Heterocyclic trpv1 receptor ligands

A compound or a pharmaceutically acceptable derivative thereof, selected from:

• wherein each W is independently N or C(R3) and each B is independently N(R3), C(═O), C(═S) or C(R3)2, provided that when a W group is N then no said nitrogen atom can be connected to 2 or more nitrogen atoms;
• U is selected from —OAr2, —N(R20)Ar2, —SAr2, —S(═O)Ar2, and —S(═O)2Ar2;
• Ar1 is:
• provided that when Ar1 is connected to the 7-position of a 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R1 is —Cl, then R2 is not —CH2OH;
• Ar2 is:
• c is the integer 0, 1, or 2;
• Y1, Y2, and each Y3 are independently selected from —C(R20)2—, —N(R21)—, and —O—, wherein no more than one of Y1, Y2, and Y3 can be O and no more than a total of two (C1-C6)alkyl groups are substituted on all of Y1, Y2, and Y3;
• R12a and R12b are each independently selected from —H and —(C1-C6)alkyl;
• E is ═O, ═S, ═CH(C1-C6)alkyl, ═CH(C2-C6)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:
• each Z1 is independently selected from —H, —OR7, —CH2OR7, —CH2SR7, —CH2N(R20)2, and -halo;
• each Z2 is independently selected from —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —CH2OR7, -phenyl, and -halo;
• each Z3 is independently selected from —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, and -phenyl;
• each Z4 is independently selected from —H, —OH, —OR20, —(C1-C6)alkyl, and —N(R20)2;
• each J is independently selected from —OR20, —SR20, —N(R20)2, and —CN;
• provided that at least one R2 group is a group of formula Q;
• each R3 is independently:
• (a) —H, -halo, —CH2OR7, —CN, —NO2, or —NH2;
• or
• (b) —C(═NR28)N(R28)2, —OC(═O)N(R28)2, —OC(═O)N(R28)S(═O)2R28, —O(C1-C6)alkyl-N(R28)2, —O(C1-C6)alkyl-OR28, —S(═O)2N(R28)C(═O)R28, —S(═O)2N(R28)C(═O)OR28, —S(═O)2N(R28)C(═O)N(R28)2, —N(R28)C(═O)OR28, —N(R28)C(═O)N(R28)2, —N(R28)C(═NR28)N(R28)2, —N(R28)S(═O)2R28, —N(R28)S(═O)2N(R28)2, —N(R28)(C1-C6)alkyl-N(R28)2, —N(R28)(C1-C6)alkyl-OR28, or —(C1-C6)alkyl-R22;
• or
• (c) a group of the formula —R23-M-A-R24;
• or
• (d) 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
• (e) 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 optionally 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, —C(═O)—(C1-C6)alkyl, 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, —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, —C(═O)R7, —C(═O)OR7, —OC(═O)R7, or —OC(═O)OR7;
• each R14 is independently:
• (a) —H, —CN, —OH, -halo, —N3, or —NO2;
• or
• (b) —(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-(C1-C6)alkyl, —(C1-C6)alkoxy-(C2-C6)alkenyl, —(C1-C6)alkoxy-(C2-C6)alkynyl, —(C1-C6)alkoxy-(C3-C8)cycloalkyl, —OC(halo)3, —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, —(C1-C6)alkyl-C(═O)OR7, —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 of which is optionally substituted with 1, 2 or 3 independently selected R20 groups;
• or
• (c) a group of formula —R30—R31—R32;
• each R20 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
• each R21 is independently —(C1-C6)alkyl,
• each R22 is independently selected from:
• (a) —H, —OH, -halo, —NH2, —CN, —NO2, —C(═O)NH2, and —C(═O)OR7;
• or
• (b) —(C1-C6)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C6)alkoxy, —(C1-C8)alkanoyl, —(C1-C8)alkoxycarbonyl, —(C1-C8)alkanoyloxy, —(C1-C8)alkylthio, —(C1-C6)alkoxy-(C1-C6)alkyl, -phenyl, -phenyl(C1-C6)alkyl, -phenoxy, -phenyl-(C1-C6)alkoxy, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, —(S(═O)2)—(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, —(C1-C10)alkyl-(5- to 10-membered)heteroaryl, —(C1-C10)alkyl-(3- to 7-membered)heterocycle, —(C1-C10)alkyl-(7- to 10-membered)bicycloheterocycle, —P(═O)(ORW)2, and —OP(═O)(ORW)2, each of which is optionally substituted with 1, 2 or 3 independently selected R5 groups;
• each RW is independently selected from —H, —(C1-C6)alkyl, -phenyl, —(C1-C6)alkyl-phenyl, —(C1-C10)alkyl-(5- to 10-membered)heteroaryl, —(C1-C10)alkyl-(3- to 7-membered)heterocycle, and —(C1-C10)alkyl-(7- to 10-membered)bicycloheterocycle;
• each R5 is independently:
• (a) —OH, -halo, —NH2, —C(═O)NH2, —CN, —NO2, or —C(═O)OH;
• or
• (b) —(C1-C6)alkyl, —(C1-C6)alkoxy, —(C1-C8)alkoxycarbonyl, —(C1-C8)alkanoyloxy, —(C1-C6)alkylthio, —(C1-C6)alkoxy-(C1-C6)alkyl, —(C1-C6)hydroxyalkyl, —(C1-C6)haloalkyl, -phenyl, —NH(C1-C6)alkyl, —N((C1-C6)2alkyl)2, —(S(═O)2)(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, —(C1-C6)alkyl-phenyl, —(C1-C10)alkyl-(5- to 10-membered)heteroaryl, —(C1-C10)alkyl-(3- to 7-membered)heterocycle, or —(C1-C10)alkyl-(7- to 10-membered)bicycloheterocycle, each of which is optionally substituted with 1, 2 or 3 independently selected R14 groups;
• each M is independently a bond, —O—, —S—, —S(═O)—, —S(═O)2—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —C(═O)N(R25)—, —N(R25)C(═O)—, —N(R25)S(═O)2—, —S(═O)2N(R25)—, —N(R25)—, —OP(═O)(OR25)—, —(R25O)P(═O)(═O)—, —(R25O)P(═O)—, —P(═O)(OR25)—, —OP(═O)2(OR25)—, —(R25O)P(═O)2(═O)—, —(R25O)P(═O)2—, or —P(═O)2(OR25)—;
• each A is independently a bond or —(C1-C6)alkyl- which is optionally substituted with 1, 2 or 3 independently selected R22 groups;
• each R23 is independently:
• (a) a bond;
• or
• (b) —(C1-C6)alkyl-, —(C2-C10)alkenyl-, or —(C2-C10)alkynyl-, each of which is optionally substituted with
• (i) 1, 2 or 3 independently selected R22 groups;
• or
• (ii) 1 or 2 substituents independently selected from —OH and —(C1-C6)alkyl which is optionally substituted with 1 or 2 independently selected R22 groups;
• or
• (c) R23 and R24 together, R23 and R25 together, or R23, R24 and R25 together form a (C3-C10)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to 10-membered)bicycloheterocycle, each of which is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R22 groups;
• R24 and R25 are each independently:
• (a) —H or —C(═O)OH;
• or
• (b) —(C1-C6)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C8)alkanone, —(C1-C6)alkoxy-(C1-C6)alkyl, —(C1-C8)alkoxycarbonyl, —(C1-C8)alkanoyloxy, —(C1-C6)alkoxy, —NH(C1-C6)alkyl, C6)alkyl)2, —OR25, —(C3-C10)cycloalkyl, -phenyl, -(5- to 10-membered)heteroaryl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is optionally substituted with 1, 2 or 3 independently selected R22 groups;
• or
• (c) R23 and R24 together, R23 and R25 together, R24 and R25 together, or R23, R24 and R25 together form a (C3-C10)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to 10-membered)bicycloheterocycle, each of which is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R22 groups;
• each R28 is independently:
• (a) —H;
• or
• (b) —(C1-C6)alkyl, -phenyl, or -benzyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from -halo, —(C1-C6)alkyl, —(C1-C6)haloalkyl, —O(C1-C6)alkyl, —NH2, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2;
• each R30 is independently —O—, —NH—, or —S—;
• each R31 is independently —C(═O)— or —(C1-C6)alkyl which is unsubstituted or substituted with an oxo group;
• each R32 is independently —OR33, —C(═O)OR33, —SR33, or —N(R34)2;
• each R33 is independently —H, —P(═O)(OH)2, —P(═O)(OH)(O(C1-C6)alkyl), —P(═O)(O(C1-C6)alkyl)2, —(C1-C6)alkyl, or —(C1-C6)alkoxy-(C1-C6)alkyl, wherein the portion of each R33 moiety comprising alkyl is optionally substituted with 1, 2 or 3 independently selected R8 groups;
• each R34 is independently:
• (a) —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, or —(C2-C10)alkynyl, each of which is optionally substituted with 1, 2 or 3 independently selected R8 groups;
• or
• (b) two geminal R34 groups together form a (3- to 7-membered)heterocycle that is optionally substituted with 1, 2 or 3 independently selected R8 groups;
• each -halo is independently —F, —Cl, —Br, or —I;
• n is the integer 1, 2 or 3;
• p is the integer 1 or 2;
• each b is independently selected from the integers 1 and 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;
• and
• t is the integer 0, 1, 2 or 3.