Substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity

A compound having the formula:

• 93
• or a pharmaceutically-acceptable salt thereof wherein;
• n is an integer selected from 1 through 4;
• A and Q are independently selected from the group consisting of —CH2(CR37R38)v—(CR33R34)u-T-(CR35R36)w—H,
• 94
• with the provisos that one of A and Q must be AQ-1 and that one of A and Q must be selected from the group consisting of AQ-2 and —CH2(CR37R38)v—(CR33R34)u-T-(CR35R36)w—H;
• T is selected from the group consisting of a single covalent bond, O, S, S(O), S(O)2, C(R33)═C(R35), and C≡C;
• v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35, and R36 is aryl or heteroaryl;
• u and w are integers independently selected from 0 through 6;
• A1 is C(R30);
• D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1 J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
• B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, C(R30), N, O, S and a covalent bond with the provisos that no more than 5 of B1, B2, D3, D4, J3, J4 and K2 are a covalent bond, no more than two of B1, B2, D3, D4, J3, J4 and K2 are O, no more than two of B1, B2, D3, D4, J3, J4 and K2 are S, no more than two of B1, B2, D3, D4, J3, J4 and K2 are simultaneously O and S, and no more than two of B1, B2, D3, D4, J3, J4 and K2 are N;
• B1 and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4 and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the group consisting of C(R33)═C(R35) and N═N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33)═C(R35), and that no more than one of the group of said spacer pairs can N═N unless the other spacer pairs is other than C(R33)═C(R35), O, N, and S;
• R16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, and trialkylsilyl;
• X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy) with the proviso that there is no R16 wherein X is H or F;
• R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
• R2 is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
• R3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
• Y is selected from a group consisting of a covalent single bond, (C(R14)2)q wherein q is an integer selected from 1 through 4 and (CH(R14))g—O—(CH(R14))p wherein g and p are integers independently selected from 0 through 2;
• R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;
• Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))j—O—(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
• R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
• R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
• R30, when bonded to A1, is taken together to form an intra-ring linear spacer connecting the A1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R10, R11, R12, R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
• R30, when bonded to A1, is taken together to form an intra-ring branched spacer connecting the A1-carbon at the point of attachment of R30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R10 and R11, R10 and R31, R10 and R32, R10 and R12, R11 and R31, R11 and R32, R11 and R12, R31 and R32, R31 and R12, and R32 and R12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
• R4, R5, R6, R7, R8, R9, R10, R11, R12, R31, R31, R32, R33 R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consistubg of hydrido and halo
• R9, R10, R11, R12, R13, R31, and R32 are independently selected to be oxo with the provisos that B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, R10, R11, R12, R13, R31, and R32 are simultaneously oxo, and that R9, R10, R11, R12, R13, R31, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
• R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, are used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are used at the same time;
• R9 and R11, R9 and R12, R9 and R13, R9 and R31, R9 and R32, R10 and R12, R10 and R13, R10 and R31, R10 and R32, R11 and R12, R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
• R37 and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.