Compounds as cannabinoid receptor ligands
View Patent ↗The present application relates to cannabinoid receptor ligands of formula (I) wherein X 1 , A 1 , R x , R 2 , R 3 , R 4 , and z are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions.
1. A compound according to formula (I),
or a pharmaceutically acceptable salt thereof, wherein
X 1 is O, S, S(O), S(O) 2 , or N(R bx ); wherein R bx is hydrogen, alkyl, haloalkyl, alkoxyalkyl, —C(O)O(alkyl), monocyclic cycloalkyl, —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl), or haloalkoxyalkyl; and
A 1 is -G 1a -G 1b , —(CR 1a R 1b ) q1 -G 1c , —(CR 1a R 1b ) q1 -A 2 , —(CR 1g R 1h ) q2 -A 4 , —N(R b )C(O)R a , —N(R b )C(O)OR d , —N(R b )C(O)N(R b )(R c ), —N(R b )(R c ), or —N═C(R p )(R q ); or
X 1 and A 1 together is N═N(R cx ); wherein R cx is alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;
R p is hydrogen, alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , —C(O)OR d , —C(O)R d , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;
R q is hydrogen, alkyl, haloalkyl, —N(R b )(R c ), —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ; or
R p and R q , together with the carbon atom to which they are attached, form a monocyclic 5-, 6-, 7-, or 8-membered cycloalkyl or heterocycle ring, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, haloalkyl, and halogen;
A 2 is —C(O)R a , —S(O) 2 R d , —C(O)N(R b )(R c ), —C(S)N(R b )(R c ), —S(O) 2 N(R b )(R c ), —C(═NOR f )R a , —CN, —N(R c )C(O)R m , —N(R c )C(O)OR d , —N(R c )S(O) 2 R d , —N(R c )C(O)N(R b )(R c ); —N(R c )S(O) 2 N(R b )(R c ), -L 1 -G 1d , -L 1 —(CR 1a R 1b ) q3 -G 1d , -L 1 —(CR 1a R 1b ) q1 ,-A 3 , —O—(CR 1a R 1b ) q2 —O—alkyl, —OH, or —O(haloalkyl);
A 3 is C(O)R h , —S(O) 2 R e , —C(O)N(R h ) 2 , —C(S)N(R h ) 2 , —S(O) 2 N(R h ) 2 , —C(═NOR h )R h , —N(R h )C(O)R h , —N(R h )C(O)OR e , —N(R h )S(O) 2 R e , —N(R h )C(O)N(R h ) 2 , —N(R h )S(O) 2 N(R h ) 2 , —CN, —OR j , or —N(R h ) 2 ;
A 4 is cycloalkyl, alkoxy, or N(R 1m ) 2 ;
L 1 is O or N(R b );
R a and R c , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, —(CR 1a R 1b ) q3 —O—alkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d or —(CR 1a R 1b ) q3 -G 1d ;
R b , at each occurrence, is each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, —(CR 1c R 1d ) q3 -(cycloalkyl), or haloalkoxyalkyl;
R d , at each occurrence, is alkyl, haloalkyl, —(CR 1a R 1b ) q3 —O-alkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;
R j is hydrogen, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);
R m is haloalkyl, —(CR 1a R 1b ) q3 —O-alkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;
R 1b , at each occurrence, is independently hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR h , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )C(O)OR e , or —N(R h )S(O) 2 R e ;
R 1g , at each occurrence, is independently hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR h , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )C(O)OR e , or —N(R h )S(O) 2 R e ; provided that at least one occurrence of R 1g is halo, C 1 -C 4 haloalkyl, —OR h , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )C(O)OR e , or —N(R h )S(O) 2 R e ;
R 1m is hydrogen, alkyl, haloalkyl, alkylcarbonyl, formyl, or alkoxyalkyl; or two R 1m taken together with the nitrogen atom to which they are attached form a heterocyclic ring, optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl, hydroxy, oxo and haloalkyl;
G 1a and G 1b , are each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl;
G 1c is cycloalkenyl, heterocycle, aryl, or heteroaryl;
wherein the ring as represented by G 1a is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, ═N—CN, ═N—OR f , —CN, oxo, —OR f ,—OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R f , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), and —N(R f )C(O)N(R f ) 2 ;
wherein the cycloalkyl of A 4 and the rings as represented by G 1b and G 1c , are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of G 1d , —(CR 1c R 1d ) q3 -G 1d , alkyl, alkenyl, alkynyl, halo, haloalkyl, ═N—CN, —CN, oxo, —OR f , —OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R f , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), —N(R f )(R f )C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —C(═NOR f )(R a ), —(CR 1c R 1d ) q3 —OR f , —(CR 1c R 1d ) q3 —OC(O)R f , —(CR 1c R 1d ), q3 —OC(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —S(O) 2 R e , —(CR 1c R 1d ) q3 —S(O) 2 N(R f ) 2 , —(CR 1c R 1d ), q3 —C(O)R f , —(CR 1c R 1d ) q3 —C(O)OR f , —(CR 1c R 1d ) q3 —C(O)N(R f ) 2 , —(CR 1c R 1d ), q3—N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f )C(O)R f , —(CR 1c R 1d ) q3 —N(R f )S(O) 2 R e , —(CR 1c R 1d ) q3 —N(R f )C(O)(R e ), —(CR 1c R 1d ) q3 —N(R f )C(O)N(R f ) 2 , and —(CR 1c R 1d ), q3 —CN;
G 1d , at each occurrence, is independently a monocyclic heterocycle, a monocyclic heteroaryl, a phenyl, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl; optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of —N(R h ) 2 , —CN, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, and hydroxy;
R e and R i , at each occurrence, are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, or —(CR 1c R 1d ) 3 -(monocyclic cycloalkyl);
R f , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(CR 1c R 1d ) q3 —OR g , monocyclic cycloalkyl, monocyclic heterocycle, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);
R g and R h , at each occurrence, are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);
wherein the cycloalkyl, the monocyclic cycloalkyl, and the monocyclic heterocycle, as a substituent or part of a substituent, of R b , R bx , R e , R i , R f , R g , R h , and R j , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, halo, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl;
R 2 is —(CR 2a R 2b ) q5 -G 2 ;
G 2 is a 4-, 5-, 6-, 7-, 8-, or 9-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; two non-adjacent atoms of said heterocycle ring can be optionally linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; each ring G 2 is optionally fused with a monocyclic ring selected from the group consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle and heteroaryl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl;
R 3 and R 4 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —NO 2 , —CN, halo, —OR h , —N(R h ) 2 , —C(O)R h , —C(O)O(R h ), haloalkyl, —(CR 3a R 3b ) q6 —OR h , —(CR 3a R 3b ) q6 —N(R h ) 2 , —(CR 3a R 3b ), q6 —C(O)R h , or —(CR 3a R 3b ) C(O)O(R h );
R 3 and R 4 , together with the carbon atoms to which they are attached, optionally form a 4-, 5-, 6-, or 7-membered monocyclic ring that contains zero, one or two additional double bond, zero or one oxygen atom, and zero, one or two nitrogen atom as ring atoms; two non-adjacent atoms of said monocyclic ring can be optionally linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, said monocyclic ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl; two substituents on the same carbon atom of said monocyclic ring, together with the carbon atom to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered monocyclic cycloalkyl ring, wherein the monocyclic cycloalkyl ring is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of alkyl and haloalkyl;
G 3 is cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, C 1 -C 4 haloalkyl, ═N—CN, ═N—OR h , —CN, oxo, —OR h , —OC(O)R h , —OC(O)N(R h ) 2 , —S(O) 2 R i —S(O) 2 N (R h ) 2 , —C(O)R h ,—C(O)OR h , —C(O)N(R h ) 2 , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), and —N(R h )C(O)N(R h ) 2 ;
R 1a , R 1h R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , and R 3b , at each occurrence, are each independently hydrogen, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
R x , at each occurrence, is independently G 1d , alkyl, alkenyl, alkynyl, haloalkyl, —CN, —OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R f , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), —N(R f )C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —OR f , —(CR 1c R 1d ) q3 —OC(O)R f , —(CR 1c R 1d ) q3 —OC(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —S(O) 2 R e , —(CR 1c R 1d ) q3 —S(O) 2 N(R f ) 2 , —(CR 1c R 1d ) q3 —C(O)R f , —(CR 1c R 1d ) q3 —C(O)OR f , —(CR 1c R 1d ) q3 —C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f )C(O)R f , —(CR 1c R 1d ) q3 —N(R f )S(O) 2 R e , —(CR 1c R 1d ) q3 —N(R f )C(O)O(R e ), —(CR 1c R 1d ) q3 —N(R f )C(O)N(R f ) 2 , or —(CR 1c R 1d ) q3 —CN;
q1 is 1, 2, 3, or 4;
q2 and q4, at each occurrence, are each independently 2, 3, 4, or 5;
q3 is 1, 2 or, 3;
q5 and q6, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6; and
z is 1, 2, 3, or 4;
with the proviso that
(i) when X 1 is N(R bx ) wherein R bx is hydrogen, alkyl, haloalkyl or alkoxyalkyl; and R 2 is —(CR 2a R 2b ) q4 —OH or —(CR 2a R 2b ) q4 —O-alkyl; then A 1 is not —(CR 1a R 1b ) q1 —OH;
(ii) when X 1 is O; and G 1b and G 1c are heterocycle, then G 1b and G 1c are each connected to the parent moiety through the ring carbon atom; and
(iii) when X 1 is S(O) 2 and R 2 is —(CR 2a R 2b ) q4 —O-alkyl; then A 1 is not N(H) 2 , N(alkyl)(H), or N (alkyl) 2 .
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —CN, halo, —OR h , haloalkyl, —(CR 3a R 3b ) q6 —OR h , or —(CR 3a R 3b ) q6 —N(R h ) 2 .
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx ); and
A 1 is —(CR 1a R 1b ) q1 -G 1c .
4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx ); and
A 1 is —(CR 1a R 1b ) q1 -A 2 .
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
7. The compound according to claim 2 or a pharmaceutically acceptable salt, thereof, wherein
X 1 is O or N(R bx ); and
A 1 is —(CR 1a R 1b ) q1 —OH.
8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
9. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx ); and
A 1 is —N(R b )C(O)R a , —N(R b )C(O)OR d , —N(R b )C(O)N(R b )(R c ), —N(R b )(R c ), or —N═C(R p )(R q ).
10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
11. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx ); and
A 1 is —N(R b )(R c ).
12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
13. The compound according to claim 1 having formula (II),
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx ).
15. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx );
R 3 and R 4 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —CN, halo, —OR h , haloalkyl, —(CR 3a R 3b )—OR h , or —(CR 3a R 3b )—N(R h ) 2 ; and
A 1 is —(CR 1a R 1b ) q1 -G 1c , —(CR 1a R 1b ) q1 -A 2 , —N(R b )C(O)Ra, —N(R b )C(O)OR d , —N(R b )(R c ), or —N═C(R p )(R q ).
16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
17. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx );
R 3 and R 4 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —CN, halo, —OR h , haloalkyl, —(CR 3a R 3b )—OR h , or —(CR 3a R 3b )—N(R h ) 2 ; and
A 1 is —(CR 1a R 1b ) q1 —OH.
18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
19. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
X 1 is O or N(R bx );
R 3 and R 4 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —CN, halo, —OR h , haloalkyl, —(CR 3a R 3b )—OR h , or —(CR 3a R 3b )—N(R h ) 2 ; and
A 1 is —N(R b )(R c ).
20. The compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein
G 2 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; or G 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; and each G 2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl.
21. The compound according to claim 1 selected from the group consisting of
2-[(2R)-azetidin-2-ylmethoxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
2-[(2S)-azetidin-2-ylmethoxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylazetidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2S) -piperidin-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpiperidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]- 1,3-thiazol-2(3H)-ylidene]-2-[(2R) -piperidin-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2R)-1-methylpiperidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2R)-1-methylazetidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
2-(azetidin-3-ylmethoxy) -N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3R) -piperidin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-methylazetidin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S) -piperidin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-methylpiperidin-3-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1 -methylpiperidin-4-yl)methoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(piperidin-4-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-methyl-1H-imidazol-5-yl)methoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(pyridin-2-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(pyrazin-2-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-oxidopyridin-2-yl)methoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(pyridin-3-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2R) -tetrahydrofuran-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2S) -tetrahydrofuran-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2R) -pyrrolidin-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3R) -pyrrolidin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S) -pyrrolidin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-methylpyrrolidin-3-yl]methoxy}-5-(trifluoromethyl)benzamide;
2-[(4-benzylmorpholin-2-yl)methoxy]-N-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
2-{[(2R)-2-amino-3-hydroxypropyl]oxy}-N-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1,4-dimethylpiperazin-2-ylmethyl]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{2-[methyl(phenyl)amino]ethoxy}-5-(trifluoromethyl)benzamide;
2-(benzyloxy)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H) -ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(1,3-oxazol-5-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(1,3-thiazol-2-ylmethoxy)-5-(trifluoromethyl)benzamide;
2-(2-tert-butylhydrazino)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
tert-butyl2-[2-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H) -ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]hydrazinecarboxylate;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S) -1-methyl-5-oxopyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2S) -pyrrolidin-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S) -1 -ethylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S) -1 -isopropylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
2-{[(2S)-1-acetylpyrrolidin-2-yl]methoxy}-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S) -1 -(methylsulfonyl)pyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2R) -(1-methyl-1-oxidopyrrolidin-2-yl)methoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(3-hydroxy-3-methylbutoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl) benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(1H -pyrazol-5-ylmethoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-4-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S) -1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{2-[(2-hydroxyethyl)amino]ethoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-cyano-2-{[(2S)-1 -methylpyrrolidin-2-yl]methoxy}benzamide;
N-[(2Z)-4,5-dimethyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methyoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H) -ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S) -morpholin-3-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({2-[(tetrahydro-2H-pyran-2-yloxy)imino]propyl}oxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({(2R)-3-hydroxy-2-[(trifluoroacetyl)amino]propyl}oxy)-5-(trifluoromethyl)benzamide;
2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(2S) -morpholin-2-ylmethoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-methyl-1H-imidazol-5-yl)methoxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1 -methyl-1H-imidazol-4-yl)methoxy]-5-(trifluoromethyl)benzamide;
2-{[(2R)-2-amino-3-hydroxypropyl]oxy}-N-[(2Z) -5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2Z)-2-(hydroxyimino)-3,3-dimethylbutyl]oxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2E)-2-(hydroxyimino)-3,3-dimethylbutyl]oxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(3,3-dimethyl-2-oxobutoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[2-(hydroxyimino)propyl]oxy}-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-methyl-2-(1H-pyrrol-1-yl)propoxy]-5-(trifluoromethyl)benzamide;
2-[(acetylamino)oxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({(2S)-1-[2-(hydroxyimino)propyl]pyrrolidin-2-yl}methoxy)-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(diethylamino)oxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(isopropylamino)oxy]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-({[2,2,2-trifluoro-1-methylethylidene]amino}oxy)benzamide;
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2R)-2-hydroxypropyl]oxy}-5-(trifluoromethyl)benzamide;
2-{[2-(tert-butoxyimino)propyl]oxy}-N-[2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;
N-[(2Z)-5-tert-butyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-[(cyclopentylideneamino)oxy]-5-(trifluoromethyl)benzamide; and
N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({[1-methyl-2-oxopropylidene]amino}oxy)-5-(trifluoromethyl)benzamide;
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.