Antagonists of the vanilloid receptor subtype 1 (VR1) and uses thereof
View Patent ↗The present invention is directed to compounds of formula (I) wherein variables X 1 , X 2 , Y, R 1a , R 1b , R 2a , R 2b , A 1 , A 2 , A 3 , and A 4 are as defined in the description, and methods of use to treat pain, neuropathic pain, allodynia, pain associated with inflammation or an inflammatory disease, inflammatory hyperalgesia, bladder overactivity, and urinary incontinence.
1. A compound having formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
X 1 is —(CR 1a R 1b ) m —, —(CR 1a R 1b ) n G 1 -, or —(CR 1a R 1b ) p -G-C(R 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 lb ) q —R E .
2. The compound of claim 1 wherein
Y is —O—;
A 1 is N;
A 2 is CR 4 ;
A 3 is CR 5 ;
A 4 is CR 6 ; and
R 4 , R 5 and R 6 are as defined in claim 1 .
3. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is N;
A 3 is CR 5 ;
A 4 is CR 6 ; and
R 3 , R 5 and R 6 are as defined in claim 1 .
4. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is CR 4 ;
A 3 is N;
A 4 is CR 6 ; and
R 3 , R 4 and R 6 are as defined in claim 1 .
5. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is CR 4 ;
A 3 is CR 5 ;
A 4 is N; and
R 3 , R 4 and R 5 are as defined in claim 1 .
6. The compound of claim 1 wherein
Y is —O—;
A 1 is N;
A 2 is N;
A 3 is CR 5 ;
A 4 is CR 6 ; and
R 5 and R 6 are as defined in claim 1 .
7. The compound of claim 1 wherein
Y is —O—;
A 1 is N;
A 2 is CR 4 ;
A 3 is N;
A 4 is CR 6 ; and
R 4 and R 6 are as defined in claim 1 .
8. The compound of claim 1 wherein
Y is —O—;
A 1 is N;
A 2 is CR 4 ;
A 3 is CR 5 ;
A 4 is N; and
R 4 and R 5 are as defined in claim 1 .
9. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is N;
A 3 is N;
A 4 is CR 6 ; and
R 3 and R 6 are as defined in claim 1 .
10. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is N;
A 3 is CR 5 ;
A 4 is N; and
R 3 and R 5 are as defined in claim 1 .
11. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is CR 4 ;
A 3 is N;
A 4 is N; and
R 3 and R 4 are as defined in claim 1 .
12. The compound of claim 1 wherein
Y is —O—;
A 1 is CR 3 ;
A 2 is CR 4 ;
A 3 is CR 5 ;
A 4 is CR 6 ; and
R 3 , R 4 , R 5 and R 6 are as defined in claim 1 .
13. The compound of claim 12 wherein
X 1 is —(CR 1a R 1b ) m —;
m is 1, 2, 3 or 4; and
R 1a and R 1b are as defined in claim 1 .
14. The compound of claim 13 wherein
m is 1;
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
15. The compound of claim 14 wherein
Z is indazolyl independently substituted with 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, haloalkyl, halogen, —NO 2 , —CN, —OH, alkoxy, haloalkoxy, —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 .
16. The compound of claim 15 that is selected form the group consisting of:
methyl 4-(3-(7-fluorospiro[chroman-2,1′-cyclobutane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(7-fluorospiro[chroman-2,1′-cyclobutane]-4-yl)-3-(1H-indazol-4-yl)urea;
1-(7-fluorospiro[chroman-2,1′-cyclobutane]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea;
7-tert-butylspiro[chroman-2,1′-cyclobutan]-4-amine; and
1-(7-tert-butylspiro[chroman-2,1′-cyclobutane]-4-yl)-3-(1H-indazol-4-yl)urea.
17. The compound of claim 13 wherein
m is 1;
X 2 is —(CR g R h ) q —N(H)C(O)N(H)-Z;
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 according to claim 1 ;
R g and R h are independently hydrogen or alkyl, and
q is 1, 2, 3, 4, 5 or 6.
18. The compound of claim 12 wherein
X 1 is —(CR 1a R 1b ) n G 1 —;
n is 1, 2 or 3;
R 1a and R 1b are as defined in claim 1 ; and
G 1 is O, N(R x ), or S.
19. The compound of claim 18 wherein
G is O;
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
20. The compound of claim 19 , wherein the compound is selected form the group consisting of:
1-(1H-indazol-4-yl)-3-(2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)urea;
methyl-4-(3-(2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)-3-(1H-indazol-4-yl)urea;
7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one;
7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-amine;
methyl 4-(3-(7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea; and
1-(7-fluoro-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-yl)-3-(2-methyl-2H-indazol-4-yl)urea.
21. The compound of claim 18 wherein
G is N(R x );
R x is selected from hydrogen, alkyl, haloalkyl, R y , —C(O)Oalkyl, or —C(O)OR y ;
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
22. The compound of claim 21 , wherein the compound is selected form the group consisting of:
1-(1H-indazol-4-yl)-3-(1′-methylspiro[chroman-2,4′-piperidine]-4-yl)urea; and
Methyl 4-(3-(1′-methylspiro[chroman-2,4′-piperidine]-4-yl)ureido)-1H-indazole-1-carboxylate.
23. The compound of claim 18 wherein
X 2 is —(CR g R h ) q —N(H)C(O)N(H)-Z;
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 according to claim 1 ;
R g and R h are independently hydrogen or alkyl, and
q is 1, 2, 3, 4, 5 or 6.
24. The compound of claim 12 wherein
X 1 is —(CR 1a R 1b ) p -G 1 —C(R 1a R 1b )—;
R 1a and R 1b are as defined in claim 1 ; and
p is 1 or 2.
25. The compound of claim 24 wherein
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
26. The compound of claim 24 wherein
X 2 is —(CR g R h ) q —N(H)C(O)N(H)-Z;
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 according to claim 1 ;
R g and R h are independently hydrogen or alkyl, and
q is 1, 2, 3, 4, 5 or 6.
27. The compound of claim 13 wherein
m is 2;
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
28. The compound of claim 27 wherein
Z is indazolyl independently substituted with 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, haloalkyl, halogen, —NO 2 , —CN, —OH, alkoxy, haloalkoxy, —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 .
29. The compound of claim 28 that is selected form the group consisting of:
methyl 4-(3-(6-methylspiro[chroman-2,1′-cyclopentane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(1H-indazol-4-yl)-3-(6-methylspiro[chroman-2,1′-cyclopentane]-4-yl)urea;
methyl 4-(3-(7-ethoxyspiro[chroman-2,1′-cyclopentane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(7-ethoxyspiro[chroman-2,1′-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea; methyl 4-(3-(6,7-dimethylspiro[chroman-2,1′-cyclopentane]-4-yl)ureido)-1H-indazole-1-carboxylate; and
1-(6,7-dimethylspiro[chroman-2,1′-cyclopentane]-4-yl)-3-(1H-indazol-4-yl)urea.
30. The compound of claim 13 wherein
m is 2;
X 2 is —(CR g R h ) q —N(H)C(O)N(H)-Z;
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 according to claim 1 ;
R g and R h are independently hydrogen or alkyl, and
q is 1, 2, 3, 4, 5 or 6.
31. The compound of claim 13 wherein
m is 3;
X 2 is —N(H)C(O)N(H)-Z; 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 according to claim 1 .
32. The compound of claim 31 wherein
Z is indazolyl independently substituted with 1, 2, 3 or 4 substituents selected from the group consisting of oxo, alkyl, haloalkyl, halogen, —NO 2 , —CN, —OH, alkoxy, haloalkoxy, —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 .
33. The compound of claim 32 that is selected form the group consisting of:
methyl 4-(3-spiro[chroman-2,1′-cyclohexan]-4-ylureido)-1H-indazole-1-carboxylate;
1-(1H-indazol-4-yl)-3-(spiro[chroman-2,1′-cyclohexane]-4-yl)urea;
methyl 4-(3-(7-fluorospiro[chroman-2,1′-cyclohexane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(7-fluorospiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl 4-(3-(6,7-dimethylspiro[chroman-2,1′-cyclohexane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(6,7-dimethylspiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl 4-(3-(6,8-dichlorospiro[chroman-2,1′-cyclohexane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(6,8-dichlorospiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
7-tert-butylspiro[chroman-2,1′-cyclobutan]-4-amine;
methyl 4-(3-(6,8-difluorospiro[chroman-2,1′-cyclohexane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(6,8-difluorospiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
methyl 4-(3-(6-ethoxyspiro[chroman-2,1′-cyclohexane]-4-yl)ureido)-1H-indazole-1-carboxylate;
1-(6-ethoxyspiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1H-indazol-4-yl)urea;
1-(7-fluorospiro[chroman-2,1′-cyclohexane]-4-yl)-3-(1-methyl-1H-indazol-4-yl)urea;
1-(1-methyl-1H-indazol-4-yl)-3-(spiro[chroman-2,1′-cyclohexane]-4-yl)urea;
1-(1H-indazol-4-yl)-3-(7-methoxyspiro[chroman-2,1′-cyclohexane]-4-yl)urea; and
1-(1H-indazol-4-yl)-3-(1′-methylspiro[chroman-2,4′-piperidine]-4-yl)urea.
34. The compound of claim 13 wherein
m=3;
X 2 is —(CR g R h ) q —N(H)C(O)N(H)-Z;
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 according to claim 1 ;
R g and R h are independently hydrogen or alkyl, and q is 1, 2, 3, 4, 5 or 6.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
36. The pharmaceutical composition of claim 35 further including a non-toxic pharmaceutically acceptable carrier and diluent.