Formula (IA″) compounds comprising (piperidin-4-yl)pyridine or (1,2,3,6-tetrahydropyridin-4-4yl) as TRPV1 antagonists

A compound of formula (IA″):

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein
• X is O;
• W is C;
• the dashed line denotes the presence or absence of a bond, and when the dashed line is present as a bond to provide one bond of a double bond then R4 is absent, otherwise R4 is —H, —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —C(O)N(R13)2, —S(O)2R10, or —NO2;
• R10 is —(C1-C4)alkyl;
• each R13 is independently —(C1-C4)alkyl, —(C7-C4)alkenyl, —(C1-C4)alkynyl, or -phenyl;
• Ar1 is
• Ar2 is
• c is the integer 0, 1, or 2;
• Y1, Y2, and Y3 are independently C, N, or O;
• wherein no more than one of Y1, Y2, or Y3 can be O, and for each Y1, Y2, and Y3 that is N, the N is bonded to one R21 group, and for each Y1, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided that there are no more than a total of two (C1-C6)alkyl groups substituted on all of Y1, Y2, and Y3;
• R12a and R12b are independently —H or —(C1-C6)alkyl;
• E is ═O, ═S, ═CH(C1-C5)alkyl, ═CH(C2-C5)alkenyl, —NH(C1-C6)alkyl, or ═N—OR20;
• R1 is —H, -halo, —(C1-C4)alkyl, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, or —OCH2(halo);
• each R2 is independently:
• (a) -halo, —OH, —O(C1-C4)alkyl, —CN, —NO2, —NH2, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, or -phenyl, or
• (b) a group of formula Q;
• wherein Q is
• Z1 is —H, —OR7, —SR7, —CH2—OR7, —CH2—SR7, —CH2—N(R20)2, or -halo;
• Z2 is —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —CH2—OR7, -phenyl, or -halo;
• each Z3 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, or -phenyl;
• provided that at least one R2 group is a group of formula Q, and provided that when Z1 is —OR7 or —SR7, then Z2 is not -halo;
• each R3 is independently:
• (a) —H, —(C1-C6)alkyl, or —CH2OR7;
• or
• (b) two R3 groups together form a (C2-C6)bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups, and which bridge optionally contains —HC═CH— within the (C2-C6)bridge;
• or
• (c) two R3 groups together form a —CH2—N(Ra)—CH2— bridge, a
• bridge, or a
• bridge;
• Ra is —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —CH2—C(O—Rc, —(CH2)—C(O)—ORc, —(CH2)—C(O)—N(Rc)2, —(CH2)2—O—Rc, —(CH2)2—S(O)2—N(Rc)2, or —(CH2)2—N(Rc)S(O)2—Rc;
• Rb is:
• (a) —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, -(3- to 7-membered)heterocycle, —N(Rc)2, —N(Rc)—(C3-C8)cycloalkyl, or —N(Rc)-(3- to 7-membered)heterocycle;
• or
• (b)-phenyl, -(5- or 6-membered)heteroaryl, —N(Rc)-phenyl, or —N(Rc)-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R7 groups;
• each Rc is independently —H or —(C1-C4)alkyl;
• each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C1-C6)haloalkyl, —(C1-C6)hydroxyalkyl, —(C1-C6)alkoxy(C1-C6)alkyl, —(C1-C6)alkyl-N(R20)2, or —C(O)N(R20)2;
• each R8 and R9 is independently:
• (a) —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2-OH groups;
• or
• (b) —H, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, —OCH2(halo), —SC(halo)3, —SCH(halo)2, —SCH2(halo), —CN, —O—CN, —OH, -halo, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7OH, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
• each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
• each R14 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, —(C1-C6)alkoxy-(C1-C6)alkyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), -(3- to 7-membered)heterocycle, —(C1-C6)haloalkyl, —(C2-C6)haloalkenyl, —(C2-C6)haloalkynyl, —(C2-C6)hydroxyalkenyl, —(C2-C6)hydroxyalkynyl, —(C1-C6)alkoxy(C2-C6)alkyl, —(C1-C6)alkoxy(C2-C6)alkenyl, —(C1-C6)alkoxy(C2-C6)alkynyl, —(C1-C6)alkoxy(C3-C8)cycloalkyl, —CN, —OH, -halo, —OC(halo)3, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7OH, —OR7, —SR7, —O(CH2)bOR7, —O(CH2)bSR7, —O(CH2)bN(R7)2, —N(R7)(CH2)bOR7, —N(R7)(CH2)bSR7, —N(R7)(CH2)bN(R7)2, —N(R7)COR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —S(O)R7, or —S(O)2R7, —S(O)2N(R7)2, —SO2C(halo)3, —SO2(3- to 7-membered)heterocycle, —C(O)N(R7)2, —(C1-C5)alkyl-C═NOR7, —(C1-C5)alkyl-C(O)—N(R7)2, —(C1-C6)alkyl-NHSO2N(R7)2, or —(C1-C6)alkyl-C(═NH)—N(R7)2;
• each R20 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
• each R21 is independently —H, —(C1-C6)alkyl,
• each halo is independently —F, —Cl, —Br, or —I;
• n is the integer 1, 2, or 3;
• each b is independently 1 or 2;
• q is the integer 0, 1, 2, 3, or 4;
• r is the integer 0, 1, 2, 3, 4, 5, or 6;
• s is the integer 0, 1, 2, 3, 4, or 5;
• t is the integer 0, 1, 2, or 3;
• and
• m is the integer 0, 1, or 2.