Cholesteryl Ester Transfer Protein Inhibitors

A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein

• The phenyl ring A of Formula I optionally has —N═ in place of —(CH)═ at one of the 4 positions that is not attached to A1 or —CR15R16- in Formula I;
• A1 is selected from the group consisting of:
• (a) an aromatic ring selected from phenyl and naphthyl;
• (b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
• (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds and optionally a carbonyl group or —N(O)— group, wherein the point of attachment of A1 to the phenyl ring A is a carbon atom of A1;
• and
• (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally 1-2 double bonds, wherein the point of attachment of A1 to the phenyl ring A is a carbon atom of A1;
• wherein A1 is optionally substituted with 1-5 substituent groups independently selected from Rb;
• A2 is selected from the group consisting of:
• (a) an aromatic ring selected from phenyl and naphthyl;
• (b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
• (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds and optionally a carbonyl group or —N(O)— group, wherein the point of attachment of A2 is a carbon atom of A2;
• (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally 1-2 double bonds, wherein the point of attachment of A2 is a carbon atom of A2;
• and
• (e) a —C3-C8 cycloalkyl ring optionally having 1-3 double bonds;
• wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Rc;
• Each Ra and Rc is independently selected from the group consisting of —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl optionally having 1-3 double bonds, —OC1-C6alkyl, —OC2-C6 alkenyl, —OC2-C6 alkynyl, —OC3-C8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C1-C6alkyl, —C(═O)C3-C8 cycloalkyl, —C(═O)H, —CO2H, —CO2C1-C6alkyl, —C(═O)SC1-C6alkyl, —NR10R11, —C(═O)NR10R11, —NR10C(═O)OC1-C6 alkyl, —NR10C(═O)NR10R11, —S(O)xC1-C6 alkyl, —S(O)yNR10R11, —NR10S(O)yNR10R11, halogen, —CN, —NO2, and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally 1-3 double bonds,
• wherein when Ra and Rc are selected from the group consisting of a heterocyclic ring, —C3-C8 cycloalkyl, —OC3-C8 cycloalkyl, and —C(═O)C3-C8 cycloalkyl, the heterocyclic ring and —C3-C8 cycloalkyl groups of Ra and Rc are optionally substituted with 1-5 substituent groups independently selected from halogen, —C1-C3 alkyl, and —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 alkyl are optionally substituted with 1-7 halogens,
• and when Ra and Rc are selected from the group consisting of —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6alkyl, —OC2-C6 alkenyl, —OC2-C6 alkynyl, —C(═O)C1-C6alkyl, —CO2C1-C6alkyl, —C(═O)SC1-C6alkyl, —NR10C(═O)OC1-C6 alkyl, and —S(O)xC1-C6 alkyl, the alkyl, alkenyl, and alkynyl groups of Ra and Rc are optionally substituted with 1-13 halogens and are optionally substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR10R11, (d) —C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC1-C4alkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from —OC1-C2 alkyl, (f) —OC3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO2H, (h) —C(═O)CH3, and (i) —CO2C1-C4alkyl which is optionally substituted with 1-9 halogens;
• wherein 2 groups Ra that are on adjacent carbon atoms of the phenyl or optional pyridyl ring A of Formula I may optionally be joined to form a bridging group selected from —CH2CH2CH2-, —CH2CH2CH2CH2-, and —CH═CH—CH═CH—, thereby yielding a cyclopentyl, cyclohexyl, or phenyl ring fused to the phenyl ring or optional pyridyl ring A of Formula I, wherein said cyclopentyl, cyclohexyl, or phenyl ring that is fused to the phenyl or optional pyridyl ring A of Formula I is optionally substituted with 1-2 groups Ra, with the proviso that two adjacent groups Ra cannot be joined to form an additional fused ring;
• Each Rb is independently selected from the group consisting of —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl optionally having 1-3 double bonds, —OC1-C6alkyl, —OC2-C6 alkenyl, —OC2-C6 alkynyl, —OC3-C8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C1-C6alkyl, —C(═O)C3-C8 cycloalkyl, —C(═O)H, —CO2H, —CO2C1-C6alkyl, —C(═O)SC1-C6alkyl, —NR10R11, —C(═O)NR10R11, —NR10C(═O)OC1-C6 alkyl, —NR10C(═O)NR10R11, —S(O)xC1-C6 alkyl, —S(O)yNR10R11, —NR10S(O)yNR10R11, halogen, —CN, —NO2, phenyl, and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally 1-3 double bonds,
• wherein when Rb is selected from the group consisting of a heterocyclic ring, —C3-C8 cycloalkyl, —OC3-C8 cycloalkyl, and —C(═O)C3-C8 cycloalkyl, the heterocyclic ring and —C3-C8 cycloalkyl groups of Rb are optionally substituted with 1-5 substituent groups independently selected from halogen, —C1-C3 alkyl, —C2-C3 alkenyl, —NR10R11, —OC1-C3 alkyl, —CO2H, —CN, and —CO2C1-C3alkyl, wherein —C1-C3 alkyl and —C2-C3 alkenyl in all uses are optionally substituted with 1-7 halogens and optionally one group —OH, and when Rb is selected from the group consisting of —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6alkyl, —OC2-C6 alkenyl, —OC2-C6 alkynyl, —C(═O)C1-C6alkyl, —CO2C1-C6alkyl, —C(═O)SC1-C6alkyl, —NR10C(═O)OC1-C6 alkyl, and —S(O)xC1-C6 alkyl, the alkyl, alkenyl, and alkynyl groups of Rb are optionally substituted with 1-13 halogens and are optionally substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR10R11, (d) —C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC1-C4alkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from —OC1-C2 alkyl, (f) —OC3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO2H, (h) —C(═O)CH3, and (i) —CO2C1-C4alkyl which is optionally substituted with 1-9 halogens,
• and when Rb is phenyl, said phenyl is optionally substituted with 1-5 halogens and is optionally substituted with 1-3 substituents independently selected from C1-C4 alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —C3-C6 cycloalkyl, —OC1-C4alkyl, —OC2-C4 alkenyl, —OC2-C4 alkynyl, —OC3-C6 cycloalkyl, —C(═O)C1-C4alkyl, —C(═O)H, —CO2H, —CO2C1-C4alkyl, —NR10R11, —C(═O)NR10R11, —NR10C(═O)OC1-C4 alkyl, —NR10C(═O)NR10R11, —S(O)xC1-C4 alkyl, —S(O)yNR10R11, —NR10S(O)yNR10R11, —CN, —NO2, and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally 1-3 double bonds and optionally 1-3 substituents independently selected from halogen, —CH3, —OCH3, —CF3, and —OCF3;
• wherein when the substituents on phenyl when Rb is phenyl are selected from —C1-C4 alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —C3-C6 cycloalkyl, —OC1-C4alkyl, —OC2-C4 alkenyl, —OC2-C4 alkynyl, —OC3-C6 cycloalkyl, —C(═O)C1-C4alkyl, —CO2C1-C4alkyl, —NR10C(═O)OC1-C4 alkyl, and —S(O)xC1-C4 alkyl, then the alkyl, alkenyl, alkynyl, and cycloalkyl groups of said substituent groups optionally comprise 1-5 halogen substituents and optionally one substituent selected from —OH, —NR10R11, —OCH3 which is optionally substituted with 1-3 F, and phenyl which is optionally substituted with 1-3 substituents independently selected from halogen, —CH3, —OCH3, —CF3, and —OCF3;
• n is an integer selected from 0 and 1;
• p is an integer from 0-4;
• x is an integer selected from 0, 1, and 2;
• y is an integer selected from 1 and 2;
• Z is phenyl or a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally comprising a carbonyl group and 1-3 double bonds, said heterocyclic ring being connected by a carbon atom to the N to which said heterocyclic ring is attached, wherein said phenyl or 5-6-membered heterocyclic ring optionally comprises 1-3 substituents independently selected from halogen, C1-C4 alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —OC1-C4alkyl, —OC2-C4 alkenyl, —OC2-C4 alkynyl, —C(═O)C1-C4alkyl, CO2C1-C4alkyl, —NR10R11, —C(═O)NR10R11, —NR10C(═O)OC1-C4 alkyl, —NR10C(═O)NR10R11, —S(O)xC1-C4 alkyl, —S(O)yNR10R11, —NR10S(O)yNR10R11, —OH, —CN, and —NO2, wherein the alkyl, alkenyl, and alkynyl groups of said substituents are optionally substituted with 1-5 halogens and optionally one substituent selected from —OH, —CO2H, and —CO2C1-C4alkyl;
• R1, R12, R13, R14, R15, and R16 are each independently selected from the group consisting of H, —OH, halogen, —C1-C4 alkyl, —C3-C6 cycloalkyl, —OC1-C4 alkyl, and —NR10R11, wherein —C1-C4 alkyl, —C3-C6 cycloalkyl, and —OC1-C4 alkyl are each optionally substituted with 1-9 halogens and are each optionally substituted with 1-2 groups independently selected from —OH, —C(═O)CH3, —OC(═O)CH3, —OC1-C2 alkyl, and —OC1-C2 alkyleneOC1-C2alkyl, wherein R1 and R12 together may optionally form an oxo group;
• and
• R10 and R11 are each independently selected from H, —C1-C5 alkyl, —C(═O)C1-C5 alkyl and —S(O)yC1-C5 alkyl, wherein —C1-C5 alkyl in all instances is optionally substituted with 1-11 halogens.