Antagonists of the vanilloid receptor subtype 1 (VR1) and uses thereof

A compound having formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein

• X1 is —(CR1aR1b)m—, —(CR1aR1b)nG1-, or —(CR1aR1b)p-G-C(R1aR1b)—;
• m is 1, 2, 3 or 4;
• n is 1, 2 or 3;
• p is 1 or 2;
• G1 is O, N(Rx), or S;
• R1a and R1b, at each occurrence, are independently hydrogen, alkyl, halogen, or haloalkyl;
• R2a and R2b, at each occurrence, are independently hydrogen, alkyl, halogen, or haloalkyl;
• Rx is hydrogen, alkyl, haloalkyl, Ry, —C(O)Oalkyl, or —C(O)ORy;
• Ry at each occurrence is independently arylalkyl or heteroarylalkyl;
• wherein the aryl moiety of the arylalkyl and the heteroaryl moiety of the heteroarylalkyl are independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, halogen, alkoxy and haloalkyl;
• A1 is N or CR3;
• A2 is N or CR4;
• A3 is N or CR5;
• A4 is N or CR6;
• provided that only one or two of A1, A2, A3 and A4 can be N;
• R3, R4, R5 and R6 are each independently selected from the group consisting of, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, —CN, —NO2, —OH, alkoxy, haloalkoxy, —ORE, —O—(CR1aR1b)q—RE, —N(RA)(RB), —C(O)RB, —C(O)N(RA)(RB), —C(O)ORB, —S(RB), —S(O)RB, —S(O)2RB, —S(O)2N(RA)(RB), RE and —(CR1aR1b)q—RE;
• q is 1, 2, 3, 4, 5 or 6;
• RA at each occurrence is independently hydrogen, alkyl or haloalkyl;
• RB at each occurrence is independently hydrogen, alkyl, alkenyl, haloalkyl, RE or —(CR1aR1b)q—RE,
• RE at each occurrence is independently a monocyclic or bicyclic ring, independently selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl;
• wherein each RE is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, haloalkyl, halogen, oxo, —CN, —NO2, —OH, alkoxy, haloalkoxy, —NH2, —N(H)(alkyl), —N(alkyl)2, —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)Oalkyl, —N(alkyl)C(O)Oalkyl, —C(O)H, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH2, —C(O)N(H)(alkyl), —C(O)N(alkyl)2, —S(alkyl), —S(O)alkyl, —S(O)2alkyl, —S(O)2N(H)2, —S(O)2N(H)(alkyl) and —S(O)2N(alkyl)2,
• Y is —S—, —S(O), —S(O)2, —O—, —N(R7)— or —C(R1aR1b)—;
• R7 is hydrogen, alkyl, alkenyl, alkoxy, haloalkyl, —C(O)ORB, RE, or —(CR1aR1b)q—RE;
• X2 is —N(H)C(O)N(H)-Z or —(CRgRh)q—N(H)C(O)N(H)-Z;
• Rg and Rh are independently hydrogen or alkyl;
• and
• Z is a monocyclic or bicyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, heteroaryl and aryl;
• wherein each Z is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, haloalkyl, halogen, —NO2, —CN, —OH, alkoxy, haloalkoxy, hydroxyalkyl, —NH2, —N(H)(alkyl), —N(alkyl)2, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH2, —C(O)N(H)(alkyl), —C(O)N(alkyl)2, —S(alkyl), —S(O)alkyl, —S(O)2alkyl, —S(O)2N(H)2, —S(O)2N(H)(alkyl), —S(O)2N(alkyl)2, RE, and —(CR1aRlb)q—RE.