Patent ID: 6479508
Filing Date: 2002-11-12
Classification: A61P,C07D,Y10S

Abstract:
A compound of formula I: wherein:X is CH and A is N; or X is N and A is COR7 or CR5, wherein R5 is H, halogen, or (C1-6) alkyl and R7 is H or (C1-6 alkyl); Y is O or S; Z is OH, NH2, NMeR3, NHR3; OR3 or 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from: COOH and â€”O(C6-10)aryl-(C2-6)alkenyl-COOH; R6 is H, halogen, (C1-6 alkyl) or OR7, wherein R7 is H or (C1-6 alkyl); R1 is selected from the group consisting of 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C1-3)alkyl, (C2-6)alkenyl, phenyl(C2-6)alkenyl, (C3-6)cycloalkyl, (C1-6)alkyl, CF3, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, wherein said heterocycle, phenyl, phenyl(C2-6)alkenyl and phenyl(C1-3)alkyl), alkenyl, cycloalkyl, (C1-6)alkyl, and heterobicycle are all optionally substituted with from 1 to 4 substituents selected from: OH, halogen, CF3, amino, cyano, phenyl(C1-4)alkoxy, COOH, â€”OCH2CONHCH2Ph, (C1-4)alkyl, â€”OCH2CONH(CH2)2-3N(CH3)2, (C1-4)alkoxy, â€”OCH2CO-(morpholino), pyrrolidinyl, carboxy(C2-4)alkenyl, phenoxy, â€”NH(C2-4)acyl, â€”O(CH2)mOH, m being an integer from 2 to 4, SO3, and NO2; R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-3)alkyl, (C6-10)bicycloalkyl, norbornane, phenyl, and pyridyl, all of which is optionally substituted with from 1 to 4 substituents selected from halogen, (C1-6)alkyl, â€”CH2OH, O-benzyl and OH; R3 is selected from H, (C1-6)alkyl, (C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-6)alkyl, (C6-10)aryl, (C6-10)aryl(C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl(C2-6)alkenyl, (C6-10)aryl(C2-6)alkenyl, N{(C1-6) alkyl}2, NHCOO(C1-6)alkyl(C6-10)aryl, NHCO(C6-10)aryl, (C1-6)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH, COO(C1-6)alkyl, (C1-6)alkyl, (C1-6)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C2-4)alkenyl, (C2-4)alkenyl-(C1-6)alkyl-COOH, and carboxy(C2-4)alkenyl, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from: (C1-6 alkyl), CF3, OH, (CH2)pCOOH, COOH, NHCH(C1-6alkyl)2, NHCO(C1-6 alkyl), NH2, NH(C1-6 alkyl), and N(C1-6 alkyl)2, wherein p is an integer from 1 to 4; 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from: halogen, OPO3H, sulfonamido, SO3H, SO2CH3, â€”CONH2, â€”COCH3, (C1-3)alkyl, (C2-4alkenyl)COOH, tetrazolyl, COOH, â€”CONH2, triazolyl, OH, NO2, NH2, â€”O(CH2)pCOOH, hydantoin, benzoyleneurea, (C1-4)alkoxy, cyano, azido, â€”Oâ€”(C1-6)alkyl COOH, â€”Oâ€”(C1-6)alkyl COOâ€”(C1-6)alkyl, â€”NHCOCOOH, â€”NHCOCONHOH, â€”NHCOCONH2, â€”NHCOCONHCH3, â€”NHCO(C1-6)alkyl-COOH, â€”NHCOCONH(C1-6)alkyl-COOH, â€”NHCO(C3-7)cycloalkyl-COOH, â€”NHCONH(C6-10)aryl-COOH, â€”NHCONH(C6-10)aryl-COO(C1-6)alkyl, â€”NHCONH(C1-6)alkyl-COOH, â€”NHCONH(C1-6)alkyl-COO(C1-6)alkyl, â€”NHCONH(C1-6)alkyl-(C2-6)alkenyl-COOH, â€”NH(C1-6)alkyl-(C6-10)aryl-O(C1-6)alkyl COOH, â€”NH(C1-6)alkyl-(C6-10)aryl-COOH, â€”NHCH2COOH, â€”NHCONH2, â€”NHCO(C1-6)hydroxyalkyl COOH, â€”OCO(C1-6)hydroxyalkyl COOH, (C3-6)cycloalkyl COOH, â€ƒâ€”NHCN, â€”NHCHO, â€”NHSO2CH3, and â€”NHSO2CF3; 6- or 10-membered aryl being optionally substituted with from 1 to 4 substituents selected from: halogen, OPO3H, sulfonamido, SO3H, SO2CH3, â€”CONH2, â€”COCH3, (C1-3)alkyl, (C2-4alkenyl)COOH, tetrazolyl, COOH, â€”CONH2, triazolyl, OH, NO2, NH2, â€”O(CH2)pCOOH, hydantoin, benzoyleneurea, (C1-4)alkoxy, cyano, azido, â€”Oâ€”(C1-6)alkyl COOH, â€”Oâ€”(C1-6)alkyl COOâ€”(C1-6)alkyl, â€”NHCOCOOH, â€”NHCOCONHOH,â€”NHCOCONH2, â€”NHCOCONHCH3, â€”NHCO(C1-6)alkyl-COOH, â€”NHCOCONH(C1-6)alkyl-COOH, â€”NHCO(C3-7)cycloalkyl-COOH, â€”NHCONH(C6-10)aryl-COOH, â€”NHCONH(C6-10)aryl-COO(C1-6)alkyl, â€”NHCONH(C1-6)alkyl-COOH, â€”NHCONH(C1-6)alkyl-COO(C1-6)alkyl, â€”NHCONH(C1-6)alkyl-(C2-6)alkenyl-COOH, â€”NH(C1-6)alkyl-(C6-10)aryl-O(C1-6)alkyl COOH, â€”NH(C1-6)alkyl-(C6-10)aryl-COOH, â€”NHCH2COOH, â€”NHCONH2, â€”NHCO(C1-6)hydroxyalkyl COOH, â€”OCO(C1-6)hydroxyalkyl COOH, (C3-6)cycloalkyl COOH, â€ƒâ€”NHCN, â€”NHCHO, â€”NHSO2CH3, and â€”NHSO2CF3; coumarin, (C1-6)alkyl-amino, di-(C1-6)alkyl-amino, C(halogen)3, â€”NH(C2-4)acyl, â€”NH(C6-10)aroyl, â€”CONHCH(CH2OH)2, â€”CO(C1-6)alkyl-COOH, â€”COâ€”NH-alanyl, â€”(CH2)pCOOH, â€”OCH2Ph, -CONHbenzyl, â€”CONHpyridyl, â€”CONHCH2pyridyl, â€”CONH(C2-4)alkylN(C1-6alkyl)2, â€”CONH(C2-4) alkyl-morpholino, â€”CONH(C2-4) alkyl-pyrrolidino, â€”CONH(C2-4) alkyl-N-methylpyrrolidino, â€”CONH(C2-4) alkyl(COOH)-imidazole, â€”CONHCH2CH(OH)CH2OH, â€”CONH(C1-6) alkyl-COOH, â€”CONH(C6-10) aryl-COOH, â€”CONH(C6-10) aryl-COO(C1-6) alkyl, â€”CONH(C1-6) alkyl-COO(C1-6) alkyl, â€”CONH(C6-10) aryl-(C1-6)alkyl-COOH, â€”CONH(C6-10) aryl-(C2-6)alkenyl-COOH, â€”CONH(C2-6) alkyl-CONH-9 or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from: COOH, (C6-10)aryl and (CH2)pCOOH, wherein p is an integer from 1 to 4; â€”CONH(C6-10) aryl-5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from: COOH and (CH2)pCOOH, wherein p is an integer from 1 to 4; â€”CONH(C1-6alkyl)CONH(C6-10aryl), said aryl being optionally substituted with from 1 to 4 substituents selected from: COOH and (CH2)pCOOH, wherein p is an integer from 1 to 4; â€”O(CH2)ptetrazolyl, wherein p is an integer from 1 to 4; and n is zero or 1; or a detectable derivative or salt thereof; wherein the detectable derivative is selected from a compound of the formula (I) labeled with a fluorescent label or a colorimetric label; with the proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not a five membered heterocycle containing S and N; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R1 is (C2-10)alkyl, (C3-10)alkenyl, (C3-6)cycloalkyl or phenyl, then R2 is not phenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not 5-nitro-2-furyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is optionally substituted alkyl or cycloalkyl, then R1 is 5-aryl-2-furyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 6-phenylbenzofuran-2-yl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is n-Pr, then R1 is not 2,3-benzofuranyl or phenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Me, then R1 is not phenyl or methoxy-2,3-benzofuranyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is Et, then R1 is not methoxy-2,3-benzofuranyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-8)alkyl, then R1 is not ethenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, then R1 is not substituted or unsubstituted phenyl, heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is lower alkyl, cycloalkyl or hydroxyalkyl, then R1 is not alkenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl, then R1 is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl, then R1 is not (C5-15)aryl, (C2-6)alkenyl or (C3-10)heteroarylene; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is (C1-2)alkyl, then R1 is not phenyl or aryl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 2-hydroxyphenyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not methyl, ethyl or vinyl; and with the further proviso that if X is CH, Y is O, Z is OH, n=1, then R1 is not 5-azabenzimidazol-2-yl; and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, and R2 is (C1-4)alkyl or hydroxy(C1-4)alkyl then R1 is not C1-4alkyl optionally substituted by OH, COOH or halo; and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, R1 is heteroaryl or phenyl, then R2 is not heteroaryl or phenyl; and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is (C1-3)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, and further substituted with aryl or heteroaryl, n=0 or 1, and R1 is (C2-10)alkyl, (C3-6)cycloalkyl or phenyl, then R2 is not optionally substituted phenyl; and with the further proviso that if X is CH, Y is O, Z is NMeR3 or NHR3 (wherein R3 is alkyl), n=0, and R2 is alkyl, cycloalkyl or aryl, then R1 is not a substituted 2-benzofuryl group; and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is alkyl, n=0, and R2 is alkyl or cycloalkyl, then R1 is not a substituted benzofuryl group or benzofuran-2-yl; and with the further proviso that if X is CH, Y is O, Z is NHR3 wherein R3 is Me, n=0, and R2 is Me, then R1 is not methoxy-2,3-benzofuranyl; and with the proviso that if X is CH, Y is O, Z is NHR3 (wherein R3 is alkyl or aryl), n=0, and R2 is alkyl not substituted with OH, then R1 is not aryl or heterocycle; and with the further proviso that if X is CH, Y is O, Z is NHR3 (wherein R3 is alkyl, cycloalkyl, aryl or heteroaryl), n=0, and R2 is alkyl or cycloalkyl, then R1 is not aryl, heteroaryl or alkyl; and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 or NMeR3 (wherein R3 is (C1-4)alkyl), n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl bearing an N-substituted sulfonamido group; and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, cycloalkyl, aryl or heterocycle, n=0, and R2 is alkyl or cycloalkyl, then R1 is not 3,4-dialkoxyphenyl, 3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene; and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl, n=0, and R2 is alkyl, cycloalkyl or hydroxyalkyl, then R1 is not tetrazolyl; and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl, n=0, and R2 is lower alkyl, then R1 is not substituted phenyl or heteroaryl; and with the further proviso that if X is CH, Y is O, Z is OH or NHR3 wherein R3 is H, alkyl, phenyl or benzyl, n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl; and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl or hydroxyalkyl, then R1 is not fluoroalkyl; and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=0, and R2 is alkyl, then R1 is not alkenyl or aryl; and with the further proviso that if X is CH, Y is O, Z is NHR3 (wherein R3 is thiazolyl), n=1, and R2 is (C1-8)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, phenyl or heteroaryl, then R1 is not phenyl, phenyl(C2-4)alkenyl, heteroaryl, heterocycle, (C1-8)alkyl, (C2-6)alkenyl, or (C3-7)cycloalkyl; and with the further proviso that if X is CH, Y is O, Z is OH or NH2, n=1, and R2 is (C1-5)alkyl, then R1 is not methyl or optionally halogenated phenyl; and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2 is n-Pr, then R1 is not phenylethenyl; and with the further proviso that if X is CH, Y is O, Z is NH2, n=0, and R2 is alkyl, then R1 is not substituted phenyl or naphthyl; and with the further proviso that if X is CH, Y is O, Z is NH2 or NHR3 wherein R3 is (C1-4)alkyl, benzyl or p-fluorophenylmethyl, n=0, and R2 is (C1-4)alkyl, then R1 is not phenyl substituted with acylamino; and with the proviso that when n=0 and Y=O, then Z is not OH or OR3, wherein R3 is H, (C1-6)alkyl or (C6-10)aryl(C1-6)alkyl, wherein said alkyl and said aryl are optionally substituted with from 1 to 4 substituents selected from the group consisting of: OH, COOH, COO(C1-6)alkyl, (C1-6)alkyl, (C1-6)alkyl-hydroxy, halogen, (C1-6)alkylamino, di-(C1-6)alkyl-amino, C(halogen)3, â€”NH(C2-4)acyl and (CH2)pCOOH in which p is an integer from 1 to 4; and with the proviso that when n=0 and Y=O, then Z is not OR3 wherein R3 is (C6-10)aryl(C1-6)alkyl, optionally substituted with from 1 to 4 substituents selected from the group consisting of: cyano, NO2, â€”COCH3, â€”CONH2, â€”NH2, sulfonamido, â€”SO2CH3, â€”NHSO2CH3 and (C1-4)alkoxy; and with the proviso that when n=0 and Y=O, then Z is not NH2, NMeR3 or NHR3, wherein R3 is H, or (C1-6)alkyl optionally substituted with from 1 to 4 substituents selected from the group consisting of: OH, COOH, COO(C1-6)alkyl, halogen, (C1-6)alkylamino and di-(C1-6)alkyl-amino; and with the proviso that when n=1 and Y=O, then Z is not OH or OR3 wherein R3 is (C1-6)alkyl.