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

1. A method of treating a disorder selected from the group consisting of pain, neuropathic pain, allodynia, pain associated with inflammation, inflammatory hyperalgesia, bladder overactivity, and urinary incontinence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein

X 1 is —(CR 1a R 1b ) m —, —(CR 1a R 1b ) n G 1 -, or —(CR 1a R 1b ) p -G 1 -C(CR 1a R 1b )—;

m is 1, 2, 3 or 4;

n is 1, 2 or 3;

p is 1 or 2;

G 1 is O, N(R x ), or S;

R 1a and R 1b , at each occurrence, are independently hydrogen, alkyl, halogen, or haloalkyl;

R 2a and R 2b , at each occurrence, are independently hydrogen, alkyl, halogen, or haloalkyl;

R x is hydrogen, alkyl, haloalkyl, R y , —C(O)Oalkyl, or —C(O)OR y ;

R y 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;

A 1 is N or CR 3 ;

A 2 is N or CR 4 ;

A 3 is N or CR 5 ;

A 4 is N or CR 6 ; provided that only one or two of A 1 , A 2 , A 3 and A 4 can be N;

R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, —CN, —NO 2 , —OH, alkoxy, haloalkoxy, —OR E , —O—(CR 1a R 1b ) q —R E , —N(R A )(R B ), —C(O)R B , —C(O)N(R A )(R B ), —C(O)OR B , S(R B ), —S(O)R B , —S(O) 2 R B , —S(O) 2 N(R A )(R B ), R E and —(CR 1a R 1b ) q —R E ;

q is 1, 2, 3, 4, 5 or 6;

R A at each occurrence is independently hydrogen, alkyl or haloalkyl;

R B at each occurrence is independently hydrogen, alkyl, alkenyl, haloalkyl, R E or —(CR 1a R 1b ) q —R E ;

R E 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 R E is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, haloalkyl, halogen, oxo, —CN, —NO 2 , —OH, alkoxy, haloalkoxy, —NH 2 , —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)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , —S(alkyl), —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 N(H) 2 , —S(O) 2 N(H)(alkyl) and —S(O) 2 N(alkyl) 2 ;

Y is —S—, —S(O), —S(O) 2 , —O—, —N(R 7 )— or —C(R 1a R 1b )—;

R 7 is hydrogen, alkyl, alkenyl, alkoxy, haloalkyl, —C(O)OR B , R E , or —(CR 1a R 1b ) q —R E ;

X 2 is —N(H)C(O)N(H)—Z or —(CR g R h ) q —N(H)C(O)N(H)—Z;

R g and R h 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, —NO 2 , —CN, —OH, alkoxy, haloalkoxy, hydroxyalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , —S(alkyl), —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 N(H) 2 , —S(O) 2 N(H)(alkyl), —S(O) 2 N(alkyl) 2 , R E , and —(CR 1a R 1b ) q —R E .

2. The method of claim 1 wherein the disorder is bladder overactivity.

3. The method of claim 1 wherein the disorder is urinary incontinence.

4. The method of claim 1 wherein the disorder is pain.

5. The method of claim 1 wherein the disorder is inflammatory hyperalgesia.