeutic agent inflammatory disease which is useful for treating or preventing a disease or condition selected from the group consisting of Hyperproliferative diseases or diseases 151494.doc •95- 201120018 Diseases, as well as the second pathophysiological vascular overgrowth are characterized by the above acceptable (four) or sensitizing agents. For example, in order to achieve synergistic therapeutic effects and prevent tumor cell hoppers, for the same reason, current chemotherapy usually involves the administration of a mixture of different cytotoxic and/or cytostatic compounds to improve & efficacy and reduce tumors. The possibility of cell adaptation. In the case of I, the invention relates to a pharmaceutical composition comprising a compound of the invention and radiation therapy. The any composition of the present invention may be admixed with (iv) an acceptable diluent, excipient or carrier or a mixture thereof. Even if a compound of the invention (including pharmaceutically acceptable salts thereof, N-oxides thereof, salts of such N-oxides, s-derivatives, and pharmaceutically acceptable solvates) can be administered alone, It is also administered in combination with pharmaceutical carriers, excipients or diluents, especially for human therapy. Such pharmaceutical compositions are useful for human or animal use in human and veterinary medicine. Examples of such excipients suitable for use in a variety of different forms of the pharmaceutical compositions described herein can be found in "Handb00k 〇f pharmaceutieal" edited by A Wade and PJ Weller.

Excipients, 2nd edition' (1994). Acceptable carriers or diluents for therapeutic use are well known in the art and are described, for example, in

Remington's Pharmaceutical Sciences, Mack Publishing Company (A. R Gennaro, ed., 1985). For the preparation of a pharmaceutical composition from a compound of the invention, the pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, lozenges, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one of -96-151494.doc 201120018 or a plurality of materials which may also act as diluents, flavoring agents, binding agents, preservatives, tablet disintegrating agents or encapsulating materials. In the powder, the carrier is a fine solid mixed with the finely active component. In the tablet, the active ingredient is mixed with a carrier having the necessary binding characteristics in a suitable ratio and compressed into a desired shape and size. The powders and lozenges preferably contain from 5% to 80%, more preferably from 20% to 70%, or a plurality of active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa Oil and the like. The term "formulation" is intended to include a formulation of the active compound with the encapsulating material as a carrier for forming a capsule, the active ingredient of the capsule with or without other carriers being surrounded by the carrier and thereby associated therewith. Similarly, cachets and rhomboid tablets are also included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration. In the preparation of a suppository, a low melting wax such as a mixture of a fatty acid glyceride or a cocoa butter is first melted and the active component is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of suitable size to allow it to cool' and thereby solidify. Liquid open y formulations include solutions, suspensions and emulsions such as water or water/propanol solutions. Liquid forms are especially preferred for topical application to the eye. In the parenteral 'primary shot, the water-soluble I glycol solution & A solution suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, stabilizers and thickeners as needed. 151494.doc • 97- 201120018. It can be prepared for oral use by dispersing the finely active component in water and viscous materials (for example, natural or synthetic gums, resins, methylcellulose, sodium methylcellulose, and other well-known suspending agents). An aqueous suspension. Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. The preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents and the like. The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into several unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a package preparation 'the package contains discrete amounts of preparations' such as packaged tablets, capsules, and vials or powders in the occupation. The unit dosage form can be a capsule, a key, a cachet or a diamond tablet itself. 'Or it may be any suitable form of packaging. Interestingly, HIF inhibitors (such as the compounds of the invention) prevent tumor resistance to chemotherapeutic drugs and can make cancer cells more sensitive to radiation therapy (see, for example, palay〇〇r ST et al. Int j cancer hired u 15th; 123(10):2430_7 and l semenza,

Nature Reviews, 2003, January, Vol. 3). Useful second therapeutic agents which may be combined with the compounds of the invention to produce a pharmaceutical composition of the invention include, but are not limited to (others referred to as inhibitors, cytotoxic compounds, and cytostatic compounds. HIF-1 inhibitors may, for example, be selected Free group of the following composition·· px_478(s_2 Amino-3-[4-N,N-bis(2-chloroethyl)amino]phenylpropionic acid N-oxide di-salt 151494.doc -98- 201120018 Acidate] 'lifting isomerase _ 丨 inhibitor, such as 8,9-dimethoxy _5_(2_ N,N-methylaminoethyl)_2,3-methylenedioxy Dibenzo[C,h][1,6]naphthyridin-6-one (also known as ARC-111 or topovaie) or (S)-10-[(dimethylamino) Methyl]·4ethyl_4 9-dihydroxy·丨Η·pyrano[3',4':6,7]pyridazino[l,2-b]quinoline-3,14-(4Η , 12Η)-dione monohydrochloride (also known as tropotecan); echin〇mycin; chetomin (NSC289491); cyclosporine A ), 3-[2-[4-[bis(4-fluorophenyl)methylene]_!•hexa-argon η-pyridyl]_2,3_di-rho-2-thio(thiox〇)-4 (lH)-啥嗤琳嗣 (R59949 ΡΙΚ3Κ/ Akt/mTor signaling cascade inhibitors, for example, LY294002, wortmannin or rapamycin; MAPK signaling cascade inhibitors such as MEK1 inhibitor PD98059; soluble bird bitter Indole cyclase stimulator 'for example, 3 · (5' hydroxymethyl-2,-furanyl)-l-pyryl. Lead azole (YC-1); heat shock protein 90 inhibitor 'specifically, root red shell Radicill, radicicol analog KF58333 or geldanamycin; microtubule disrupting agent, specifically such as taxol (1), vincristine or 2- Methoxyestradiol; histone deacetylase inhibitors such as FK228; thioredoxin inhibitors, specifically PX-12 or pleurotin; UCNO-1; diphenyl Iodine rust salts, genestein and carbazole Xyainido-triazole. Many cytotoxic or cytostatic inhibitions are known to those skilled in the art of treatment of hyperproliferative diseases or conditions such as tumors or cancer diseases. Compounds, for example, cytotoxic and cytostatic compounds include (but not Limited to pure or 151494.doc -99- 201120018 mixed antiestrogens, such as fasl〇dex, tamoxifen or raloxifene; topoisomerase Any inhibitor of π or π, such as camppt〇thecin (topoisomerase) or etoposide (topoisomerase; any compound that acts by inhibiting aromatase activity, such as anastroxo 0 sit (anastr〇z〇le) or come. Letrozole; any preparation that interferes with HER2 signaling, such as herceptin; any compound that chelate DNA, such as doxorubicin. Particularly preferred cell growth inhibiting or cytotoxic drugs which can be combined with the compounds of the present invention are alkylating substances, antimetabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, and antiandrogens. , antiestrogens, platinum compounds, hormones and antihormones, interferons and cell cycle dependent protein kinase (CDK) inhibitors, cyclooxygenase and/or lipoxygenase inhibitors, biogenic fatty acids and fatty acids Derivatives (including prostaglandins and leukocytes), protein kinase inhibitors, protein phosphatase inhibitors, lipid kinase inhibitors, platinum coordination complexes, ethyleneimene, methylmelamine, Trifoliate (trazine), vinca alkaloids, pyrimidine analogs, purine analogs, alkyl lactones, folic acid analogs, anthrones, substituted ureas, procarbazine derivatives, especially amines Acetate (acediasulfone), aclarubicine, ambazone, aminoglutethimide, L-aspartate, sulfur. Azathioprine, bleomycin, busulfan, leucovorin, carboplatin, carpecitabine, carmustine, selecau Celecoxib, chlorambucil 151494.doc •100· 201120018 (chlorambucil), cis-platin, cladribine, cyclophosphamide, cytarabine ), dacarbazine, dactinomycin, dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel Docetaxel, doxorubicin, enediyne, epi+rubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, Ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorourine. Fluorouracil fluoxymesterone, flutamide, fosfestrol, sputum. _ (furazolidone), gemcitabine, gonadotropin-releasing hormone analogue, hexamethylmelamine, hydroxy carbamide, hydroxy methyl nitrofurantoin, Caproic acid gestation _ (hydroxyprogesteronecaproat), hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon gamma, irinotecan, bright Leuprolide, lomustine, lurototecan, mafenide sulfate 〇1 amide, mechlorethamine, medroxyprogesterone Acetate), megastrolacetate, melphalan, mepacrine, mercaptopurine, amidoxime 151494.doc -101 - 201120018 (methotrexate), metronidazole Metronidazole), mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid Nalidixic acid), nifuratel, nifuroxazide, nifuralazine, nifurtim〇x, nimustine, nimo Ninazole, nitrofurantoin, nitrogen mustards, oleomucin, ox〇linic acid, pentamidine, pentostatin, Phenozopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine ), pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine ), scriflavinium chloride simos; semustine, streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine , Sulfonamide sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, transverse amine veins Sulfaguanidine), sulfaguanole, sulfamethizole, reductive amine 0 oxa 0 sitting • 102- 151494.doc 201120018 (sulfamethoxazole), co-trimoxazole, sulfamethoate Sulfadimethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, suifaperin, sulfaphenazole, suifathiazole ), sulfisomidine, staurosporin, tamoxifen's taxol, teniposide, tertiposide, testosterone ), testosteron propionate, thioguanine, thiotepa, tinidazole, topotecan; triaziquone Treosulfan, trimethoprim, trofosfamide, UCN-01, vinblastine, vincristine, vindesine, vincaine, Vinoreibine, and zornbicin, or their respective derivatives or analogs thereof. Several of the above drugs have been administered simultaneously for cancer therapy, and it is therefore envisioned that more than one cell growth inhibiting and/or cytotoxic drug may be included in the compositions of the present invention. As noted above, HIF inhibitors make cancer cells more susceptible to chemotherapy and radiation therapy. Thus, in order to effectively treat a hyperproliferative disease or condition, the compounds of the invention may be administered in combination with other active pharmaceutical agents and/or in combination with other anti-cancer, anti-tumor or anti-proliferative disease therapies. In one sample, the invention provides a method of treating a hyperproliferative disease or condition, comprising in a patient undergoing radiation therapy, chemotherapy, immunotherapy, laser/

151494.doc -103- S 201120018 The compounds of the invention are administered to the patient before, during and/or after microwave thermotherapy or gene therapy using antisense DNA and RNA (see, for example, M〇eller et al., Cancer Cell 2004 5429- 441). In a further aspect, the invention provides (as outlined above) the use of a compound of the invention or a composition of the invention for the preparation of a medicament for treatment comprising treating or preventing a disease selected from the group consisting of Condition: inflammatory disease, hyperproliferative disease or condition, hypoxic-related conditions such as diabetic retinopathy, ischemia-reperfusion injury, ischemic myocardium and limb disease, ischemic attack, sepsis and septic Shock (see, for example, Uu FQ et al, Exp Cell Res. April 1, 2008; 314(6): 1327.36); and diseases characterized by pathophysiological vascular overgrowth, such as in osteosarcoma Angiogenesis (see 'Example: Yang, Qing_cheng et al., Dier

Junyi Daxue Xuebao (2008), 29(5), 504-508), macular degeneration (especially age-related macular degeneration) and vascular proliferative retinopathy (see, for example, Kim JH et al., J Cell Mol Med., 2008 1 19th)) As previously known and described, 'HIF inhibitors (e.g., compounds of the invention) are useful in the treatment of inflammatory diseases or conditions. For example, it has been shown that oxygen-dependent HIF isoforms are greatly upregulated in psoriasis skin (see, for example, Rösenberger c et al, J Invest Dermatol. 2007 October; 127(10): 2445-52). In addition, the HIF inhibitor neovastat has been shown to inhibit airway inflammation in asthma (see, for example, 'Lee SY et al., Vascul Pharmacol. November-December 2007; 47(5-6): 313-8 ). In addition, recent evidence also suggests that HIF participates in joint inflammation and destruction of rheumatoid arthritis under hypoxic conditions (see, for example, 'Ahn, J. K. et al., Rheumatology (Oxford, 151494.doc 201120018).

United Kingdom) (2008), 47(6), 834-839). Thus, in a preferred embodiment of the use of the invention, the inflammatory disease is selected from the group consisting of atherosclerosis; rheumatoid arthritis; asthma; inflammatory bowel disease; psoriasis, especially psoriasis, head Psoriasis, drops of psoriasis, heterotypic psoriasis; neurodermatitis; ichthyosis; alopecia areata; total baldness; partial alopecia; alopecia areata; diffuse alopecia (alopecia diffusa); atopic dermatitis; skin lupus erythematosus; Myositis; atopic eczema; morphea; scleroderma, serpentine alopecia, androgenetic alopecia; atopic dermatitis; irritant contact dermatitis; contact dermatitis; pemphigus vulgaris; deciduous blister Sore; proliferative pemphigus; scar mucosal pemphigoid; bullous pemphigoid; mucosal acne; dermatitis; dermatitis herpetiformis Duhring; urticaria; Sexual necrosis nodular erythema; simple pruritus; nodular pruritus; acute pruritus (prurig〇acuta wide linear IgA skin disease; pleomorphic sun skin disease; uterine erythema; skin treatment; drug therapy; Sexual purpura ((4) Lushan (10) (6) progressiva); vesicular eczema; eczema; fixed drug rash; photoallergic skin reaction; and perioral dermatitis. Because &amp; 'further preferred embodiment of the invention covers - or more Combinations of a compound of the present invention with a medicament currently used for the treatment of such inflammatory diseases or conditions can be determined by those skilled in the art of pharmacology. The therapeutic agents used in combination can be selected, for example, from the group below. : anti-inflammatory solid antioxidants, therapeutic antibodies or fusion proteins that chelate or bind to certain cytokines or cell epitopes associated with the inflammatory process, or di-haloate reductase inhibitors (eg, methotrexate). The compounds of the invention exhibit anti-proliferative effects. In addition, <-inhibitors (e.g., 151494. doc 105-201120018 compounds of the invention) are effective agents for the treatment of various cancer diseases (see review by Jr. (eg) Gregg L. Semenza, Nature Reviews, 2003 1 〇月 'Volume 3 and review article nJ. Mabjeesh et al, Histo Histopathol (2007), 22: 559-572). Therefore, hyperproliferative diseases are selected from the following The use of the present invention is also preferred: tumor or cancer disease, precancerous lesions, dysplasia, histiocytosis, vascular proliferative diseases, and virus-induced proliferative diseases. Therefore, a preferred embodiment of the use of the present invention In the case, the hyperproliferative disease is selected from the group consisting of tumors or cancer diseases consisting of: diffuse large B-cell lymphoma (DLbcl); T-cell lymphoma or leukemia, for example, skin tau cell lymphoma (CTCL), non Peripheral T-cell lymphoma of the skin, lymphoma associated with human tau lymphocyte virus (HTLV), adult cell leukemia/lymphoma (atll), acute lymphoblastic leukemia, acute non-lymphocytic leukemia, acute myeloid leukemia, chronic Lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma; myeloma, multiple myeloma, mesothelioma, solid tumors in children, Glioma, bone cancer, and soft tissue sarcoma; common adult percutaneous tumors, such as head and neck cancer (eg, oral cancer, laryngeal cancer, and food) Cancer), genitourinary cancer (eg, prostate cancer, bladder cancer, kidney cancer (especially malignant renal cell carcinoma (RCC)), uterine cancer, ovarian cancer, testicular cancer, rectal cancer, and colon cancer), lung cancer (eg, small cells) Cancer and non-small cell lung cancer, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin cancer' ulcer and mastoid squamous cell carcinoma, [cancer , brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, 151494.doc •106· 201120018 medullary carcinoma, osteosarcoma, soft tissue sarcoma, Ewing sarcoma (Ewing, s sarcoma), reticulum sarcoma, and card Boss sarcoma (Kap〇si, s sarcoma), fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovium Tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, glioblastoma, papillary adenocarcinoma, cystadenocarcinoma, bronchial ductal carcinoma, fine Problastoma, embryonal carcinoma, Wilmsi tunior, small cell lung cancer, epithelial cancer, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, blood vessel Blastoma, acoustic neuroma 'oligodendroglioma, meningioma' neuroblastoma, retinoblastoma, glaucoma, hemangioma, heavy chain disease and metastasis. The precancerous lesions which can be treated with the compound of the present invention are preferably selected from the group consisting of: precancerous lesions, especially photo-linear keratosis 'skin angle, linear cheilitis, tar keratosis, arsenic keratosis, X-ray keratosis, Bowen's disease, Bowen-like papulosis, malignant freckle-like sputum, sclerosing moss, and lichen rubber mucosae Precancerous lesions of the digestive tract, especially mucosal erythema, mucosal leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, calf ulcer, hypertrophic stomach disease (gastropathia hypertrophica) Gigantea), borderline carcinoma, neoplastic intestinal polyps, rectal polyps, porcelain gallbladder; gynecological precancerous lesions, especially ductal carcinoma in situ (CDIS), cervical intraepithelial neoplasia (CIN), endometrium Hyperplasia (grade), vulvar dystrophy, vulvar epithelium 151494.doc •107- 201120018 Intrinsic neoplastic lesions (VIN), hydatidiform mole; urological precancerous lesions, especially vesicular papilloma, weidus Erythema (Queyrat's erythroplasia), the testicular intraepithelial neoplasia (the TIN), carcinoma in situ (the CIS); precancerous lesions caused by the chronic inflammation, in particular pyoderma, osteomyelitis, acne conglobata, lupus vulgaris, and fistula. Dysplasia is usually a precursor to cancer and can be seen, for example, in the most turbulent form of epithelial non-neoplastic cell growth&apos; involving the loss of structural orientation of individual cell-consistent stone cells. Dysplastic cells usually have abnormally large and well-stained nuclei and exhibit polymorphism. When there is chronic irritation or inflammation, dysplasia characteristically occurs. The compounds of the invention may be used to treat cancer, including, but not limited to, non-performing ectodermal dysplasia, anterofacial dysplasia, asphyxiating cerebral rhyme: abnormal, atrial-finger dysplasia , bronchial dysplasia, abnormal brain development, cervical dysplasia, abnormal development of cartilage ectoderm, abnormal development of clavicular bone, abnormal development of congenital ectodermal, abnormal development of Gu bone, Gu wrist (4) dysplasia, skull (4) Dysplasia, abnormal dentine dysplasia, abnormal dysplasia, dysplasia dysplasia, glaze f development, cerebral ocular dysplasia, half limb (four) f abnormality, and diisologous dysplasia , bone fiber dysplasia, ... L fibromuscular development of the retina ... Γ skeletal dysplasia, hereditary kidney - lymph, sexual external * layer f abnormal 'less _ layer of cell reduction thymic dysplasia (lymPh〇penic 151494. Doc -J08- 201120018 thymic dysplasia), breast dysplasia, mandibular dysplasia, metaphyseal dysplasia, Mondini dysplasia (M〇ndini &amp; (4), single bone fiber dysplasia, mucosal epithelial dysplasia (muc〇ephheliai dyspUsia), multiple epiphyseal dysplasia (muhipie dysplasia), ear and ear vertebral dysplasia, ocular dysplasia, vertebral bone development = often, teeth Dysplasia, abnormal development of the lower limbs, apical periodontal bone I month heterojunction, multi-bone fiber dysplasia, pseudo-chondral hypoplasia, vertebral bone dysplasia, retinal dysplasia, transparent septal-optical development, vertebrae Abnormalities and ventricular dysplasia. Although the hormone receptor system refers to the receptor group activated by the hormone 17 estradiol (estrogen). There are two types of estrogen receptors: Er, which is a cellular hormone receptor. a member of the family; the G protein-coupled receptor GPR30 (GPER) is a G-protein somatic itch... wide and body [not estrogen and estrogen receptors such as Dan Kongfei, ovarian cancer, parotid gland , skin II, ° 刖 腺 腺 adenocarcinoma and endometrial cancer and other diseases. Because the inventors of the present invention can inhibit the transcriptional activity of estrogen receptor mediation, it can be used to treat these Therefore, in another preferred embodiment, the proliferative disorder benefits from the female ... the condition of the treatment according to the present invention is excessively attenuated by the health%, the disease. The compound of the present invention:::Γ The disease-causing compound caused by the weakening of the conduction may inhibit the _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ And/or tumors, endometrial tumors, and sub+ disorders are selected from the group consisting of breast tumors & tumors. The disease can be measured by estrogen receptors by various methods known in the art 151494.doc 201120018 The activity is enhanced, including determining the degree of ER expression in the diseased tissue by, for example, measuring an amount of the protein expressing the immunological method, by measuring the amount of the nucleic acid encoding the ER, such as RT-PCR, northern ink. Point methods, nuclear concatenations, and the like, and methods for determining the activity of a nucleic acid construct comprising an ER-receptor recognition element that drives expression of a detectable reporter gene (eg, CAT, luciferase, GFP, etc.), such as Experimental part described below in greater detail. Preferably, the condition benefiting from attenuating estrogen receptor signaling exhibits an increase in estrogen receptor signaling of at least 1%, preferably at least 20%, 30%, 40% in the diseased tissue compared to healthy tissue. 50%, 60%, 70% of the symptoms. Preferably, the increase is based on an increase in the expression of the nucleic acid comprising the ER-receptor recognition element and the reporter gene driven by the element. In therapeutic use as an estrogen receptor signaling antagonist that acts by inhibiting cell replication, the compounds used in the present invention are administered at an initial dose of from about 0.02 mg/kg to about 20 mg/kgi per day. A daily dose range of from about 5 mg/kg to about 2 mg/kg is preferred, and about 5 paws are optimal in the range of doses up to about 1 mg/kg. However, the dose can be viewed at the patient's request. The severity of the condition being treated and the compound being used will vary. It is within the abilities of the physician to determine the appropriate dosage for the particular situation. In general, the treatment will be started with a smaller dose that is less than the optimal dose of the compound. Thereafter, stepwise; The dosage is increased until the optimal effect in this condition is reached. For convenience, the total daily dose may be divided into portions and administered in multiple doses as needed. The compounds of the invention may be administered by a variety of well known routes. Including oral, • 1J0- 151494.doc 201120018 by rectal, intragastric, intracranial and parenteral administration, such as intravenous, intramuscular, intranasal, intradermal, subcutaneous and similar routes of administration. Administration and especially intravenous administration (preferably by accumulation injection) is preferred. Depending on the route of administration, different pharmaceutical formulations are required and some formulations may require a protective coating to be applied to the drug formulation to prevent this. Invention The compound degrades in, for example, the digestive tract. Thus, preferably, the compound of the present invention is formulated into a syrup, an infusion or injection solution, a lozenge, a capsule, a caplet, a lozenge, a liposome, a suppository, a plaster, an emergency end tape, An extended release capsule (retard capSUie), a powder or a sustained release formulation. Preferably, the diluent is a water buffer, a buffer salt solution or a salt solution, and the carrier is preferably selected from the group consisting of cocoa butter and vitebes〇le. Particularly preferred pharmaceutical forms for administration of the compounds of the present invention are those which are suitable for injectable use and include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. The final solution or dispersion form must be sterile and fluid. Typically, the solution or dispersion includes a solvent dispersion containing, for example, a water 'buffered aqueous solution' such as a biocompatible buffer, ethanol, Polyols, such as glycerol propanol 'polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. The compounds of the invention may also be formulated into liposomes, especially for non-menstrual Intestinal administration. The plastid provides the advantage of a longer half-life in circulation (compared to free drug) and a more uniform extended release of the encapsulated drug. The sterility of the injection or injection solution can be recognized by any number of industries. Techniques include, but are not limited to, the addition of agents such as antibacterial or antifungal agents, such as p-benzoic acid, butanol, benzophenone, sorbic acid or 151494.doc 111 · 201120018 thimerosal. Isotonic agents, such as sugars or salts, especially sodium sulphate, are included in the rounds 4&amp;, the main or injectable solutions. The various ingredients listed above may be included in the appropriate solvent by the required amount And then sterilized to prepare a sterile injectable solution containing one or several of the present hair. The above solution is vacuum dried or cold-dried as needed to obtain a sterile powder. Preferably, the diluent of the present invention is water, a physiologically acceptable buffer, a physiologically acceptable buffer solution or a salt solution. Preferred carriers are cocoa butter and: such as (10). In addition to the preferred excipients already mentioned above, the following excipients may be selected, but not limited to, for the various pharmaceutical forms of the compounds of the invention: a) binding agents such as lactose, mannitol, crystalline sorbitol , monohydrogen phosphate, calcium phosphate, sugar, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc , calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glyceride and sodium stearyl fumarate; C) disintegrants, such as starch, croscarmellose, A Cellulose sodium, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinylpyrrolidone and the like. Other suitable excipients can be found in Handbook of Pharmaceutical

Published by Excipients' American Pharmaceutical Association, which is incorporated herein by reference. It should be understood that the severity of the end-effect disorder and the particular type of treatment that can be treated with a compound of the invention, as well as the individual patient being treated (eg, the total health of the patient 151494.doc-112·201120018), may cause a therapeutic or prophylactic effect. Different doses of each compound are required. Determination of the appropriate dosage is within the discretion of the attending physician. It is expected that in the therapeutic or prophylactic use of the invention, the average daily dose of the compound of the invention will range from about 0.1 mg to about 3 g. However, in a preferred use of the invention, the compound of the invention is present in the range of from 丨〇 to 丨〇〇〇mg, preferably from 10 1 ^ to 5 〇〇 mg, more preferably from 5 〇 mg to 2 〇〇. The amount in the range of mg is administered to individuals in need thereof. The duration of treatment and frequency of administration using the compounds of the invention will vary depending on the severity of the condition being treated and the condition and specific response of the individual patient. As is known in the art, the pharmaceutically effective amount of a given composition will also depend on the route of administration. Hanging, if administered through the gastrointestinal tract (eg, by suppository, rectum, or by intragastric probe), the amount required is higher; and if the route of administration is parenteral (eg, intravenous), the amount is required. Lower. In general, if administered rectally or intragastrically, a compound of the invention will be administered in the range of from 5 mg to 3 g, preferably from 5 mg to 5 mg; and if parenteral administration is employed, Compounds of the invention will be administered in the range of from 10 mg to 500 mg. The pharmaceutical composition of the present invention can be administered prophylactically if it is known that a person has the risk of suffering from a condition treatable by the use of the compound of the present invention. In such cases, it is preferred to administer each of the compounds of the invention on a daily basis, preferably in the preferred and particularly preferred dosages outlined above. Sustainability of this administration until the risk of suffering from various conditions has decreased. However, in most cases, the compounds of the invention are administered immediately after the diagnosis of the disease/condition. In such cases, preferably, the first dose of the compound of the invention is administered once, twice, one-to-human or four times per day. Preferably, the administration is interrupted for one day, one week or one month and then repeated until the symptoms of each disease 151494.doc • 113· 201120018 no longer worsens or until the symptoms improve. Within the meaning of the present invention, if a combination of substituents or variables achieves a stable or chemically feasible compound, the combination is permissible. A stable compound or a chemically feasible compound is a compound which does not substantially change at a temperature of _ or lower in the absence of water jet or other chemically reactive conditions for at least one week. The invention likewise contemplates any of the compounds of the compounds disclosed herein.

The four-level classification of nitrogen groups. By this four-stage acidification, water or oil soluble or dispersible products can be obtained. The modifications and variations of the present invention are obvious to those skilled in the art, and such modifications and changes may be made without departing from the scope of the invention. Although the present invention has been described in connection with the preferred embodiments thereof, it should be understood that the claimed invention should not be construed as being limited to the specific embodiments. In fact, various modifications apparent to those skilled in the art to which the present invention is disclosed are intended to be included within the scope of the invention. The following examples and figures are merely illustrative of the invention and are not to be construed as limiting the scope of the invention as defined by the scope of the claims. Synthesis Examples All of the materials used in the examples are commercially available or can be synthesized by one of ordinary skill in the art of organic chemistry without the undue effort to follow, for example, the routine laboratory practices outlined in the real m. According to the following route, for example, the formula hl of the present invention 2, 3 • two scent life 151494.doc 201120018 pathway 1:

Route 2:

Η (1) Other steps:

A compound of the formula 1.2 is prepared starting from 6-bromo-3,4-dihydro-2-indole-1,4-benzo[b][l,4]thiazine (8) instead of the compound (1) using a similar route. Compounds of formulas 1.3 and 1.4 can be prepared by selective oxidation of a compound of formula 1.2 according to standard procedures as outlined in the reaction scheme below: 151494.doc -115- 201120018

0=0=0 R1 o=s=o 1.2 The general reaction procedure described above is as follows: General procedure A. In the vain column, the surname is Gutian vr b

(=Pd(dPPf)Cl2) (0.1 eq.) and a flask corresponding to a heteroaromatic or aromatic acid or phthalic acid ester (1.2 eq.), and slowly added 2 〇M K2C 〇3 aqueous solution (3.5 eq.). The mixture was at 88. Heat underarm for 4 h. After cooling, the mixture was purified by flash column chromatography (eluent, ethyl acetate/hexane, EtOAc: EtOAc: EtOAc) General Procedure B. Stir a flask containing the amine compound (1) or (2) (1.0 eq.), corresponding sulfonium (1.1 eq.) and pyridine (1 〇 equivalent) in CHAl2 at room temperature. 12 h. The reaction mixture was washed with concentrated aqueous Nh 4 C1, then washed with brine and dried over MgSO 4 . The organic solvent is evaporated, and the crude product is purified by preparative HPLC or flash column chromatography (EtOAc, ethyl acetate /hexane) to afford compound 1.1 or (3) (70% to quantitative yield). 151494.doc -116- 201120018 General procedure C. Thermal reaction. Purify the compound (3) (1.0 eq.) contained in methanol with a n 2 purge under a drastic drop. (1 ((1卩?£)) (: 12 (0.1 eq.) and corresponding reaction tube of heteroaromatic or aromatic acid or folic acid ester (1 eq.), and slowly add 2.0 M K2C 〇 3 aqueous solution (2.5 eq. sealed container, and react the mixture in carousel reaction) The unit was heated at 85 ° C for 1 h. After cooling, the mixture was diluted with CHzCl 2 'filtered through diatomaceous earth and eluted using ch 2 c 12 . The organic solvent was evaporated and purified by preparative hplc or flash column chromatography The crude product was purified by ethyl acetate / heptane to give compound J i (42-90 〇 / 〇 yield). General procedure C · Microwave reaction: Purify the compound contained in methanol with n2 under vigorous stirring ( 3) (1.0 equivalents), Pdwppocijo" equivalent) and a 2_5 mi microwave reaction vessel corresponding to a heteroaromatic or aromatic acid or face acid ester (丨 equivalent) and slowly add 2.0 M K2C03 aqueous solution (2.5 equivalents). And mix the mixture in a microwave oven at 9 〇. After the minifEM Discover microwave system was set up, the mixture was diluted with CHAh, filtered through diatomaceous earth and eluted using ch2C12. The organic solvent was taken up and purified by preparative HPLC or flash column chromatography (ethyl acetate). The crude product was purified to give the compound j 丨 (42_9 〇% yield). General procedure D. bis(pentamethylene) dim (2 equivalents), pd (dppf) Ci2 (〇) equivalents and potassium acetate ( 4.0 eq.) was added to a flask containing the compound (i) (i.e. equivalent) in degassed hydrazine, 4-dioxane. The reaction mixture was heated to 95 &lt;t and stirred for 4 hours. The mixture was diluted with ethyl acetate (50 ml), filtered through a short-purchase column, and further dissolved in ethyl acetate. 151494.doc •117· 201120018 Analysis: combined organic (iv) (4) (10) brine, dried over anhydrous Mgs〇4 And evaporate. Purify the residue by flash column chromatography (Shiqi gum, ethyl acetate / heptane, 1:3) to obtain a milky white or beige solid _acid from the purpose of (4) (50-88% In the subsequent steps, follow the general procedure described above. The compound (4) is converted into the compound 1.1. The general private sequence E' dissolves the compound of the formula J.2 (1 〇 equivalent) in the called (3). 3-Phosperoxybenzoic acid is added at room temperature. (1·〇 equivalent), and the mixture was dropped for 3 minutes. The progress of the reaction was monitored by LCMS. After completion, the reaction was quenched by adding ho, followed by extraction in c^c! 2 (3χ^ organic layer through

NajO4 was dried and the solvent was removed under reduced pressure. The crude product was further purified by preparative lcms. General Procedure F. The compound of formula 1.2 (1·〇 equivalent) was dissolved in CH 2 Ci 2 . 3-O-peroxybenzoic acid (2.5 equivalents) was added at room temperature, and the mixture was stirred for 48 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction was quenched by the addition of h2, followed by extraction (3x) in CH/b. The organic layer was dried over Na 2 SO 4 and solvent was evaporated under reduced pressure. The crude product was further purified by preparative LCMS. 6-Bromo-3,4-dihydro-2H-1,4-benzo[b][l,4]thiazine (8) was prepared by the method shown in the following reaction scheme: 151494.doc - 118- 201120018

Br

F no2 (5)

H VIII, S COOH

OH

5-Bromo-2-fluoronitrobenzene (5) (1·〇 equivalent) was dissolved in DMF in a round bottom flask. Thioethanolate (1.1 equivalents) and K2C03 (2.5 equivalents) were added. The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography (TLC). After 16 h, the reaction was complete and water was added to the reaction mixture. The aqueous mixture thus obtained was washed with CH2C12 and acidified to pH 1 using dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; It was used in the next step without any further purification. Compound (6) (1.0 eq.) was dissolved in glacial acetic acid in a round bottom flask, and iron powder (4.0 eq.) was added. The mixture was heated to 70 C with stirring for 1 h. After the reaction was completed, the mixture was allowed to cool to room temperature and diluted with water. The aqueous mixture was extracted using acetic acid. The resulting organic layer was dried over NhSCU and solvent was evaporated under reduced pressure. The crude product was dissolved in ash and the solution was evaporated. This procedure was repeated several times, I to completely remove the acid. No further purification is required. The whiteish yellowish compound (7) was obtained in a 55% yield. Compound (7) (1.0 equivalent) was dissolved in anhydrous THF t in a round bottom flask 151494.doc • 119·201120018. Slowly add 1 μb of H3*thf complex solution in THF (10.0 equivalents) and then stir the mixture for another 3 h. After monitoring the reaction by TLC, quench the reaction by adding water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na.sub.2.sub.4, and the solvent was removed under reduced pressure. further purified by flash column chromatography (cyclohexane / ethyl acetate 3:1 as solvent) The crude product was purified to give compound (8) (yield: (dd, 1H, J=7.66 Hz, J=2.44 Hz), 6.35 (bm, 1H), 3.5-3.4 (m, 2H), 2.97-2.92 (m, 2H). Use the general procedure A described above To D to prepare the compound of formula I listed in Table X below, using the general procedure described above to human-D from 6-di-3,4-dihydro-2H-benzo[b][ l, 4] thiazine begins to prepare compounds of formula I of the X-series s. Compounds of formula I are prepared starting from the corresponding benzothiazine-compound 1.2 using the general procedure E*F described above, respectively, to prepare X-based SO or S02. Analysis of Compound I as follows: Method A: HPLC/MS using a Waters X-bridge C18-column, 5 μπι particle size, 4.6 x 150 mm (diameter x length), flow rate of i.75 ml/min, using a linear gradient (water to sterol, 0.2 〇/〇) The citric acid was used as a modifier) from 9.1 〇 min from the initial 99:1 to 1:99, followed by 1.80 min. The mass signal was determined using a Waters 3 1 〇〇 mass detector. Method B ·· HPLC/MS, used Waters X-bridge C! Column, 5 μm particle size, 4.6 x 150 mm (diameter X length), flow rate 1.75 ml/min, using a linear gradient (water to acetonitrile, 0. 2 ° / citric acid as modifier) ), from 9.1 〇 151494.doc -120- 201120018 min from the initial 99:1 to 1:99, followed by 1.80 min. The mass signal was measured using a Waters 3 1 00 mass detector. The analysis is listed in Table A according to Method A. Compounds of Examples 1 to 22 in I. The compounds of Examples 23 to 52 listed in Table I were analyzed according to Method B.

(I) Table 1

Ex. # R1 R2 X Rt (HPLC) 『mini MS 1 4-methylphenyl 5_ylyl-2-11 thiophene 0 9.09 M+l: 397 2 3-fluoro-4-methylphenyl 4 -Cyanophenyl 0 9.26 M+l: 409 3 3-Fluoro- 4-methoxyphenyl 4-cyanophenyl 0 8.96 M+l: 425 4 4-nitrophenyl 4-cyanophenyl 0 9.84 M+HC02H: 466 5 4-aminophenyl 4-cyanophenyl 0 8.18 M+l: 392 6 4-decyloxyphenyl 4-cyanophenyl 0 8.9 M+l: 407 7 4 -methylphenyl 4-cyanophenyl 0 9.08 M+l: 391 8 3-fluoro-4-mercaptophenyl 5 -yl-2-yl phenyl 0 9.42 M+l: 415 9 3-fluorine 4-methoxyphenyl 5-cyano-2-thienyl 0 9.12 M+l: 431 10 6-decyloxy-3-. Bipyridyl 4-cyanophenyl 0 8.99 M+l: 408 11 6-decyloxy-3-pyridyl 5-lacyl-2-σ-septenyl 0 9.16 M+l: 414 12 6-methyl 3-pyridyl 5-ranyl-2-11 phenantyl 0 8.6 M+l: 398 13 4-dimethylaminophenyl 5-cyano-2-thienyl 0 9.06 M+1:426 14 4-dimethylaminophenyl 4-cyanophenyl 0 8.94 M+1: 420 15 benzoquinone-1,4-dioxazide -6-yl 5-cyano-2-thienyl 0 9 M +l: 441 16 4-Fluoro-3-indolylphenyl 5·disc-2-enoyl 0.41 M+l: 415 151494.doc -121 - 201120018

Ex. # R丨R2 X Rt (HPLC) 『mini MS 17 4-decylphenyl 4-mercapto-3-methoxyphenyl 0 9.29 M+l:421 18 3_fluoro-4-mercaptobenzene 4- 4-mercapto-3-methoxyphenyl 0 9.49 M+l: 439 19 4-methylphenyl 5-indolyl-3-thienyl 0 9.59 M+l: 397 20 4-decyloxybenzene Base 5_ gas-based-3-supplemented base 0 9.46 M+l: 413 21 3-fluoro-4-methylphenyl 5-carbyl-3-indolyl 0 9.82 M+l: 415 22 3-fluoro 4-methoxyphenyl 4-cyano-3-methoxyphenyl 0 9.03 M+l: 455 23 4-decylphenyl 4-cyanophenyl S 8.68 low strength 24 6-decyloxy ° pyridine-3-yl 4-cyanophenyl S 8.34 M+l: 424 25 6-methionine ° -3-yl 4-cyanophenyl S 7.94 M+l: 479 26 4- Oxyphenyl 4-cyanophenyl S 8.39 low strength 27 3-fluoro-4-methoxyphenyl 5-cyano-2-thienyl S 8.48 low strength 28 5-methyl-2-11 thiophene 5-cyano-2-thienyl S 8.72 low strength 29 4-epoxyphenyl 5-cyano-2-thienyl S 9.01 low strength 30 4-decyloxyphenyl 4-cyanophenyl so 7.75 M +l:439 31 4-decyloxyphenyl 4-cyanophenyl S〇2 7.45 M+l: 455 32 4-decylphenyl 3_yloxy σ 喊 -2--2-yl 0 8.10 M+l :381 33 4-B Phenyl 4-cyanophenyl 0 7.80 M+l: 419 34 5-decylthiophen-2-yl 4-cyanophenyl 0 8.32 low strength 35 4-refenyl phenyl 5 _ 2-Base 0 7.34 M-1: 425 36 2,3-Dihydrobenzo[b][l,4] Dioxol-6-yl 4-cyanophenyl 0 7.99 Low strength 37 6- Gas 1* ratio sigma-3 -yl 4-cyanophenyl 0 8.07 low strength 38 6-gas ΰ ratio bite-3 · group 5 - gas group ° cephen-2-yl 0 8.22 low strength 39 6-(曱 基 )) 〇 -3- -3-yl 4-cyanophenyl 0 8.33 M+l: 424 40 4-(pentafluorothio)phenyl 5-carbon 1 phen-2-yl 0 8.94 M +l: 509 41 6-methyl 0 ratio. 3-amino-4-cyanophenyl 0 7.96 M+l: 392 42 4-decylphenyl 5-cyano '•biidine-2-yl 0 9.17 M+l:392 151494.doc •122· 201120018

Ex. # R1 R2 X Rt (HPLC) 『mini MS 43 4-methylphenyl 6-cyano. Bis-2-yl 0 9.23 M+l: 392 44 4-methylphenyl 2-cyanopyrimidine-5-yl 0 9.22 M+l: 393 45 4-methylphenyl 5-cyanothiazole-2 - group 0 9.76 M+l: 398 46 2,3-dihydrobenzo[b][l,4]dioxine-6-yl 5-cyanothiophen-3-yl 0 9.48 M+l : 441 47 6-(Dimethylamino)pyridin-3-yl 5-cyanothiophen-2-yl 0 10.07 M+l: 427 48 6-(Dimethylamino)pyridin-3-yl 6- Cyano acridine·3-yl 0 9.75 M+l: 422 49 6-(Dimethylamino)pyridin-3-yl 5-cyano"pyridin-2-yl 0 9.54 M+l: 422 50 6 -(dimethylamino)pyridin-3-yl 2-cyanopyrimidine-5-yl 0 9.37 M+l: 423 51 6·amine group ratio -3-yl 5-cyano-[pyridine]-3 -Base 0 6.18 M+l: 394 52 6·Amino group ratio 淀-3-yl 5-steryl group thiophene-2-yl group 0 6.58 M+l: 399

Ex: Example Rt: retention time The compounds of formula I listed in Table II below can be prepared using the general procedures described above. Table II:

Ex. # R1 R2 X Rt (HPLC) [min] MS 53 4-Trifluoromethylphenyl 4-cyano-3-methoxyphenyl 0 54 4-Phenylphenyl 4-cyano-3- Methoxyphenyl 0 55 4-methoxyphenyl 4-cyano-3-indolylphenyl 0 56 4-aminophenyl 4-cyano-3-methoxyphenyl 0 57 4- Nonylphenyl 4-cyano-3-methoxyphenyl 0 58 4-decylthiophenyl 4-cyano-3-indolylphenyl 0 59 4-ethylphenyl 4-cyano-3 -methoxyphenyl 0 151494.doc -123 - 201120018

Ex. # R1 R2 X Rt (HPLC) [min] MS 60 4-Trifluoromethoxyphenyl 4-cyano-3-indolylphenyl 0 61 4-aminophenyl 5-cyano-3 -thienyl 0 62 4-dimethylaminophenyl 5-cyano-3-thienyl 0 63 4-ethylphenyl 5-cyano-3-thienyl 0 64 phenyl 5-alkyl_3_σ Desfyl group 0 65 4-hydroxyphenyl 5-aryl group ratio -3-yl 0 66 4-methoxyphenyl 5-cyano-1-methylpyrrol-3-yl 0 67 4-gas- 3-mercaptophenyl 5-nitro D ratio _3·yl 0 68 4-dimethylaminophenyl 5-nitro-pyrrol-3-yl 0 69 5-methylsepenyl 4- Cyano-3-fluorophenyl 0 70 5-decyl-2-thienyl 4-cyano-3-ethylphenyl 0 71 6-isopropyl-3-° ratio octyl 5-cyano-3 -σ塞基基0 72 5-decylsophenenyl 4-cyano-3-methoxyphenyl 0 73 5-methyl-2-nonylphenyl 4-cyanophenyl 0 74 5-ethyl -2-Supplemented 4-ylcyano-3-indolylphenyl 0 75 5 ·ethyl-2·α-sepyl 4-yl-3-fluorophenyl 0 76 6-ethyl·3- Λ Λ 5 5 _ 5 5 5 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77 -Thienyl 0 79 6-II Aminoamino-3-° ratio octyl 5_ carbyl-3-indolyl 0 80 6-amino-3·11 butyl 5-carbo-3-indolyl 0 81 phenyl 2-nitrogen Thiazole-4-yl 0 82 4-ethylphenyl 2-fluorothiathiazole-4-yl 0 83 4-dimethylaminophenyl 2-mercaptothiazol-4-yl 0 84 3-fluoro-4 - mercaptoaminophenyl 2-mercaptothiazol-4-yl 0 85 5-fluorenyl succinyl-2-yl 5-fluoroylpyrrol-2-yl 0 86 5-decylfuran-2- 2-mercaptothiazole-5-yl 0 151494.doc •124· 201120018

Ex. # R1 R2 X Rt (HPLC) [min] MS 87 5-mercaptopurine-2_yl-5-enhanced sigma domain_2-yl group 0 88 5-methyl-brown-2-1 base 5_ Nitrogen-based 2_d-sequenyl 0 89 5-ethyl-2_α-sequenyl 6-disordered π than -3-yl 0 90 5-ethyl-2·α-sepeno 6-random ·5-gas ° ratio -3-yl 0 91 4-gas-5-ethyl-2-thienyl 6-cyano-5-decyloxypyridin-3-yl 0 92 5-ethyl alpha fumon-2 5-cyano-4-indolyl-pyrrole-2-yl 0 93 5-mercapto-2-thienyl-6. Specific -3-yl 0 94 5-decyl-2·α-sequenyl 6-ranyl-5-rat ° bit -3-yl 0 95 5-methyl-2-thienyl 6-nitro- 5-methoxyl ratio _ 3-base 0 96 5-ethyl ketone β-nan-2-yl 5-cyanofuran-2-yl 0 97 5-ethyl-2-thienyl 5--radical- 2-11 Serenyl 0 98 5 · Ethyl-2-α-sepenyl 5-alkyl 11 Fu shing-2-yl 0 99 5-ethyl-2-α-sepeno 2-cyanothiazole-5 -Based on 0 100 5-ethyl-2-α-sentyl 5-cyanoyl ratio °-2-yl 0 101 5-methyl-2-thienyl 5-yl-2-111 thiophene 102 5 · mercapto-2-thienyl 5- chaotic base. Nan-2-yl 0 103 5-methyl-2-11 thiophene 2圭-5_基0 104 5-methyl-2-thienyl 5-cyano-pyrrol-2-yl 0 105 5-ethyl ° 喊 -2--2-yl 6-nitropyrene π Base 0 106 5-ethyl D-furan-2-yl 6-azino-5· disorder ° bite -3 base 0 107 5 · ethyl alpha 喊 -2- 2-yl 6-murine-5-曱Oxygen 11 is more than bite _ 3_yl 0 108 5_ethyl alpha pentan-2-yl 5 - cyclyl-2-suppressyl 0 109 5-decylfuran-2-yl 6 · nitrogen ratio bite -3·基 0 110 5-methylfuran-2-yl 6-murine-5- disorder ° bit-3-yl 0 111 5-methylfuran-2-yl 6-iL-yl-5-methoxy Base ratio bite · 3 · base 0 112 5 · ethyl σ pentan-2-yl 2-cyanothiazole-5-yl 0 151494.doc -125- 201120018

Ex. # R1 R2 X Rt (HPLC) [min] MS 113 3-fluoro-4-methoxyphenyl 4-cyanophenyl S 114 4-aminophenyl 4-mercaptophenyl S 115 phenyl 3-methoxy-4-cyanophenyl S 116 6-methoxypyridin-3-yl 4-cyano-3-fluorophenyl S 117 4-aminophenyl 4-indolyl-3- gas Phenyl S 118 4-methoxyphenyl 5 - gasyl-2- sigma s-yl S 119 4-aminophenyl 4- yl group ° ratio - 2 · group S 120 4-methylphenyl 5 - cyano group. Bior-2-yl S 121 4-epoxyphenyl 3-decyloxy-4-cyanophenyl S 122 4-methylphenyl 4-mercapto-3-fluorophenyl S 123 phenyl 5- gas σ 夫 喘 -3- -3- 基 基 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 125 125 125 125 125 125 125 Base_2·σ-sepenoyl S 127 4-aminophenyl 5-nitro-3-thienyl S 128 4-indolyl 3-methoxy-4-cyanophenyl so 129 4-methyl Phenyl 4-mercapto-3-fluorophenyl so 130 phenyl 5-cyanofuran-3-yl so 131 4-methylphenyl 5-nitro"pyrrol-2-yl so 132 3-fluoro- 4-decyloxyphenyl 4-mercaptophenyl S〇2 133 4-methylphenyl 4-mercaptophenyl S〇2 134 4-aminophenyl 4-cyanophenyl S〇2 135 4 -(methylthio)phenyl 4-cyanophenyl S〇2 136 phenyl 5-mercapto-2-thienyl S〇2 137 4-aminophenyl 5 · thioxenyl S〇2 Example 1. General cell culture maintenance and cell proliferation assay MCF-7 human breast cancer cells Caki-l and A498 renal clear cell carcinoma 151494.doc • 126- 201120018 and PC-3 prostate adenocarcinoma cells were obtained from ATCC (LGC Promochem ). MIA PaCa-2 pancreatic cancer cells were purchased from ECACC (ΗΡΑ Culture Collection). The CellSensor® HRE-bla HCT116 cell line (colorectal cancer) was obtained from Invitrogen. HeLa cervical adenocarcinoma cell line was obtained from Chemical Biology Core Facility (EMBL), 95% air humidified at 37 ° C, 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) : MCF-7; HeLa; MIA PaCa-2; PC-3) growth, the medium supplemented with 10 ° /. Fetal bovine serum (FBS), 100 U/ml penicillin and 100 pg/ml streptomycin and 2 mM L-glutamic acid. Keeping the Caki-Ι cell line under the same atmospheric conditions in McCoy's 5A medium (additions as described above), while containing FBS, penicillin/streptomycin and L-glutamic acid (as above) and Adding sodium pyruvate (1 mM) to Eagle's minimum essential medium (Eagle, s

The A498 cell line was cultured in Minimum Essential Medium) (MEM). The HLT116 cell line was grown in McCoy's 5 A medium under the same atmospheric conditions. The medium was divided by blasticidin as a selection marker (final concentration of 5 pg/ml) and was supplemented as described above. 〇% fbs and penicillin/streptomycin. Cell proliferation experiments were performed in 96-well tissue culture plates in which 2000 cells were seeded per well in 100 μM of relevant medium. The cells were then incubated for 24 h under the conditions and then the compound was added. When the ecm value of the compound was measured, a compound of 5 5% μl 11 Torr in 5 '5% DMSO was added to each well at various concentrations to achieve a final constant percentage of 0.5% DMSO at the desired lx compound concentration. Cells were treated with 5.5% 151494.doc -127- 201120018 DMSO as a positive control. The cells were then incubated for an additional 72 h and then measured. To determine the degree of inhibition of cell proliferation, cells were treated with ATPlite solution according to the manufacturer's instructions (PerkinElmer, ATPlite 1-step Luminescence ATP Detection Analysis System) and illuminated in an Envision HTS Multilabeled Plate Reader (PerkinElmer) according to the established protocol. Luciferase readings were measured. The raw data is entered into the ActivityBase database (IDBS, ID Business Solutions) and the EC50 value is calculated using the IDBS program ActivityBase XE. Reference: EC5〇&lt;100 ηΜ · ++ + 100-500 nM : + + &gt;500 ηΜ : + Instance No. MCF-7 HeLa 1 +++ +++ 2 +-H- +-Η- 3 4 + + 5 ++ -Η- 6 +++ 7 8 +++ +-Η- 9 10 -Η- -Η- 11 +++ -thh 12 +++ 151494.doc •128· 201120018 Instance No. MCF-7 HeLa 13 +++ +++ 14 +-H- +++ 15 -I~H- 16 +++ 17 +++ 18 +++ -H-+ 19 +++ -HH 20 +++ +- H- 21 +++ -H~h 22 +++ -HH- 23 +++ +++ 24 ++ +++ 25 + + 26 +++ +++ 27 +++ +++ 28 ++ + +++ 29 ++10 30 ++ -H- 31 ++ +4- 32 ++ - 34 ++ - 35 + - 36 ++ - 37 ++ - 38 ++ _ 39 ++ 40 + - 41 +++ - 42 ++ - -129· 151494.doc 201120018 Instance No. MCF-7 HeLa 43 - 44 ++ - 45 - 46 -1-++ - 47 +++ - 48 -Η- - 49 ++ - 50 ++ - 51 + - 52 + - Other tumor cell line cell lines 3 9 HeLa +++ +++ MIAPaCa-2 +-H- PC-3 -H-+ +++ Caki-1 +-H- + ++ A498 +++ 2. ER transfection assay Transfection assays were performed using the MCF-7 cell line to determine the effect of compounds on estrogen receptor (ER)-mediated transcriptional activity. The ERE-tk-luc construct coupled to luciferase was obtained from Dr. G. Reid (EMBL). Briefly, MCF-7 cells were maintained as previously described and seeded in 100 μΐ medium at a concentration of 3500 cells/well on the first day of the experiment and incubated for 24 h under standard conditions. After the initial incubation period, 5 ng of ERE-tk-luc construct (per well) and Exgene 500 transfection reagent (Fermentas) were used containing 151494.doc -130 - 201120018 1 50 mM NaCl and 20 mM Tris pH 8.4 Transfection was carried out in the final buffer solution. The plates were then maintained in the incubator under cell culture conditions for 3-4 hours&apos; followed by addition of the compound at 11X concentration to obtain the final desired compound concentration in 0.5% DMSO (in the same manner as the proliferation assay previously described). The degree of inhibition of er_signaling was determined by luciferase reading after 24 h of incubation. The cells were treated with briteliteTM plus solution according to the manufacturer's instructions (PerkinElmer, britelite plus, ultra-high sensitivity luminescence reporter gene analysis system) and measured in the illuminating mode on the Envisi〇n HTS multilabel plate reader (perkinElmer) according to the established protocol. Photozyme containing

Hey. Import raw data into the ActivityBase database (IDBS, ID

In Business Solutions, use the 10 shame program ActivityBase χΕ to calculate IC5. value. Reference: EC5 〇 &lt;100 nM : +++ 100-500 nM : ++ &gt; 500 nM : + Example No. Evaluation 3 9 „ ------- As shown in these experiments, the compounds of the present invention are capable of Inhibition of transcriptional activity mediated by estrogen receptor elements in heart-positive cell lines. The utility of ER-modulators for the treatment of breast cancer, sublingual or sputum cancer, and metastatic bone disease has been known in the literature. References 151494.doc • 131 · 201120018

Park &amp; Jordan (2002) Trends Mol. Med. 8(2): 82-88. Steiner et al. (2001) Urology 57 (4 Zengzi ij 1): 68-72 0 Campisi et al. (1993) Eur J. Gynaecol. Oncol. 14(6): 479-483 ° 3. HIF/HRE Reporter gene analysis The reporter gene cell line stably transfected with CellSensor® HRE-bla HCT-116 from Invitrogen was used to determine inhibition of HIF signaling response induced by chemical treatment under chemically induced hypoxia, as determined by the manufacturer's instructions. . Cells were maintained as previously described and seeded at 15,000 cells/well into a 384-well clear bottom plate (Corning 3712) in 32 μM assay medium (Opti-MEM [Invitrogen], 0.5% FBS, 100 U/ml penicillin, 1 〇〇pg/ml streptomycin, 0.1 mM non-essential amino acid [NEAA], 1 mM sodium pyruvate, 5〇11\4 1^?£8|&gt;117.3]). After incubation of 2 11 , compounds (4 μM) were then added to the cells at a concentration of 10X in 5% DMSO and incubated for 30 min under standard conditions. To induce hypoxic conditions, 4 μΐ 2 mM deferoxamine (DFO) solution was added to the cells, followed by incubation for 24 h under standard analytical conditions (as described above). Control wells included wells containing only medium (no cells) and wells treated with 0.5% DMSO instead of compound. Prior to reading, the substrate loading solution was prepared as described in the manufacturer's protocol and 10 μM was added to each well. After 2 h of incubation, at room temperature and in the dark at two wavelengths (blue channel: excitation wavelength 409 nm, emission wavelength 460 nm; green channel: excitation wavelength 409 nm, emission wavelength 151494. Doc -132· 201120018 530nm) Fluorescence was measured on a PerkinElmer Envision HTS. At the time of analysis, the average signal of cell-free pores at 46〇 nm and 530 nm was subtracted from the blue and green channel data. The blue/green emission ratio of each well is then calculated by dividing the background corrected blue emission value by the background corrected green emission value. IC50 values were determined from these ratios using GraphPad Prism (Prism 5, GraphPad Software Corporation). Reference: EC5〇&lt;100 nM : +++ 100-500 nM : ++ &gt;500 nM : + instance number evaluation 1 +++ 2 +++ 3 -H-+ 4 ++ 5 ++ 6 ++ + 7 +++ 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 15l494.doc -133 · 201120018 Instance number evaluation 18 +++ 19 20 +++ 21 +++ 22 +++ 23 +++ 24 +-H- 25 + 26 +-M- 27 -HH- 28 -H-+ 29 ++ + 30 ++ 31 ++ 34 Ή - The results of these experiments show that the compounds of the invention are capable of inhibiting the transcriptional activity of hypoxia regulatory elements under hypoxic conditions. The compounds of the invention have no other benchmarks (eg, compound PX-478 or LNA (locked nucleic acid) antisense construct EZN-2968; both entities are currently the only known HIF inhibitor products in clinical development phase I) The size of the performance. 4. Caspase-3/7 analysis The activation of the caspase-3/7 signal after treatment with the test compound was carried out using the caspase-Glo® 3/7 kit (Promega). Briefly, HeLa cells were seeded at a concentration of 1000 cells/well in 50 μM medium into 96-well plates and incubated for 24 h under the conditions previously described. Compounds (〇 5% DMSO at all final concentrations) were then added to each well at various concentrations of 151494.doc -134- 201120018 and incubated for an additional 24 h. The plates were then removed from the incubator and equilibrated to room temperature. After adding 50 μM of caspase_G1〇 reagent to all wells, the plates were shaken at 300 rpm for 30 s and after 3 min of incubation. Luminescence was measured on an Envisi〇n HTS (PerkinElmer). Reference: EC5〇&lt;100 nM : +++ 100-500 nM : ++ &gt;500 nM : + Example No. Evaluation 1 -H-+ 3 +-H- 6 -H-+ 9 + Section 11 -H- + 19 -H-+ After treatment with the compound of the present invention, a significant activation of the caspase_3/7 response was observed, indicating a major factor in the observed decrease in cell proliferation caused by the mechanism of action of the apoptotic compound. . 151494.doc 135-

Claims (1)

201120018 VII. Patent application scope: 1. 2,3-dihydroanthracene compound of formula (1), 〇=S=〇θα where X R1 is 0 or heart 〇)&quot;, where η is Ο, 1 or 2; The base of this group or C combined with the star Wang Meng # g L,, a; 5 set aside # early %, 5 or 6 members of the heteroaryl, which stupid early ring 5 or 6 members of the short a group of undoped or unsubstituted or having one, two or three identical or different groups rU; Rla is selected from the group consisting of 团 ^ 团, cyano, νο2, 丽, OH, SH , C Γ pr pr Cl_Ci ❶-alkyl, C2-ClQ-alkenyl, L2-Li〇-alkynyl, « ¥ . 6-alkoxy, G-cv alkylthio, Schiff-CVCV alkyl, c p Cl'C4_院 K基-cvc4-alkyl, fluorinated C丨-c2-alkyl, ^rrmR3 4 SF5, fluorinated C丨-c2-alkoxy, C(〇)R3, NR4R5, N 6 (0R)R and C(〇)〇R8, or bonded to the adjacent carbon powder early', the two groups RU can also form a bridged OO-Alk-O, which is composed of Λ , , , Alk is selected from CH2 CH2CH2, CHF and CF2; a phenyl or C or N-bound monocropping 5- or 6-membered heteroaryl group, wherein the base is early ring 5 Or 6 members of the heterocyclic group V have a CN group and may additionally carry 1, 2 or 3 identical red p2a phases or different groups R2a; R is selected from the group consisting of &lt;fresh.halogen, Cyano, N02, 151494.doc 201120018 NH2, OH, SH, (:, -(:!〇-alkyl, (VC, .-alkenyl, C2-C1G-alkynyl, CVCe-alkoxy, Q-) CV alkylthio 'hydroxy-CVCV alkyl, (: 〗 - (: 4 · alkoxy 4-C4 · alkyl, fluorinated Ci-C) - alkyl, SF5, fluorinated Ci-CV alkoxy, C(0)R3, NR4R5, N(OR6)R7 and c(〇)〇r8, or two groups R2a bonded to adjacent carbon atoms may also form a bridging moiety O-Alk'-O, wherein Aik, From CH2, CH2CH2, CHF and CF2; r3 is cvcv alkyl; R is hydrogen or CVCV alkyl; R5 is cvc6•院基, 经基_c2_c6_Hyun, Crk alkoxy-C2_ R4 R6 R7 R8 C4- An alkyl group or a group C(0)RX, wherein rj^Ci_c4 alkyl; or R together with the nitrogen atom to which it is bonded form an N-bonded 5- or 6-membered saturated nitrogen heterocycle; hydrogen or C, -C6- Alkyl; hydrogen or CVC6-alkyl; hydrogen, cvcv fluorenyl, thiol-C2_C6•alkyl or alkoxy-C2-C4-mercapto; And of the salts can be accessed, and (if ^ 1 and r2 of - or both based membered nitrogen containing heteroaryl s) acceptable salt thereof and oxides such N_ N- oxides. 2. 3. Two::, where R, is unsubstituted or has a phenyl group of 1, 2 or different groups of Rh or 6 members as claimed in item 2 of the I &amp; mussels base.呗2 compound, of which Rl 151494.doc 201120018 # Ar1 where # represents an attachment point to the S〇2 group, K system ~ or C-R11, L system or c-R12, Μ system or c-R13, wherein R, R12 and R13 are independently of each other hydrogen义之—^ L and VIII have a compound containing 4, such as the compound of claim 3, the group: ... is selected from the base R1 of the formula AmArl. Arl.l Arl .5 and wherein R11, R12 and R13 are Arl.4 wherein # represents an attachment point to the S〇2 group, which is independently hydrogen or has one of the meanings of Rh given. 5. The compound of claim 3 or 4, wherein r 11 , u J 3 are, if present, independently of one another selected from the group consisting of 151494.doc 201120018 hydrogen, halogen, OH, CN, SH, CVC4 alkyl , C2-C4-alkenyl, C2-C4-alkynyl, CVC4-alkoxy, CrCV alkylthio, fluorinated fluorenyl-alkyl, fluorinated Cl-alkoxy, NH2, NR4R5, hydroxy-Ci- C4-alkyl and (VC4-alkoxy-CVCV alkyl; R if present) are selected from the group consisting of hydrogen, halogen, OH, SH, CN, N〇2, (:丨-(:4 alkane) Base, C2-C4 alkenyl, c2-c4 alkynyl, C1-C4-alkoxy, C1-C4-sulfuryl, IL-Ci-C2-alkyl, SF5, fluorinated CVC2-alkoxy, NH2 , hydroxy-CVC4-alkyl, Ci-C4-alkoxy-(VC4-alkyl, C(0)R3, NR4R5 and C(0)0R8; or, if K is C-R11 and L is C-R12 And R11 and R12 may together form a partial group O-Alk-O, wherein Aik is selected from the group consisting of CH2, CH2CH2, CHF and CF2. 6. The compound of claim 4, wherein R is a formula Arl.l or Arl. A group of claim 6, wherein the compound of claim 6 wherein R&quot; is selected from the group consisting of hydrogen, halogen, hydrazine H, hydrazino, and second defeat Anthracenyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy; R12 is selected from the group consisting of halogen, hydrazine H, SH, CN, N〇2, Ci-C4 , C2-C4 dilute group, C2-C4 alkynyl group, Ci-Cr alkoxy group, C--C4_sulfuryl group, Dunhua C!-alkyl group, SF5, fluorinated C1-alkoxy group, NH2, hydroxyl group- (VC4-alkyl, CrCV alkoxy-C1-C4-alkyl, C(0)R3 and NR4R5; or, if K is C-R&quot; and L is C-R12, then Rn and R12 may also be together 151494.doc -4- 201120018 The moiety "lk_0, which is derived from eH CHF and CF2; 2 CH2CH2, and if r13 is present, is hydrogen. 8. If the compound of item i is found, one or three are the same or different The group of the combination of the member of claim 8, wherein R1 is a group having the formula: Ε or # A, G, E (Ar2) (Ar2.) where # represents the attachment point of the R1 and S〇2 groups, 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 〇, S or NR丨8, G· is 〇, S or N-R19, wherein R, R15, R16 and R17 are independently of each other hydrogen or have the meaning given One, and wherein Ri« and Ri9 are selected from the group consisting of ruthenium, osmium, NH2, OH, CVC. -alkyl, c2_CiG_dilutyl, c c1 〇-alkynyl, Cl-C6-alkoxy'-based alkyl, ke-C2-C4-alkyl, fluorinated CVC2-alkyl, fluorinated Ci_c2_ Oxygen _ C(0)R3, NR4R5 and C(0)0R8. 10. The compound of claim 9, wherein R1 is selected from the group consisting of the formula: ^2 a, 2 151494.doc 201120018 Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2_9 , Ar2.10, Ar2.11, Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.l, Ar2,.2 , Ar2, .3, Ar2, .4, Ar2'.5, Ar2'.6, Ar2,.7, Ar2'.8, Ar2'.9, Ar2,.10, Ar2'.ll and Ar2'.12 Group: Ar2.1 Ar2.2 Ar2.3 Ar2.6 Ar2.9 71R Ar2.10 Ar2.11 Ar2.12 I5l494.doc -6- 201120018 8 n-mr Ar2.13 Ar2.14 Ar2.15 Ar2.16 Ar2.17 Ar2.18 Ar2.19 Ar2'.l Ar2'.2 Ar2V # R15 # R15 N ri^〇.N R14,, s. Ar2,.4 Ar2,.5 # R15 w R N I 19 R19 Ar2'.6 # R Ar2'.7 Ar2'.8 Ar2'.9 151494.doc 17 201120018 Ar2'.12 Ar2'.l〇 Ar2'.ll where # represents the attachment point of the R1 and S〇2 groups, wherein R14 and R15 have the meaning. R16 R 17 R 8 and R 9 have the compound of claim 9 or 10, wherein R14, if present, is hydrogen; if R15 is present, hydrogen; and if present, R16 is selected from the group consisting of Group of constituents: hydrogen, halogen, hydrazine, SH, CN, N02, CVC4 phenotype, C2_C4 dilute, C2_Cj radical, CVC4-homoyloxy, CVC4-sulfuryl, fluorinated Ci-alkyl, fluorinated CV Oxyloxy, NH2, thiol-Cl_C4_homolyl, Ci_c4_alkoxy-Ci-C4-alkyl, c(o)r3 and NR4R5; if present, R7 is selected from the group consisting of hydrogen, Halogen, OH, SH, CN, N〇2, C]-C4 alkyl, c2-C4 dilute, c2-C4 alkynyl, CVC4-alkoxy, C^-Cr alkylthio, fluorinated Cl_ Base, gasification C]-alkoxy, NH2, hydroxy-CrCV alkyl, Ci-C4-alkoxy-C丨-C4-alkyl, C(0)R3 and NR4R5; 18 R If present, select Free group of the following components: hydrogen, CN, C!-C4 alkyl, C2-C4 dilute, C2-C4 alkynyl, gasified C,-dishyl, Ci-C4_alkoxy-C2_C4_alkyl and By a radical -C2-C4; and if present, Rl9 is selected from the group consisting of hydrogen, CN, c--c4 151494.doc 201120018 alkyl, c2-c4 olefin a group, a c2-c4 alkynyl group, a fluorinated cv alkyl group, a c, a C4-alkoxy-C2-C4-Hyun group, and a trans-C2-C/J-dish group. 12. The compound of claim 1, wherein R1 is selected from the group consisting of phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl Oxyphenyl, 4-hexylphenyl, 4-methylphenyl, 4-methoxyoxyphenyl, 4-trifluoromethylphenyl, 4·trifluoromethoxyphenyl, 4-hydroxyl Phenyl, 4·gasphenyl, 4-(indolyl)phenyl, 4-nonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-aminophenyl, 4·nitrate Phenyl, 4-(dimethylamino)phenyl, 3-fluoro-4-indolyl-phenyl, 3-fluoro-4-indolylphenyl, 3-fluoro-4-methoxy Phenyl, 3-hydrazino-4-fluorophenyl, 4-vapor-3-cyanoindolyl, 4-carboxyindolyl, 3,4-dicyanophenyl, 3-methyl-4-cyano Phenyl, 3-fluoro-4-cyanophenyl, 3-methoxy-4-ylcyanophenyl, 3-hydroxy-4-ylcyanophenyl, 3,5-difluoro-4-cyanylphenyl , 4_pentafluorothiophenyl, 3-pyridine, 4-pyridyl, 5-cyanopyridine-3-yl, 6-isopropylpyridine·3-yl, 5-ethynylpyridine-3-yl, 5 -fluoropyridine·3_yl, 5·bromopyridine-3-yl, 5-methoxypyridin-3-yl, 5·trifluoromethoxypyridine _3_yl, 5•indenyl 咐^ D--3-yl, 6-ethyl acridine-2-yl, 5-trisylmethylpyridinyl, 6-aminopyridin-3-yl, cyanopyridine-3-yl, 6-fluoropyridine 3_ base, 6_ gas port ratio bite-3-yl, 6-mercapto D ratio bite 3_ base, 6-methylthio group π bite _3_ group, ^ trifluoromethyl pyridin-3-yl, 6 —Methoxypyridine·3—yl, 6•ethoxypyrid-3-yl, 6-difluorodecyloxy. Pyridinyl-3-yl, 6-didecylaminopyridyl small group, 2-fluoroindole. 4-yl, 2-cyanopyridine-4-yl, 2-nonylpyridine-4-yl, 2-decyloxy-4-yl, 2-trifluoromethyl. Ratio _4_ base, 2_trifluoromethoxypyridine-4-yl, 5-cyano-4-methylpyridine·%, 2 cyano winter 151494.doc •9- 201120018 thiol D ratio. -4 -yl, 6-alkyl-5 - group by base -3 - group, ♦ ° -5 -yl, 2-indolylthiopyrimidin-5-yl, 2-trifluoromethoxy Pyrimidin-5-yl, 5-methoxy-indolyl-3-yl, 5-methyl ol. Qin-3-yl, 5-gas is inferior to Qin-3-yl, 5-azinosin-3-yl, and sulphate-South-2-based. °南-3-yl, 5-methyl-fufu-2-yl, 5-cytylmethyl-pyran-2-yl, 3-azyl-pyran-2-yl, 5-nitro. Fu-2-yl, 2-π-septenyl, 3-terenyl, 5-methyl-2-π-septenyl, 5-ethyl-2-thiophenyl, 5-cyano-2- Thienyl, 4-cyano-2-thienyl, 5-methyl-3-thienyl, 5-cyano-3-thienyl, 4-cyano-3-thienyl, 5-hydroxymethyl-3 -. Steenyl, 5-dihydroxyloxy-3-thyloxy, 5-ethylidene-2-betathiophene, 4-air-5-ethyl-2-alphathiophene, 5- Nitrogen-4-murine-2-αsecenyl, 1 ·nonylpyrrol-2-yl, 1-indolyl-5-hydroxypyrrol-3-yl, 1-methylpyrazole-3-yl, 1 -methylpyrazol-4-yl, 1-ethylpyrazol-4-yl, 1-oxo-pyrazol-4-yl, 1-nonylimidazol-4-yl, 1-methylimidazole-5 -yl, 1,2-dimethylimidazolyl-4-yl, 1,2-dimercaptoimidazole-5-yl, 4-methylthiazol-2-yl, isothiazol-3-yl, isothiazole-4 -yl,isothiazol-5-yl, 5-mercaptoisothiazol-3-yl, 3-mercaptoisothiazol-5-yl, 5-mercaptoisothiazol-3-yl, 3-cyanoisothiazole- 5-yl, 2-methyloxazol-5-yl, oxazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 4-mercapto-1,2,3-thiadiazol-5-yl, 5-mercapto-1,2,3-thiadiazol-4-yl, 4-cyano-1,2,3-thiazide Diazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 5-cyano-1,3,4-thiadiazole- 2-yl, 5-cyano-1,3,4-oxadiazol-2-yl, 5-mercapto-1,3,4-oxadiazol-2-yl, 5-methyl-1,3 , 4-thiadiazol-2-yl, 1,2,4-[4Η]triazol-3-yl, 1,2,3, 4-tetrazol-5-yl and 2-methyl-1,2,3,4-tetraxyl-5-yl. 151494.doc -10- 201120018 13. 14. A compound of any of the preceding claims, wherein R 2 is a phenyl or 6 membered heteroaryl having a CN group and may have an additional Or 2 identical or different groups R2a. Such as the compound of claim 13, wherein the group of the R2 system αγ3 Where # denotes the attachment point to the imming core of (I), κ' 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 are each independently hydrogen or have one of the given meanings of R2a, and one of the conditional variables K', L' or M', or both are C - CN 〇15. The compound of claim 14 wherein R2 is selected from the group consisting of the formulas Ar3.i, Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, The groups of Ar3.9, 八^.1〇, 犷3.11 and 犷3.12, 151494.doc -Π · 201120018 Ar3.4 Ar3.1〇 where # denotes the attachment point of the imming core with (1), and wherein Ar3.11 Δ Ar3.i2 R23 is hydrogen independently of each other or has the given R2a shy I&lt;-, stripe R21 One of R22 or R23 is CN. The compound of claim 14 or 15, wherein R 21 R, if present, is independently selected from the group consisting of hydrogen, halogen, OH, CN, methyl, decyloxy, difluoromethyltrifluorofluorene a group, a difluoromethoxy group and a trifluoromethoxy group; if present, R22 is selected from the group consisting of hydrogen, halogen, OH CN, methyl, methoxy, dimethoxymethyl, trisylmethyl , difluorooxyl and trifluoromethoxy; 151494.doc •12· 201120018 Conditional group R2 1 or one of R22 or R23 is CN. 17. The compound of claim 15 or 16, wherein the R2 group is Ar3丨 or Ar3.3. 1 8. A compound according to δ, wherein R22 is CN, and wherein R21 and R are independently of each other selected from the group consisting of hydrogen, halogen, hydrazine, CN, fluorenyl, methoxy Base, difluoromethyl, trifluoromethyl, difluoromethoxy and dioxo imethoxy. The compound according to any one of claims 1 to 2, wherein R2 is a member of the heteroaryl group which has a CN group and may additionally carry one or two identical or different groups R2a. 20_ The compound of claim 19, wherein the R2 group is a group of Ar4, Ar5 or Ar6 Αγ4 Αγ5 Ar6 where # represents the attachment point of R2 and (1) of the cultivating core, Α system or C-R24, N or C-R25, D system N or C-R26, E system N or C-R27, G Is a 0, S or N-R28, G' system, S or N-R29, wherein R24, R25, R26 &amp; R27 are each independently hydrogen or have one of the meanings of the given rule 23, and wherein the ruler 28 and Ruler 29 is selected from the group consisting of 151494.doc • 13- 201120018 hydrogen, cyano, NH2, hydrazine H, CrCw-alkyl, C2-C1()-alkenyl, C2-C 1 0 -fast radical, C 1 - C 6 -alkoxy, mercapto-c 2 _ C 6 -hungyl, c 1 -C 4 -hine (oxy-C2-C4-alkyl, fluorinated CVC2-alkyl, fluorinated alkoxy And C(0)R3, NR4R5 and C(0)0R8, wherein the formula Ar4 and Ar6_8 or D or E is C-CN. 21. The compound of claim 20, wherein R2 is selected from the group consisting of Ar4. 1. Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.11, 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 Group of Ar6.3 Ar4.3 Ar4.1 Ar4.2 24 # RI o R r 27 Xs 27 Ar4.4 Ar4.5 Ar4.6 Ar4.7 Ar4.8 Ar4.9 151494.doc • 14· 201120018 R24 # .N 6 2 R R24 o # tN 6 2 R s Ar4.12 26 Ar4.10 Ar4.11 N-N N-N N-N 28 Ar4.13 Ar4.14 Ar4.15 # R 25 # R 25 R24^^s&gt;^CN R24 # R R 29 Ar5.1 Ar5.2 Ar5.3 Ar5.4 Ar5.5 Ar5.6 # FT Ar5.9 Ar5_7 Ar5.8 151494.doc -15- 201120018 Where # represents the attachment point of the imming core of R2 and (I), wherein R24, R25, R26, R27, ruler 28 and r29 have the meanings given in claim 2, and wherein the formulas are Ar4.1, Ar4 .2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.ll, Ar 4.12, Ar4.15, Ar6.1 R24 or R26 or R27 in Ar6.2 and Ar6.3 is CN. 22. The compound of claim 20, wherein R2 is selected from the group consisting of the groups Ar4.1, Ar4.2, Αγ4.3, Αγ4·4, Ar4.5, Ar5.1, Ar5.2, Ar5.3, Ar5.7 And Ar. 5.8. The compound of claim 2, 21 or 22, wherein R24, if present, is selected from the group consisting of hydrogen and cyano; and R25, if present, is selected from the group consisting of hydrogen and halogen; If present, is selected from the group consisting of hydrogen, halogen, hydrazine, CN' fluorenyl, decyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy; 7 R, if present, is selected from the group consisting of hydrogen, halogen, hydrazine, CN, fluorenyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy ; 2 8 R , if present, is selected from the group consisting of hydrogen, alkyl, CVC 4 alkenyl, C 2 -C 4 alkynyl, CVC 4 alkoxy, fluorinated C!-alkane 151494.doc I 201120018 base, fluorine Alkoxy, c^cu-alkoxy·(:2_(:4_alkyl and hydroxy-C2-C4 alkyl; if present, R29 is selected from the group consisting of hydrogen, d_c4 alkyl, c2 -c4 dilute base, c2_c4 alkynyl group, Ci_c4•院oxy, And a compound of any one of claims 1 to 12, wherein R2 is selected from the group consisting of C.sub.1, alkoxylate, CVC4-alkoxy-cvcv-alkyl, and hydroxy-C2-C4 alkyl. a group consisting of 3-cyanophenyl, 4-cyanophenyl, 4-cyano-3-fluorophenyl, 4·cyano-3-phenylphenyl, 3,4-dicyanophenyl , 3-methyl-4-cyanophenyl, 3-ethyl-4-ylcyanophenyl, 3-methoxy-4-cyanophenyl, 3-hydroxy-4-ylphenyl, 3 , 5-difluoro-4-cyanophenyl, 3-vapor-4-cyanobenzoquinone 5 oxy-bite-?-yl, 5-suppressed β 唆·3-yl, 6-nitrogen Specific bite - 3 · group, 6-cyanopyridine 2 -yl, 4-cyanopyridin-2-yl, 2-cyanopyridin-4-yl, 5-cyano-6-decyloxypyridine-3 -yl,6-cyano-5-fluoropyridin-3-yl, 5·cyano-3-fluoro-4-methoxy&quot;bipyridin-2-yl, 5-cyano-4-fluoropyridine- 2_yl, 5-cyano-4-methylpyridin-2-yl, 2-cyano-6-methylpyridin-4-yl' 6-cyano-5-hydroxypyridin-3-yl, 5- Cyanopyrimidin-2-yl, 2-cyanothiocyanyl, 2-cyanopyrimidin-5-yl, 6-cyanopyrimidin-4-yl, 5-cyano Qin 2, 5-n-yl- 6-fluorol ratio 嘻-2-yl, 5-cyano ox-3-yl, 6-nitro group Pyrazin-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-Qinyl, 3-disorganized β-pentan-2-yl, 5-cyano-β-pentan-2-yl, 4-cyano Keefnan 2 base, 2-disindolyl-3-yl, 5-cyano11f-anthracene, 5-cyano-4_gofan-2-yl, 5-cyano-4 -chlorofuran-2-yl, 3-cyano-2-thia 151494.doc -17· 201120018 phenyl, 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-ox-2-thienyl, 3-cyanopyrrole- 1-Based, 3-cyano-4-mercaptopyrrolidin-1-yl, 4-cyano group. Bior-2-yl, 5-cyanoquinol-2-yl, 3-cyano-1-methylpyrrol-2-yl, 1-methyl-5-cyanopyrrol-2-yl, 1- Mercapto-4-yl group 0 to each 2-yl, 5-iso-group-4-methyl-α, bis--2-yl, 1-methyl-2-disorganopyrrol-3-yl, 5-cyano-pyrrol-3-yl, 1-methyl-5-cyanopyrrol-3-yl, 2-cyanooxazol-4-yl, 2-cyanooxazol-5-yl, 2- Cyanoimidazolyl-4-yl, 2-disorganized β-m-β-s--5-yl, 2-n-yl-1 -indolyl-α-α-s--4-yl, 4-oxylimidin-1-yl, 2 -Cyano-1-methylimidazolium-5-yl, 2-cyanothiazol-4-yl, 2-cyanothiazol-5-yl, 4-cyanooxazol-2-yl, 5-cyano Zyridin-2-yl, 4-mercapto[deg.] m. 2-yl, sit-2-yl, 4-aryl-1-methylimidazol-2-yl, 5-cyano-1-indolyl imidazole -2-yl, 5-cyanothiazol-2-yl, 4-cyanothiazol-2-yl, 3-cyanoisoxazole-5-yl, 5-cyanoisoxazole-3-yl, 3 - cyanoisothiazol-5-yl, 5-cyanoisothiazol-3-yl, 3-cyano, ratio -5-yl, 5-nitro-D ratio. Sitting -3 -yl, 3-disorganized -1 - fluorenyl alpha is more than 11 -5 -yl, 5-carbonyl-1 -methylpyrene ratio. Sitting -3 - base, 3 - gas base ° ° sitting -1 - base, 4 - aperture π ratio 0 sitting -1 - base, 3-gas radical - 4 gas ** than β sitting -1- base, 3-nitro-4-chloro 1 ntb wow-1 -yl, 5-cyano-1,3,4-oxadiazol-2-yl, 5-cyano-1,3,4-thiadiazole- 2-Based, 5-cyano-1,2,4-triazol-3-yl, 5-cyano-4-indolyl-1,2,4-triazol-3-yl. The compound according to any one of the preceding claims, wherein X is oxime. The compound of any one of the preceding claims, wherein X is S, SO or S02. 151494.doc • 18- 201120018 27. The compound of claim 1 which is selected from the group consisting of 5-(4-methylsulfonyl-3,4-dihydro-2H-benzo[bni,4]oxazine-6 · thiophene-2-carbonitrile, 4-(4-(3,fluoro-4-indolylphenyl)-3,4-dihydro-2H-benzo[b][l,4] ° ° ° Qin-6-yl)benzonitrile, 4-(1 2-(3-fluoro-4-methoxyphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l , 4]oxazin-6-yl)benzonitrile, 4-(4-(4-nitrophenyl lanthanyl)-3,4-dihydro-2H-benzo[b][l,4]° Ester. Qin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H·benzo[13][1,4] cacao- 6-yl)benzonitrile, 4-(4-(4-methoxyphenyl hydrazino)-3,4-dihydro-2-indole-benzo[b][1,4]cato-6-yl) Nitrile, • 19-1 (4-indolylsulfonyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl) nitrite, 2 (4-( 3-fluoro-4-methylphenylsulfonyl)·3,4-dihydro-2H-benzo[bKl,4]oxazin-6-yl)thiophene-2-carbonitrile, 5-(4- (3-Gas-4-methoxyphenylsulfonyl)_3,4·dihydro-2H_benzo[b][l,4]caco-6-yl)thiophene-2-carbonitrile, 4 - (4-(6-decyloxyacridin-3-ylsulfonyl)_3,4·2 Hydrogen·2H_benzo[b][l,4]oxazin-6-yl)benzonitrile, 5-(4-(6-decyloxy.pyridinyl-3-ylsulfonyl)_3,4· Dihydro·2H_benzo[b]|l,4]°oxazine-6-yl)N-phenan-2-carbonitrile, 5-(4-(6-methyl.pyridin-3-ylsulfonate) ))·3,4-dihydro-2H-benzo[b][ 1,4] 151494.doc 201120018 恶-6-yl) ° phen-2- carbonitrile, 5-(4-(4- (didecylamino)phenylphenyl)-3,4-dihydro-2H-indigo[b][l,4]oxazin-6-yl)thiophene-2-carbonitrile, 4- ( 4-(4-(didecylamino)phenylsulfonyl)_3,4·dihydro-2H-benzo||gt; 1,4]oxazin-6-yl)benzonitrile, 5- (4 -(2,3-dihydrobenzo[b][l,4]dioxenylsulfenyl)-3,4-dihydro-2H-benzo[b][l,4] Pyridin-6-yl)thiophene-2-carbonitrile, 5-(4-(4-fluoro-3-methylphenyl hydrazino)·3,4-dihydro-2H-benzo[b][l , 4] oxazin-6-yl) porphin-2-carbonitrile, 2-methoxy-4-(4-indolyl benzoyl-3,4·dihydro-2H-benzo[b][ 1,4]oxan-6-yl) nitrite, 4-(4-(3-fluoro-4-mercaptophenylsulfonyl)·3,4·dihydro-2H-benzo[b][ l,4]oxazin-6-yl)-2-methoxybenzonitrile, 4-(4-(3-fluoro-4-methoxyphenyl continued) Base)_3,4_dihydro-2h_benzo[b][l,4]oxazin-6-yl)_2-methoxybenzonitrile, 4-(4-indolylsulfonyl-3,4 -dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiophene-2-carbonitrile, 4-(4-(4-decyloxyphenylsulfonyl)-3, 4-dihydro-2H-benzo[b][1,4] 嘻-6-yl)β-cephen-2-pyrene, 2,3-carbo-4-[(4-mercaptophenyl) ) 醯 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] _Benzo[b][1,4]thiazin-6-yl)benzonitrile, 4 [4 (4-methoxybenyl)-based _3,4_dihydro-2H-stupid[b] [i 4]Sigh 151494.doc -20- 201120018 azine-6-yl) nitrite, 4·[4_(6·methoxypyridine-3-yl)sulfonyl-3,4-dihydro·2Η_ Benzo[b]H,4]thiazine-6-yl)benzonitrile, 4·[4_(6·(4-morpholinyl)pyridyl)indolyl-3,4-dihydro-2-indole-benzene And [b][l,4]thiazide_6_yl)benzonitrile, 5-[4-(3-fluoro_4_methoxyxanthine) sulfonyl-3,4-dihydro-2H -Benzene [匕1'4]. Plug noise-6-yl) porphin_2_carbonitrile, 5-[4-(5-methyl-2-thienyl) dimethyl sulfanyl group, 34 dioxin, 2h thiazol-6-yl) thiophene_2 _曱Nitrile, LJ 5-[4·(4-Phenylphenyl)sulfonyl·3 + , 丞^4-一虱-2Η-本开[b][i,4]thiazide-6-yl) Thiophene-2-indene nitrile, yl-1-oxo-yl-3,4-dihydro-2H-benzene 4·[4_(4-decyloxy)sulfonyl[b][l,4]thiazide Pyridin-6-yl)benzonitrile 4_[4-(4. methoxyphenyl) continued fluorenyl + dioxy ion Μ 二 二 2η benzo[b][l,4]thiazine_6_ Benzobenzonitrile, a pharmaceutically acceptable nectar thereof ^ &lt; Ν Ν Ν-oxide and a pharmaceutically acceptable salt of the oxime _ oxide. 28. The compound of claim 1 which is selected from the group consisting of 2-methoxy-4-(4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2-indole_benzo[b ][l,4]oxazin-6-yl)benzonitrile, 4-(4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzoindole, 4]oxazine_ 6-yl)-2-decyloxybenzonitrile, 2-methoxy-4-(4-(4-methoxyphenylsulfonyl)_3,4·dihydro-2H_benzo[b] U,4]oxazin-6-yl) nitrite, 151494.doc •21 · 201120018 4-(4-(4-Aminophenylsulfonyl)_3,4-dihydro-2H-benzo[b] ][l,4]oxazine-6-yl)-2-nonyloxybenzonitrile, 4-(4-(4-mercaptophenylsulfonyl)-3,4-dihydro-2H-benzo[ 1)][1,4]oxazin-6-yl)-2-methoxyoxynitrile, 2-methoxy-4-(4-(4-(indolylthio)phenylsulfonyl)_3 , 4_Dihydro-2H-indigo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(4-ethylphenylsulfonyl)-3,4-dihydrogen -2H-benzo[b][l,4]oxazin-6-yl)-2-methoxyoxynitrile, 2-methoxy-4-(4-(4-(trifluoromethoxy)) Phenylsulfonyl)_3,4_dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl) )_3,4·Dihydro-2H-benzo[b][l,4]oxazine·6- Thiophene-2-carbonitrile, 4-(4-(4-(dimethylamino)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine- 6-yl)thiophene-2-carbonitrile, 4-(4-(4-ethylphenylsulfonyl)-3,4-dihydro-2H-benzo[1&gt;][1,4]oxazine -6-yl)thiophene-2-carbonitrile, 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl) Thiophene-2-carbonitrile, 4-(4-(4-hydroxyphenylsulfonyl)-3,4-dihydro-2H-benzo[1)][1,4]oxazin-6-yl) ·1. Η-° ratio of each 2-carbonitrile, 4-(4-(4-methoxyphenylsulfonyl)-3,4-dihydro-2Η-benzo[b][l,4 Oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile, 4-(4-(4-carb-3-cyanophenylsulfonyl)-3,4-dihydro- 2H-benzo[b][l,4]oxazin-6-yl)-1Η-pyrrole-2-carbonitrile, 151494.doc -22- 201120018 4-(4-(4-(dimethylamino) )phenylsulfonyl)-3,4-dihydro-2H-benzopyrene][1,4]°Evil °Q-6-yl)-111-° ratio 曱-2-曱carbonitrile, 2- Scrambled 4-(4-(5-mercaptophenan-2-yl fluorenyl)-3,4-diazo-2H-benzo[ΜΗ,4]oxazin-6-yl)benzonitrile, 2 -ethyl- 4-(4-(5-fluorenyl-α-sept-2-yl)-3,4-diazo- 2H-benzo[ b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(6-isopropylpyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[ b][l,4]oxazin-6-yl)thiophene-2-indonitrile, 2-methoxy-4-(4-(5-nonylthiophen-2-ylsulfonyl)-3,4 -dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzonitrile, 4-(4-(5-methylthiophen-2-ylsulfonyl)-3,4- Dihydro-2H-benzo[b][l,4] ° ° °-6-6-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][l,4]oxazin-6-yl)-2-fluorobenzonitrile, 4-(4-(6-ethyl). Bispin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[bHl,4]oxazin-6-yl)thiophene-2-carbonitrile, 2-air-4-(4- (5-ethyl π-cephen-2-yl sulphate)-3,4-diazo-2 Η-benzoquinone* [b][l,4]oxazin-6-yl)benzonitrile, 4- (4-(.pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiophene-2-indrene, 4 -(4-(6-(didecylamino).pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6- Thiophene-2-carbonitrile, 151494.doc -23- 201120018 4-(4-(6-Amino)pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[ b][l,4]. Evil. Qin-6-base). Phenyl-2-carbonitrile, 4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiazole-2 -carbonitrile, 4-(4-(4-ethylphenylsulfonyl)_3,4-dihydro-2H-benzo||gt;][1,4]oxazin-6-yl)thiazole-2 -carbonitrile, 4-(4-(4-(dimethylamino)phenyl)-]3,4·dihydro-2H-benzo[b][l,4]oxazin-6-yl Thiazole-2-carbonitrile, 4-(4-(3-fluoro-4-(methylamino)phenylindolyl)_3,4_dihydro-2H-benzo[b][l,4 Oxazin-6-yl)thiazole-2-carbonitrile, 5-(4-(5-methyl)-propan-2-ylindole)-3,4-dihydro-2H-benzo[b] ][l,4]oxazin-6-yl)-1Η-»bibromo-2-carbonitrile, 5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-di Hydrogen-2H-benzo[b][l,4]oxazin-6-yl)thiazole-2-carbonitrile, 5-(4-(5-methylfuran-2-ylsulfonyl)-3, 4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)furan-2-carbonitrile, 5-(4-(5-methylfuran-2-ylsulfonyl) -3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiophene-2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonate) Mercapto)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)pyridine-2-carbonitrile, 5-(4-(5-ethylthiophene-2) 3-sulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-3-fluoropyridine-2-indrene, 5-(4-(4) -gas-5-ethyl °ephen-2-yl hydrazino)_3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-3-decyloxy比bipyridine-2-carbonitrile, 151494.doc • 24- 201120018 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yl)-3-methyl-1H-pyrrole-2-indonitrile, 5-(4-(5-nonylthiophen-2-ylsulfonyl)-3,4 - Di-argon-2H-benzo[b][l,4] ° ° ° _ 6 -yl)D ratio.定-2 - Acha, 3-fluoro-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] Oxazin-6-yl)acridin-2-indrene, 3-decyloxy-5-(4-(5-methylthiophen-2-ylsulfonyl)-3,4-dihydro-2H- Benzo[b][l,4]oxazin-6-yl). Bipyridine-2-carbonitrile, 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] oxindole- 6-base). Furan-2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][ 1,4] ° -6-yl)D-cetin-2-carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][ 1 ,4]β嘻6-yl)α夫喃-2-甲猜* 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2-indole-benzene And [b][l,4] ° 嗓-6-base) ° plug. -2 -carbonitrile, 5-(4-(5-ethylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4] °嗓6-yl)-1Η -0 to 0 each-2 - Acha' 5-(4-(5-methylthien-2-ylsulfonyl)-3,4-dihydro-2-indole-benzo[b ][l,4] 6-(5-(5-fluorenylthiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzene And [b][l,4] 11 evil. Qin-6-yl)α夫喃-2-甲猜' 5-(4-(5-nonylthiophen-2-ylsulfonyl)-3,4 -Dihydro-2-indole-benzo[b][l,4] °oxazin-6-yl)°sodium-2-carbonitrile, 151494.doc -25- 201120018 5-(4-(5-methyl) Thiophen-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4].oxan-6-yl)-111-0pirox-2-carbonitrile, 5 -(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxan-6-yl).pyridin-2 -phthalonitrile, 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]. Benzene-3-pyrene ratio. Benzene-2-carbonitrile, 5-(4-(5-ethylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yl)-3-methoxypyridine-2-carbonitrile, 5-(4-(5-ethyl-f-am-2-yl)--3,4 - Nitrogen - 2H - benzo[b][l,4]. 恶-6-yl)"cephen-2-pyronitrile, 5-(4-(5-methylfuran-2-ylsulfonyl) -3,4-dihydro-2H-benzo[b][l,4] °oxazin-6-yl) ° bite-2-carbonitrile, 3-fluoro-5-(4-(5-曱-αα夫喃-2 -Based on the basis of 3,4-diazo-2H-benzo[b][l,4]oxazin-6-yl)pyridine-2-indene nitrile, 3-methyl Oxy-5-(4-(5-methylfuran-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)indole Pyridin-2-indene nitrile, 5-(4-(5-ethyl0fu0-nan-2-yl)--3,4-di- 2H-benzo[b][l,4] Pyridin-6-yl)thiazole-2-carbonitrile, 4-(4-(3-carb-4-methoxyphenyl)--3,4-diaza-2H-benzoquinone[b][ l,4]thiazin-6-yl)benzonitrile, 4-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[1^][1,4 Thiazin-6-yl)benzonitrile, 2-methoxy-4-(4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazide 11 Qin-6-yl)benzonitrile, 151494.doc -26- 201120018 Gas (4-(6-曱oxy ton bite _3 • base mineral thiol) 3,4_ dihydro 2H_ stupid [b ][l,4]thiazide·6•yl)benzonitrile, ((aminophenyl phenyl) _3,4_digas·2H benzo (9) old] . Qin·6-yl)-2-chlorobenzonitrile, ((4 phenyl phenyl hydrazinyl oxa] 3,4 _ dihydro 2h_ benzo[b][l,4].冬基)_2_methoxy oxynitrile, 2_ defeat-4·(4· benzenesulfonyl sulfhydryl-based small oxygen ion-3,4-dihydro-2H-benzo[b][l,4]thiazide Benzene_6_yl)benzonitrile, 4(4(3-Den_4_methoxyphenyl fluorenyl)_1,1-dioxyindol-3, dihydrogen-2H-benzo[bni4] Thiazin-6-based benzonitrile, 4-(4-indenesulfonyl-based, mono-l-amino-3,4-dihydro-2H-indigo[b][l,4]thiazine_ 6_yl)benzonitrile, = (4-(4-aminophenyl yl)-u-dioxyl group from diaza benzo[b][l,4]thiazin-6-yl)benzonitrile , 曱 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -(4-methoxyphenyl-decyl)-34 dihydro-2h benzo-, 4] 嗔 ° Qin-6-yl) porphin carbonitrile, 5-(4-(phenyl-decyl)-di Oxygen ion group _3,4•dihydro·2η 笨[b][l,4]thiazine_6_yl)thiophene-2-carbonitrile, 5-(4-(4-methoxyphenyl sulfonate)醯3)_3,4_Dihydro-2h- benzo[b][i,4]thiazin-6-yl)thiophene-2-indenecarbonitrile, 4-(4-(4-amino) Alkylsulfonyl)_la•dioxyindolyl-3,4-dihydroanthracene] benzo[b][l,4]°pyrazine-6-yl) sold phen-2-indolonitrile, 151494.doc • 27. 201120018 4- (4-(phenylsulfonyl)-l-oxyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)furan- 2-carbonitrile, 5-(4-toluenesulfonyl-hydrazine-oxyl-3,4-diargon-2H-benzo[b][l,4]thiazin-6-yl)-1Η- Pyrrole-2-carbonitrile, 5-(4-(4-aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl) -1Η-pyrrole-3-carbonitrile, 5-(4-nonylbenzenesulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)_ 1H- Pyrrole-2-indene nitrile, 4-(4-(4-phenylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiophene-6-yl)-2 -methoxy methoxy nitrile, 2-fluoro-4-(4-nonylbenzenesulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazolidine)benzonitrile, 4- (4-(phenyl continuation)-3,4-dihydro-211-benzo[1)][1,4]indole-6-yl)furan-2-indene nitrile, 5- (4- Toluenesulfonyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-6-yl)-1H-pyrrole-2-carbonitrile, 4- (4-(4-(曱thio)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazine-6 -yl) nitrile, 5-(4-(p-stylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazinyl)thiophene-2-carbonitrile, 4 -(4-(4-Aminophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]non-6-yl)thiophene-2-carbonitrile, A pharmaceutically acceptable salt, an N-oxide thereof, and a pharmaceutically acceptable salt of such N-oxide. 151494.doc -28- 201120018 29. The compound of claim 1, which is selected from the group consisting of 2-(hearts 笨 醯 _ 3,4-dihydro 2 Η · stupid and i, hate 嗓 winter base) -3 -carbonitrile, 4-(4-((4-ethylmercaptophenyl)sulfonyl)_3,4_dihydro-2H_indigo[b][i,4]oxazin-6,yl Nitrite, , 4·(4·((5-fluorenylthiophen-2-yl)sulfonyl)_3,4-dihydro-2H-benzo[b][l,4]oxazine_6_ Benzyl nitrile, (((5 cyano-sept-2-yl)-2H- benzo[b][i,4]oxazin-4(3Η)-yl) 醯 ))) 4-(4-((2,3-dihydrobenzo[b][1,4]dioxine_6-yl)sulfonyl)-hydrogen-2H-benzo[1)] [1,4]°Evil Qin-6-yl)benzonitrile, 4 (4 ((6-gas η ratio bite_3_ base) continued thiol)_3,4_ dihydro-2U-benzo[b][ l,4] »oxazin-6-yl)stelidonitrile, 5 (4 ((6-gas η than bite _3_yl) sulfonyl)_3,4_dihydro-2H stupid [b][i , 4] oxazine _6_yl) thiophene-2-indene nitrile, 4-(4-((6-(indolylthiopyridinyl)-3-yl) hydrazino)_3,4_dihydro-2h_ Stupid [b][l,4]. 恶 _6_ base) benzonitrile, 5 (4 ((4-(pentafluorothio)phenyl))), 3,4_dihydro-2H- Stupid [b][l,4]oxazin-6- ) thiophene-2-carbonitrile, 4-(4-((6-methylacridin-3-yl)sulfonyl)_3,4_dihydro-2H_stup [b][l,4] Pyridin-6,6-(4-indolesulfonyl-34-dihydro-2H-benzo[b][14]oxazin-6-amino)nicotinonitrile, 5-(4-indole Phenylsulfonyl·3,4·dihydro-2H•benzo[b][1,4]oxazine_6•yl). Ratio 151494.doc -29· 201120018 pyridine-2-carbonitrile, 5-( 4-nonylbenzenesulfonyl-3,4-dihydro-2H-indigo[b][l,4]oxazin-6-yl)pyrimidine-2-indene nitrile, 2-(4-nonylbenzenesulfonate 3-,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)thiazol-5-indolecarbonitrile, 4-(4-((2,3-dihydro) And [b][l,4]dioxine_6_yl)sulfonyl)-3,4-dihydro-211-benzo[15][1,4].oxazin-6-嗟) 嗟-曱-carbonitrile, 5-(4-((6-(didecylaminopyridinyl)3 sulfonyl)&gt;3,4_dihydro_211_benzo[b ][l,4]oxazin-6-yl)thiophene-2-indrene, 5-(4-((6-(didecylaminopyridinyl)-3-yl)sulfonyl)_3,4_ Dihydro-211_benzo[b][l,4]°oxazine-6-base ratio. _2_2_曱carbonitrile, 6-(4-((6-(didecylamino)pyridinyl-3-yl)sulfonyl)_3,4•dihydro-2Η·benzo[b][l , 4]oxazin-6-yl)nicotinonitrile, 5-(4-((6-(monodecylamino).pyridinyl-3-yl)sulfonyl)-3, dihydrobenzo[ b][l,4]°oxazine-6-yl) mouth. _2-A guess, 6-(4-((6-aminotoxidine-3-yl)sulfonyl)·3,4 _Dihydro-π·benzo[b][l,4]oxazinyl)nicotinonitrile, 5-(4-((6-aminopyrenepyrene 唆_3_, 甘, 疋3 violence)%)醯3)_3,4_Dihydro-2H•benzo[5][1,4]°嗓6-yl) 塞 _2 _2 _ _ _ 其 其 其 其 _2 _2 _2 _2 其 _2 _2 And a pharmaceutically acceptable salt of the N. Oxide. 30. 31. The compound of any one of items 1 to 29 for use in therapy. The compound of any of the following items f to 1 to 29 No, it is used to treat diseases or conditions selected from the group consisting of inflammatory diseases, hyperproliferative diseases 151494.doc 201120018 diseases or conditions, hypoxia-related conditions, and pathophysiological diseases. 32. A pharmaceutical composition 'which contains at least one of the applicants to 29 a compound, as appropriate, together with at least one physiologically acceptable carrier or auxiliary substance. 33. The pharmaceutical composition of claim 32, further comprising at least one group useful for treating or preventing a group selected from the group consisting of lower ribs A second therapeutic agent for a disease or condition: an inflammatory disease, a hyperproliferative disease or condition, a hypoxic-related condition, and a disease characterized by pathophysiological vascular hyperplasia. 34. The treatment or prevention is selected from the group consisting of Methods of disease or condition of the group: inflammatory money, hyperproliferative money or condition, hypoxic-related conditions, and diseases characterized by pathophysiological vascular hyperplasia, the method comprising administering to an individual in need thereof effective A compound according to any one of claims 29 to 35. The method of claim 34, wherein the disease or condition is selected from the group consisting of inflammatory diseases: atherosclerosis; Rheumatoid arthritis, · Asthma; Inflammatory bowel disease' · Psoriasis, specifically psoriasis vulgaris, head psoriasis, drops of psoriasis, heterotypic psoriasis; neurological Inflammation; ichthyosis; plaque first; full charge; partial filling; general filling; diffuse filling (alopecia diffusa) 'atopic dermatitis; skin lupus erythematosus; skin dermatomyositis; atopic eczema' hard Spot disease; scleroderma; serpentine alopecia areata; androgenetic alopecia; allergic dermatitis; irritant contact dermatitis; contact dermatitis; pemphigus vulgaris; leaf roller sore; proliferative pemphigus; Mucosal pemphigus; bullous pemphigoid; mucosal pemphigus; skin 151494.doc -31- 201120018 fire 'dermatitis herpetiformis Duhnng'; urticaria; progressive lipid necrosis Nodular erythema; single, pruritus, lang treatment, acute pruritus (prurig〇acuta); linear IgA dermatosis; pleomorphic dermatosis; sunburn erythema; Treatment of 'chrono progressive purpura (pUrpUra chr〇nica progressiva); sweat blister; eczema; fixed drug rash; photoallergic skin reaction; and perioral dermatitis. The method of claim 34, wherein the disease or condition is selected from the group consisting of a hyperproliferative disease consisting of a tumor or a cancer disease, a precancerous lesion, a dysplastic dysfunction, a histiocytosis, a vascular proliferative disorder, and Viral-induced proliferative disease. 37. The method of claim 34, wherein the disease or condition is a hyperproliferative disease, the method comprising: experiencing radiation therapy, chemotherapy, immunotherapy, laser/microwave thermotherapy, or using antisense DNA and/or RNA in the patient The compound of any one of claims i to 29 is administered to the patient before, during and/or after the gene therapy. 3. The method of claim 34, wherein the disease or condition is selected from the group consisting of a tumor or cancer disease consisting of: diffuse large B-cell lymphoma (DLBCL); T-cell lymphoma or leukemia, eg, skin τ Cellular lymphoma (CTCL), non-skin peripheral T-cell lymphoma, lymphoma associated with human tau lymphocytic virus (HTLV), adult tau cell leukemia/lymphoma (ATLL), and acute lymphoblastic leukemia, acute non-lymphocyte Leukemia, acute auditory leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease, non-Hodgkin's 151494.doc -32- 201120018 Lymphoma (non-Hodgkin's lymphoma); myeloma , multiple myeloma, mesothelioma, solid tumors in children, gliomas, bone cancers and soft tissue sarcomas; common adult solid tumors, such as head and neck cancer (eg, oral, laryngeal, and esophageal cancer), genitourinary cancer (eg , prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer, rectal cancer and colon cancer), lung cancer (eg 'small fine Cancer and non-small cell lung cancer, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin cancer, ulcer and mastoid squamous cell carcinoma, gastric cancer, Brain cancer, liver cancer, adrenal cancer, renal cancer, squamous adenocarcinoma, medullary carcinoma, osteosarcoma, soft tissue sarcoma, Ewing's sarcoma, reticulum sarcoma, and Kaposi's sarcoma , fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma , adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, glioblastoma, papillary adenocarcinoma, cystadenocarcinoma, bronchial carcinoma, seminoma, embryonal carcinoma, Wilms' tumor ), small cell lung cancer, epithelial cancer, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendrocyte , Meningioma, neuroblastoma tumor cells, retinoblastoma, glaucoma, hemangioma, disease and transfer multiple bond. 39. Use of a compound according to any one of claims 1 to 29 for the manufacture of a medicament for the treatment of a condition or disease, wherein the condition or disease is 151494.doc-33-201120018, as in claim 34 As defined in any of 38. The compound according to any one of claims 1 to 29, which is for use in the treatment of a condition or a disease, wherein the condition or disease is as defined in any one of claims 35 to 38. 151494.doc •34· 201120018 IV. Designated representative map (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: , N^^R2 (l) o=s=o Ιι I5l494.doc