Patent ID: 6559150
Filing Date: 2003-05-06
Classification: A61P,C07D

Abstract:
A compound of the Formula I: or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug,wherein:HET is the heterocyclic moiety Q is a covalent bond or CH2; X is CR9R10, C&boxH;CH2 or C&boxH;O; Y is CR9R10, O or NR2; Z is C&boxH;O, C&boxH;S or S(O)2; R1 is hydrogen, â€”CN, â€”(CH2)qN(X6)C(O)X6, â€”(CH2)qN(X6)C(O)(CH2)tâ€”A1, â€”(CH2)qN(X6)S(O)2(CH2)tâ€”A1, â€”(CH2)qN(X6)S(O)2X6, â€”(CH2)qN(X6)C(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)N(X6)(X6), â€”(CH2)qC(O)N(X6)(X6), â€”(CH2)qC(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qC(O)OX6, â€”(CH2)qC(O)O(CH2)tâ€”A1, â€”(CH2)qOX6, â€”(CH2)qOC(O)X6, â€”(CH2)qOC(O)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(X6), â€”(CH2)qC(O)X6, â€”(CH2)qC(O)(CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)OX6, â€”(CH2)qN(X6)S(O)2N(X6)(X6), â€”(CH2)qS(O)mX6, â€”(CH2)qS(O)m(CH2)tâ€”A1, â€”(C1-C10)alkyl, â€”(CH2)tâ€”A1, â€”(CH2)qâ€”(C3-C7)cycloalkyl, (CH2)qâ€”Y1â€”(C1-C6)alkyl, â€”(CH2)qâ€”Y1â€”(CH2)tâ€”A1 or â€”(CH2)qâ€”Y1â€”(CH2)tâ€”(C3-C7)cycloalky-I; â€ƒwhere the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y1 is O, S(O)m, â€”C(O)NX6â€”, â€”CH&boxH;CHâ€”, â€”Câ‰¡Câ€”, â€”N(X6)C(O)â€”, â€”C(O)NX6â€”, â€”C(O)Oâ€”, â€”OC(O)N(X6)â€” or â€”OC(O)â€”; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; R2, for each occurrence, is hydrogen, (C1-C8)alkyl, â€”(C0-C3)alkylâ€”(C3-C8)cycloalkyl, â€”(C1-C4)alkyl-A1 or A1; â€ƒwhere the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxy, â€”C(O)OX6, â€”C(O)N(X6)(X6), â€”N(X6)(X6), â€”S(O)m(C1-C6)alkyl, â€”C(O)A1, â€”C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halogens; R3 is selected from the group consisting of A1, (C1-C10)alkyl, â€”(C1-C6)alkyl-A1, â€”(C1-C6alkyl-(C3-C7)cycloalkyl, â€”(C1-C5)alkyl-X1â€”(C1-C5)alkyl, â€”(C1-C5)alkyl-X1â€”(C0-C5)alkyl-A1 and â€”(C1-C5)alkyl-X1â€”(C1-C5alkyl-(C3-C7)cycloalkyl; â€ƒwhere the alkyl groups in the definition of R3 are optionally substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1, 2, 3, 4 or 5 independently selected halogens or 1, 2 or 3 independently selected X1â€”OX3 groups; X1 is O, S(O)m, â€”N(X2)C(O)â€”, â€”C(O)N(X2)â€”, â€”OC(O)â€”, â€”C(O)Oâ€”, â€”CX2&boxH;CX2â€”, â€”N(X2)C(O)Oâ€”, â€”OC(O)N(X2)â€” or â€”Câ‰¡Câ€”; R4is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is â€”(CRaRb)aâ€”Eâ€”(CRaRb)bâ€”, where the â€”(CRaRb)aâ€” group is attached to the carbonyl carbon of the amide group of the compound of formula I and the â€”(CRaRb)b group is attached to the terminal nitrogen atom of the compound of formula I; E is â€”Oâ€”, â€”Sâ€”, â€”CH&boxH;CHâ€” or an aromatic moiety selected from â€ƒsaid aromatic moiety in the definition of E optionally substituted with up to three halo, hydroxy, â€”N(Rc)(Rc), (C1-C6)alkyl or (C1-C6)alkoxy; Ra and Rb are, for each occurrence, independently hydrogen, (C1-C6)alkyl, trifluoromethyl, phenyl or monosubstituted (C1-C6)alkyl where the substituents are imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, â€”ORc, S(O)mRc, C(O)ORc, (C3-C7)cycloalkyl, â€”N(Rc)(Rc), or â€”C(O)N(Rc)(Rc); Rc, for each occurrence, is independently hydrogen or (C1-C6)alkyl; a and b are independently 0, 1, 2 or 3, with the proviso that if E is â€”Oâ€” or â€”Sâ€” then b is 2 or 3, and with the further proviso that if E is â€”CH&boxH;CHâ€” then b is 1, 2 or 3; R7 and R8 are each independently hydrogen or optionally substituted (C1-C6)alkyl; â€ƒwhere the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, â€”C(O)Oâ€”(C1-C6)alkyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy groups, 1 to 3 â€”Oâ€”C(O)(C1-C10)alkyl groups or 1 to 3 (C1-C6)alkoxy groups; or R7 and R8 can be taken together to form â€”(CH2)râ€”Lâ€”(CH2)râ€”; where L is C(X2)(X2), S(O)m or N(X2); R9 and R10 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy and (C1-C5)alkyl optionally independently substituted with 1-5 halogens; A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, â€”OX6, â€”C(O)N(X6)(X6), â€”C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, â€”S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, â€”N(X6)(X6), â€”N(X6)C(O)(X6), â€”S(O)2N(X6)(X6), â€”N(X6)S(O)2-phenyl, â€”N(X6)S(O)2X6, â€”CONX11X12, â€”S(O)2NX11X12, â€”NX6S(O)2X12, â€”NX6CONX11X12, â€”NX6S(O)2NX11X12, â€”NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; â€ƒwhere X11, for each occurrence, is independently hydrogen or optionally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups; X12, for each occurrence, is independently hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 are taken together to form â€”(CH2)râ€”L1â€”(CH2)râ€”; L1 is C(X2)(X2), O, S(O)m or N(X2); r for each occurrence is independently 1, 2 or 3; X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1 to 5 halogens or 1-3 OX3 groups; X3 for each occurrence is independently hydrogen or (C1-C6)alkyl; X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, â€”S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7 as a ring member; X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy; m for each occurrence is independently 0, 1 or 2; with the proviso that: X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12.