TRPV1 antagonists including dihydroxy substituent and uses thereof

A compound of formula I.1:

• or a pharmaceutically acceptable salt thereof, wherein
• X is O, S, N—CN, N—OH, or N—OR10;
• R10 is —(C1-C4)alkyl;
• Ar1 is
• Ar2 is
• c is the integer 0, 1, or 2;
• Y1, Y2, and Y3 are independently C or N;
• wherein for each Y1, Y2, and Y3 that is N, the N is bonded to one R20 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, ═C(C1-C5)alkyl, ═C(C1-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, -phenyl, or -halo;
• each Z3 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, or -phenyl;
• J is —OR20, —SR20, or —N(R20)2;
• provided that at least one R2 group is a group of formula Q, and provided that when Z1 is —OR7 o —SR7, Z2 in not -halo;
• each R3 is independently:
• —H, or —(C1-C6)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 are independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, —OCH2(halo), —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;
• 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 —(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, —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, —C(O)N(R7)2, —(C1-C5)alkyl-C═NOR7, —(C1-C3)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 or —(C1-C6)alkyl;
• each halo is independently —F, —Cl, —Br, or —I;
• n is the integer 1, 2, or 3;
• each b is independently 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
• m is the integer 0, 1, or 2.

A compound of formula

• or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof, wherein
• X is O, S, N—CN, N—OH, or N—OR10;
• R10 is —(C1-C4)alkyl;
• Ar1 is
• Ar2 is
• c is the integer 0, 1, or 2;
• Y1, Y2, and Y3 are independently C or N;
• wherein for each Y1, Y2, and Y3 that is N, the N is bonded to one R20 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(C1-C5)alkenyl, —NH(C1-C6)alkyl, or ═N—OR20;
• R1 is —H, -halo, —(C1-C4)alkyl, —NO2, —CN, —OH, —OCH3, —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 —OH, —SH, —N(R20)2, —CH2—OH, —CH2—SH, or —CH2—N(R20)2;
• Z2 is —H, —CH3, or —CH2OR7 and
• each Z3 is independently —H or —CH3;
• J is —OH, —SH, or —N(R20)2;
• provided that at least one R2 group is a group of formula Q;
• each R3 is independently:
• —H or —(C1-C6)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, —OR7, —C(O)R7, —C(O)R7, —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)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-C5)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 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.

A compound of formula III:

• or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof, wherein
• X is O, S, N—CN, N—OH, or N—OR10;
• R10 is —(C1-C4)alkyl;
• each R3 is independently:
• —H or —(C1-C6)alkyl;
• m is the integer 0, 1, or 2;
• wherein Ar1 is:
• R1 is —Cl, —F, —CF3, or —CH3;
• wherein Ar2 is:
• R14 is —H, —F, —Br, —CF3, —OCF3, —(C1-C6)alkyl, —S(O)2CF3, —S(O)2(C1-C6)alkyl, —OCH3, —OCH2CH3, or —OCH(CH3)2;
• R141 is —H, —Cl, —F, —Br, —CF3, —OCF3, —S(O)2CF3, —S(O)2(C1-C6)alkyl, —OCH3, —OCH2CH3, or —OCH(CH3)2;
• and
• R8 and R9 are independently —H, —Cl, —Br, —F, —CH3, —OCH3, —OCH2CH3, —CF3, —OCF3, iso-propyl, or tert-butyl.