Patent ID: 6476263
Filing Date: 2002-11-05
Classification: A61K,C07K

Abstract:
A compound of the formula: wherein R1 is selected from the group consisting of:(a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl, (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl, (c) cycloalkenyl, (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups, (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl, (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and (h) optionally substituted saturated heterocyclic; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is â€”C(O)Y or â€”C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include &agr;-haloalkyl, &agr;-diazoalkyl, &agr;-OC(O)alkyl or &agr;-OC(O)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) optionally substituted aryl, (g) optionally substituted heteroaryl, (h) optionally substituted heterocyclic, (i) â€”NRâ€²Râ€³ where Râ€² and Râ€³ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of Râ€² or Râ€³ is hydroxy or alkoxy, and where Râ€² and Râ€³ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, (j) â€”NHSO2â€”R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic, (k) â€”NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and (l) â€”ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defmed above; X can also be â€”CR6R6Yâ€² where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Yâ€² is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, â€”OC(O)R7, â€”SSR7, â€”SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic, Xâ€² is hydrogen, hydroxy or fluoro; Xâ€³ is hydrogen, hydroxy or fluoro, or Xâ€² and Xâ€³ together form an oxo group, and n is an integer equal to 1 or 2; but, excluding the compounds: (i) wherein R1 is o-fluorophenyl, R2 is 3,4-dichlorophenyl or ethyl, R4 and R5 are hydrogen, Xâ€² and Xâ€³ are hydrogen, and X is â€”C(O)OCH3; (ii) wherein n is 1, R1 is 5-fluoro-2-nitrophenyl, Xâ€² Xâ€³ and R5 are hydrogen, R4 is 3-hydroxy-5-methoxyphenly or 3-isopropoxy-5-methoxyphenyl and R2 is benzyl; (iii) wherein n is 2, R1 is â€”CH2C(O)OCH3, R2 is â€”(CH2)2COOH, the first R4 is isopropyl and the second R4 is â€”(CH2)4NH2, Xâ€², Xâ€³ and each R5 is hydrogen and X is â€”C(O)NHCH(C(O)CH2Cl)CH2phenyl, â€”C(O)NHCH(C(O)CH3)CH2phenyl or â€”C(O)NHCH(C(O)CF3)CH2phenyl; (iv) wherein n is 2, R1 is â€”(CH2)6COOH, R2 is isopropyl, the first R4 is â€”(CH2)4NH2, the second R4 is benzyl, Xâ€², Xâ€³, and each R5 is hydrogen and X is â€”C(O)CH2Cl; (v) wherein n is 2, R1 is â€”(CH)3COOH, R2 is isopropyl, the first R4 is â€”(CH2)3NH2, the second R4 is benzyl, Xâ€², Xâ€³, and each R5 is hydrogen and X is acetyl; (vi) wherein n is 2, R1 is â€”CH2C(O)OCH3, R2 is â€”(CH2)2COOH, the first R4 is isopropyl, the second R4 is â€”(CH2)3NH2, Xâ€², Xâ€³ and each R5 is hydrogen and X is â€”C(O)NHCH(C(O)CF3)CH2phenyl; (vii) wherein n is 1, R1 is â€”CH(isopropyl)CH2COOH, Z is a bond, R2 is â€”(CH2)3NH2, R4 is benzyl, Xâ€², Xâ€³ and R5 are hydrogen, and X is â€”C(O)CH2Cl; and (viii) wherein R1 is fluoro substituted aryl, n is 1, Xâ€² and Xâ€³ are each hydrogen, R5 is hydrogen or methyl, X is â€”C(O)Y where Y is haloalkyl, alkoxy, thioalkoxy, heterocyclic, â€”CH2 heterocyclic, mono-substituted alkyl having its single substituent at the terminal position and wherein said substituent is diazo, â€”C(O)ORâ€², â€”C(O) alkyl ORâ€² or â€”C(O) NRâ€², Râ€³ wherein Râ€² and Râ€³ are independently hydrogen, alkyl, phenyl, benzyl or phenethyl, or Y is selected from the groups â€”CH2ORâ€², â€”CH2SRâ€², â€”CH2NRâ€²Râ€³ or â€”NRâ€²Râ€³ wherein Râ€² and Râ€³ are independently hydrogen alkyl, phenyl, benzyl or phenethyl.