1,3-benzoxazolyl derivatives as kinase inhibitors

Abstract

Compounds of the formula I, the preparation and use thereof for the preparation of a medicament for the treatment of diseases, in particular tumours and/or diseases that are caused, mediated and/or propagated by angiogenesis. Compounds of the formula I are effective inhibitors of tyrosine kinases, in particular TIE-2 and VEGFR, and of Raf kinases. (I)

1 - 13 . (canceled) 
     
     
         14 . A method of treating a patient suffering from a cancerous disease comprising administering to said patient an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         in which 
         R 1  is Hal, NO 2 , CF 3 , COOH, COOR or H, 
         R 2  is R, Hal, CN, NO 2 , NHR, NRR, NHCOR, NHSO 2 R, OR, CO—R, CO—NHR, CF 3 , OCF 3 , SCF 3 , SO 3 R, SO 2 R, SO 2 NR, SR, COOH or COOR, 
         R 3  is Hal or CO—NHR, 
         R 4  is H or unsubstituted or mono-, di-, tri- or tetra-R 4 -substituted A, Ar, Het, (CH 2 ) q Het or (CH 2 ) q Ar, 
         A is unbranched, branched or cyclic alkyl having 1-14 C atoms, in which one or two CH 2  groups are each optionally replaced by O, S, or —CH═CH— and/or 1-7 H atoms are each optionally replaced by F or Cl, 
         Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH, OA, CN, NO 2 , NH 2 , NHA, NA 2 , NHCOA, SCF 3 , SO 2 A, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHSO 2 A, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , CHO or COA, 
         Het is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, —(CH 2 ) b —Ar, —(CH 2 ) b -cycloalkyl, OH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2  and/or S(O) g A, 
         Hal is F, Cl, Br or I, 
         R 4  is Hal, OH, CN, NO 2 , CF 3 , OCF 3 , SCF 3 , SO 2 A or OA, 
         X is O, S, or NH, 
         {circle around (Y)} is phenyl or a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, 
         b is 0, 1, 2, 3 or 4, 
         g is 0, 1 or 2, 
         n, m, p, q are each, independently of one another, 1, 2, 3, or 4, 
         or a pharmaceutically acceptable salt, or stereoisomer thereof, including mixtures of stereoisomers in all ratios. 
       
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method according to  claim 14 , wherein said method is for treating a solid tumor in a patient. 
     
     
         21 . The method according to  claim 20 , where the solid tumor is selected from brain tumor, tumor of the urogenital tract, tumor of the lymphatic system, stomach tumor, laryngeal tumor and lung tumor. 
     
     
         22 . The method according to  claim 20 , where the solid tumor is selected from monocytic leukemia, lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma. 
     
     
         23 . (canceled) 
     
     
         24 . A method for treating a patient suffering from retinal vascularization, diabetic retinopathy, age-induced macular degeneration and/or an inflammatory disease, comprising administering to said patient an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         in which 
         R 1  is Hal, NO 2 , CF 3 , COOH, COOR or H, 
         R 2  is R, Hal, CN, NO 2 , NHR, NRR, NHCOR, NHSO 2 R, OR, CO—R, CO—NHR, CF 3 , OCF 3 , SCF 3 , SO 3 R, SO 2 R, SO 2 NR, SR, COOH or COOR, 
         R 3  is Hal or CO—NHR, 
         R is H or unsubstituted or mono-, di-, tri- or tetra-R 4 -substituted A, Ar, Het, (CH 2 ) q Het or (CH 2 ) q Ar, 
         A is unbranched, branched or cyclic alkyl having 1-14 C atoms, in which one or two CH 2  groups are each optionally replaced by O, S, or —CH═CH— and/or 1-7 H atoms are each optionally replaced by F or Cl, 
         Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH, OA, CN, NO 2 , NH 2 , NHA, NA 2 , NHCOA, SCF 3 , SO 2 A, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHSO 2 A, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , CHO or COA, 
         Het is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, —(CH 2 ) b —Ar, —(CH 2 ) b -cycloalkyl, OH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2  and/or S(O) g A, 
         Hal is F, Cl, Br or I, 
         R 4  is Hal, OH, CN, NO 2 , CF 3 , OCF 3 , SCF 3 , SO 2 A or OA, 
         X is O, S, or NH, 
         {circle around (Y)} is phenyl or a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, 
         b is 0, 1, 2, 3 or 4, 
         g is 0, 1 or 2, 
         n, m, p, q are each, independently of one another, 1, 2, 3, or 4,
 or a pharmaceutically acceptable salt, or stereoisomer thereof, including mixtures of stereoisomers in all ratios. 
 
       
     
     
         25 . A method for treating a patient suffering from osteosarcoma, osteoarthritis, or rickets, comprising administering to said patient an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         in which 
         R 1  is Hal, NO 2 , CF 3 , COOH, COOR or H, 
         R 2  is R, Hal, CN, NO 2 , NHR, NRR, NHCOR, NHSO 2 R, OR, CO—R, CO—NHR, CF 3 , OCF 3 , SCF 3 , SO 3 R, SO 2 R, SO 2 NR, SR, COOH or COOR, 
         R 3  is Hal or CO—NHR, 
         R is H or unsubstituted or mono-, di-, tri- or tetra-R 4 -substituted A, Ar, Het, (CH 2 ) q Het or (CH 2 ) q Ar, 
         A is unbranched, branched or cyclic alkyl having 1-14 C atoms, in which one or two CH 2  groups are each optionally replaced by O, S, or —CH═CH— and/or 1-7 H atoms are each optionally replaced by F or Cl, 
         Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH, OA, CN, NO 2 , NH 2 , NHA, NA 2 , NHCOA, SCF 3 , SO 2 A, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHSO 2 A, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , CHO or COA, 
         Het is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, —(CH 2 ) b —Ar, —(CH 2 ) b -cycloalkyl, OH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2  and/or S(O) g A 
         Hal is F, Cl, Br or I, 
         R 4  is Hal, OH, CN, NO 2 , CF 3 , OCF 3 , SCF 3 , SO 2 A or OA, 
         X is O, S, or NH, 
         {circle around (Y)} is phenyl or a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, 
         b is 0, 1, 2, 3 or 4, 
         g is 0, 1 or 2, 
         n, m, p, q are each, independently of one another, 1, 2, 3, or 4,
 or a pharmaceutically acceptable salt, or stereoisomer thereof, including mixtures of stereoisomers in all ratio. 
 
       
     
     
         26 . A method for treating a patient suffering from psoriasis, rheumatoid arthritis, contact dermatitis, delayed hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, an autoimmune disease, or an immunodeficiency disease, comprising administering to said patient an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         in which 
         R 1  is Hal, NO 2 , CF 3 , COOH, COOR or H, 
         R 2  is R, Hal, CN, NO 2 , NHR, NRR, NHCOR, NHSO 2 R, OR, CO—R, CO—NHR, OCF 3 , SCF 3 , SO 3 R, SO 2 R, SO 2 NR, SR, COOH or COOR, 
         R 3  is Hal or CO—NHR, 
         R is H or unsubstituted or mono-, di-, tri- or tetra-R 4 -substituted A, Ar, Het, (CH 2 ) q Het or (CH 2 ) q Ar, 
         A is unbranched, branched or cyclic alkyl having 1-14 C atoms, in which one or two CH 2  groups are each optionally replaced by O, S, or —CH═CH— and/or 1-7 H atoms are each optionally replaced by F or Cl, 
         Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH, OA, CN, NO 2 , NH 2 , NHA, NA 2 , NHCOA, SCF 3 , SO 2 A, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHSO 2 A, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , CHO or COA, 
         Het is a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, —(CH 2 ) b —Ar, —(CH 2 ) b -cycloalkyl, OH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2  and/or S(O) g A, 
         Hal is F, Cl, Br or I, 
         R 4  is Hal, OH, CN, NO 2 , CF 3 , OCF 3 , SCF 3 , SO 2 A or OA, 
         X is O, S, or NH, 
         {circle around (Y)} is phenyl or a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, 
         b is 0, 1, 2, 3 or 4, 
         g is 0, 1 or 2, 
         n, m, p, q are each, independently of one another, 1, 2, 3, or 4,
 or a pharmaceutically acceptable salt, or stereoisomer thereof, including mixtures of stereoisomers in all ratio. 
 
       
     
     
         27 . A method according to  claim 14 , wherein said cancerous disease is selected from brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia, and acute leukemia. 
     
     
         28 . The method according to  claim 14 , wherein said effective amount of said compound of formula I is administered in combination with another compound selected from 1) estrogen receptor modulators, 2) androgen receptor modulators, 3) retinoid receptor modulators, 4) cytotoxic agents, 5) antiproliferative agents, 6) prenyl-protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors 9) reverse transcriptase inhibitors, 10) growth factor receptor inhibitors and 11) angiogenesis inhibitors. 
     
     
         29 . The method according to  claim 28 , wherein the administration of said compound of Formula I and said another compound is performed. 
     
     
         30 . The method according to  claim 14 , wherein R 2  is H. 
     
     
         31 . The method according to  claim 14 , wherein {circle around (Y)} is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl. 
     
     
         32 . The method according to  claim 14 , wherein
 R 2  is H,   {circle around (Y)} is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl,   X is O, S, or NH,   n, p, are each, independently of one another, 1, 2, 3 or 4,   m is 1.   
     
     
         33 . The method according to  claim 14 , wherein said compound is selected from:
 benzoxazol-2-yl-[4-(pyridin-4-yloxy)phenyl]amine,   benzoxazol-2-yl-[4-(pyridin-4-ylsulfanyl)phenyl]amine,   N-benzoxazol-2-yl-N′-pyridin-4-ylbenzene-1,4-diamine,   2-[4-(pyridin-4-ylsulfanyl)phenylamino]benzoxazole-5-carboxylic acid,   2-[4-(pyridin-4-yloxy)phenylamino]benzoxazole-6-carboxylic acid,   2-[4-(pyridin-4-ylsulfanyl)phenylamino]benzoxazole-6-carboxylic acid,   methyl 2-[4-(pyridin-4-ylamino)phenylamino]benzoxazole-6-carboxylate,   (5-nitrobenzoxazol-2-yl)-[4-(pyridin-4-ylsulfanyl)phenyl]amine,   (5-nitrobenzoxazol-2-yl)-[4-(pyridin-4-yloxy)phenyl]amine,   N-(5-nitrobenzoxazol-2-yl)-N′-pyridin-4-ylbenzene-1,4-diamine,   (6-nitrobenzoxazol-2-yl)-[4-(pyridin-4-yloxy)phenyl]amine,   (6-nitrobenzoxazol-2-yl)-[4-(pyridin-4-ylsulfanyl)phenyl]amine,   N-(6-nitrobenzoxazol-2-yl)-N′-pyridin-4-ylbenzene-1,4-diamine,   (5-chloro-7-nitrobenzoxazol-2-yl)-[4-(pyridin-4-yloxy)phenyl]amine,   (5-chloro-7-nitrobenzoxazol-2-yl)-[4-(pyridin-4-ylsulfanyl)phenyl]amine,   N-(5-chloro-7-nitrobenzoxazol-2-yl)-N′-pyridin-4-ylbenzene-1,4-diamine,   (7-bromo-5-trifluoromethylbenzoxazol-2-yl)-[4-(pyridin-4-yloxy)phenyl]-amine,   (7-bromo-5-trifluoromethylbenzoxazol-2-yl)-[4-(pyridin-4-ylsulfanyl)phenyl]-amine,   (7-bromo-5-trifluoromethylbenzoxazol-2-yl)-[4-(4-fluorophenylsulfanyl)-phenyl]amine,   N-[4-(bromotrifluoromethylbenzoxazol-2-ylamino)phenyl]-4-fluoro-1-benzenesulfonamide,   [4-(2-amino-6-methylpyrimidin-4-yloxy)phenyl]-(7-bromo-5-trifluoromethylbenzoxazol-2-yl)amine,   N-methyl-4-[4-(bromotrifluoromethylbenzoxazol-2-ylamino)phenoxy]-pyridine-2-carboxamide,   N-methyl-4-[4-(bromotrifluoromethylbenzoxazol-2-ylamino)phenylsulfanyl]-pyridine-2-carboxamide, and   (7-bromo-5-trifluoromethylbenzoxazol-2-yl)-[4-(2,4-difluorophenylsulfanyl)-phenyl]amine,   and pharmaceutically acceptable salts, and stereoisomers thereof, including mixtures of stereoisomers in all ratios.   
     
     
         34 . The method according to  claim 14 , wherein A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl, decyl, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 
     
     
         35 . The method according to  claim 34 , wherein A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 
     
     
         36 . The method according to  claim 14 , wherein A is alkyl having 1, 2, 3, 4, 5 or 6 C atoms, in which one or two CH 2  groups are each optionally replaced by O, S, or by —CH═CH—, and 1-7 H are each optionally replaced by F or Cl. 
     
     
         37 . The method according to  claim 34 , wherein A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl, or 1,1,1-trifluoroethyl. 
     
     
         38 . The method according to  claim 14 , wherein Ar is phenyl, naphthyl or biphenyl, which in each case is mono-, di- or trisubstituted by substituents selected from A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl, ethoxycarbonyl, and aminocarbonyl. 
     
     
         39 . The method according to  claim 14 , wherein Het is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, or 2,1,3-benzoxadiazol-5-yl, which in each case is unsubstituted or mono-, di- or trisubstituted by substituents selected from carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl, phenyl, benzyl, —CH 2 -cyclohexyl, hydroxyl, methoxy, ethoxy, amino, methylamino, dimethylamino, nitro, cyano, carboxyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetamino, ureido, methylsulfonylamino, formyl, acetyl, aminosulfonyl, and methylsulfonyl, or
 Het is 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl, 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl, 2-hydroxy-6-oxopiperazin-1-yl, 2-methoxy-6-oxopiperazin-1-yl, or 2-azabicyclo[2.2.2]octan-3-on-2-yl. 
 
     
     
         40 . The method according to  claim 14 , wherein {circle around (Y)} is phenyl, pyridyl or pyrimidinyl. 
     
     
         41 . The method according to  claim 39 , wherein
 A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl, decyl, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; and   Ar is phenyl, naphthyl or biphenyl, which in each case is mono-, di- or trisubstituted by substituents selected from A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl, ethoxycarbonyl, and aminocarbonyl.   
     
     
         42 . The method according to  claim 14 , wherein
 R 1  is Hal, NO 2 , CF 3 , COOH, COOR or H,   R 2  is H,   Y is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl, and   X is O, S, or NH.