Trpv1 antagonists including dihydroxy substituent and uses thereof

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X is O, S, or N—OR10;
• L1 and L2 are each independently N or C(R3) provided that L1 and L2 are not both N;
• Ar1 is:
• Ar2 is:
• c is the integer 0, 1, or 2;
• Y1, Y2, and Y3 are each independently C, N, or O, wherein no more than one of Y1, Y2, or Y3 can be O, and for each Y1, Y2, or Y3 that is N, the N is bonded to one R21 group, and for each Y1, Y2, or 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 each independently —H or —(C1-C6)alkyl;
• E is ═O, ═S, ═CH(C1-C6)alkyl, ═CH(C2-C6)alkenyl, —NH(C1-C6)alkyl, or ═N—OR20;
• R1 is -halo, —(C1-C4)alkyl, —NO2, —CN, —S(O)2N(R20)2, —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-C6)alkenyl, —(C2-C6)alkynyl, —S(O)2(C1-C6)alkyl, —N(R20)S(O)2(C1-C6)alkyl2, or -phenyl;
• or
• (b) a group of formula Q, wherein Q is:
• Z1 is independently —H, —OR20, —N(R20)2, —CH2OR20, or —CH2N(R20)2;
• Z2 is independently —H, —(C1-C6)alkyl, or —CH2OR20;
• each Z3 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
• J is —OR20 or —N(R20)2;
• provided that at least one R2 group is a group of formula Q;
• each R3 is independently —H, —OCF3, -halo, —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C1-C6)alkoxy, —N(R20)S(O)2(C1-C6)alkyl, -(3- to 7-membered)heterocycle, —OR23, —SR23, —N(R20)(R23), —C(O)OR23, —C(O)R23, —OC(O)R23, —OC(O)NHR20, —NHC(O)R13, —C(O)N(R13)2, —S(O)2R20, —N(R20)S(O)2R13, or —CH2OR7;
• 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(C2-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 optionally 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, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
• R10 is —H, —(C1-C4)alkyl, or —(C3-C7)cycloalkyl;
• each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
• each R13 is independently —H, —(C1-C4)alkyl, —(C2-C4)alkenyl, —(C2-C4)alkynyl, -(3- to 7-membered)heterocycle, or -phenyl;
• 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)alkoxy-(C1-C6)alkyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), -(3- to 7-membered)heterocycle, —(C1-C6)haloalkyl, —(C1-C6)alkoxy(C2-C6)alkyl, —(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)C(O)R7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —S(O)R7, —S(O)2R7, —S(O)2N(R7)2, —S(O)2C(halo)3, —S(O)2(3- to 7-membered)heterocycle, —C(O)N(R7)2, —(C1-C6)alkyl-C═NOR7, —(C1-C6)alkyl-C(O)—N(R7)2, —(C1-C6)alkyl-NHS(O)2N(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,
• R22 is —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
• each R23 is independently —(C1-C6)alkyl or —(C3-C8)cycloalkyl;
• each -halo is independently —F, —Cl, —Br, or —I;
• each b is independently the integer 1 or 2;
• d is the integer 1, 2, 3, 4, or 5;
• m is the integer 0, 1, or 2;
• n is the integer 1, 2, or 3;
• p is the integer 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
• u is the integer 0, 1, 2, 3, or 4.

A compound of formula (III):

• or a pharmaceutically acceptable salt thereof, wherein
• Ar1 is:
• Ar2 is:
• Z3 is —H or —(C1-C3)alkyl;
• R1 is -halo, —(C1-C4)alkyl, —OCH3, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, or —OCH2(halo);
• each R3 is independently —H, —OCF3, -halo, —(C1-C3)alkyl, —(C1-C3)haloalkyl, —(C1-C6)alkoxy, —N(R20)S(O)2(C1-C3)alkyl, —OR23, —N(R20)(R23), —NHC(O)R13, —C(O)N(R13)2, —S(O)2R20, —N(R20)S(O)2R13, or —CH2OR7;
• each R7 is independently —H, —(C1-C3)alkyl, —(C2-C4)alkenyl, —(C2-C4)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C1-C3)haloalkyl, —(C1-C6)hydroxyalkyl, —(C1-C6)alkoxy(C2-C6)alkyl, —(C1-C3)alkyl-N(R20)2, or —C(O)N(R20)2;
• each R8 and R9 is independently —H, —Cl, —Br, —F, —CH3, —OCH3, —OCH2CH3, —CF3, —OCF3, -iso-propyl, -tert-butyl, —S(O)2CF3, —S(O)2CH3, or —S(O)2CH2CH3;
• each R13 is independently —H, —(C1-C4)alkyl, —(C2-C4)alkenyl, —(C2-C4)alkynyl, -(3- to 7-membered)heterocycle, or -phenyl;
• each R14′ is independently —H, —Cl, —F, —Br, —CF3, —OCF3, —(C1-C6)alkyl, —S(O)2CF3, —S(O)2(C1-C6)alkyl, —OCH3, —OCH2CH3, or —OCH(CH3)2;
• each R20 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
• each R23 is independently —(C1-C6)alkyl or —(C3-C8)cycloalkyl;
• each -halo is independently —F, —Cl, —Br, or —I;
• m is the integer 0, 1, or 2;
• and
• q is the integer 0, 1, or 2.