Compounds as cannabinoid receptor ligands
View Patent ↗Disclosed herein are cannabinoid receptor ligands of formula (I) wherein Y, X 1 , X 2 , X 3 , R 1 , and R 2 are as defined in the specification. Compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions are also disclosed.
1. A compound having formula (I)
or a pharmaceutically acceptable salt thereof, wherein
R 1 is aryl, wherein the aryl is independently unsubstituted or substituted by 1, 2, 3, 4, or 5 substituents as represented by T, wherein each T is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, —CN, —NO 2 , oxo, -G 1 , -L 1 -A 1 , —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(═NOR m1 )R a , —C(O)OR a , —C(O)N(R b )(R c ), —(CR e R f ) r —OR a , —(CR e R f ) r —OC(O)R a , —(CR e R f ) r —OC(O)N(R b )(R c ), —(CR e R f ) r —SR a , —(CR e R f ) r —S(O) 2 R d , —(CR e R f ) r —S(O) 2 N(R b )(R c ), —(CR e R f ) r —C(O)R a , —(CR e R f ) r —C(═NOR m1 )R a , —(CR e R f ) r —C(O)OR a , —(CR e R f ) r —C(O)N(R b )(R c ), —(CR e R f ) r —N(R b )(R c ), —(CR e R f ) r —N(R c )C(O)R a , —(CR e R f ) r —N(R c )S(O) 2 R d , —(CR e R f ) r —N(R c )C(O)O(R d ), —(CR e R f ) r —N(R c )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , and —(CR e R f ) r —CN;
A 1 is R a , —(CR e R f ) r -A 2 , —C(O)R a , —C(O)N(R b )(R c ), S(O) 2 R d , C(O)O(R d ), —N(R b )C(O)R a , —N(R b )C(O)OR d , —N(R b )(R c ), or —N═C(R b )(R c );
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 m1 )R a , —N(R c )C(O)R a , —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 ), or -L 2 -R z ;
L 1 and L 2 are each independently O or N(R b );
R 2 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR g R h ) t —OR k , —(CR g R h ) t —O-G 2 , —(CR g R h ) t —O—(CR g R h ) u -G 2 , —(CR g R h ) u —C(O)—R a , —(CR g R h ) u —C(═NOR m1 )R a , —(CR g R h ) t —SO 2 —R d , —(CR g R h ) t —N(R b )(R c ), —(CR g R h ) u -G 3 , —(CR g R h ) t —N(R b )SO 2 R d , —(CR g R h ) t —N(R b )COR a , —(CR g R h ) t —N(R b )CON(R b )(R c ), —(CR g R h ) t —N(R b )SO 2 N(R b )(R c ), —(CR g R h ) u —SO 2 N(R b )(R c ), —(CR g R h ) u —C(O)N(R b )(R c ), —(CR g R h ) u —OC(O)N(R b )(R c ), or —(CR g R h ) u —CN;
X 1 is N, and X 3 is S wherein the bond between X 1 and X 2 is a double bond and the bond between X 2 and X 3 is a single bond;
X 2 is CR 4 ;
R 3 is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, or haloalkyl;
R 3a is alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, or haloalkyl;
R 4 is hydrogen, alkyl, alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, halo, cyano, cyanoalkyl, or monocyclic heterocycle;
R 5 is hydrogen, alkyl, haloalkyl, halo, cyano, or alkoxyalkyl;
Y is CN or OR y
R y is alkyl, G 5 , or —(CR p R q ) v -G 6 ;
G 1 , G 2 and G 3 , at each occurrence, are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; wherein G 1 , G 2 , and G 3 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of G 4 , alkyl, alkenyl, alkynyl, halo, haloalkyl, ═N—CN, ═N—OR m1 , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —S(O) 2 R n , —S(O) 2 N(R m ) 2 , —C(O)R m , —C(O)OR m , —C(O)N(R m ) 2 , —N(R m ) 2 , —N(R m )C(O)R m , —N(R m )S(O) 2 R n , —N(R m )C(O)O(R n ), —N(R m )C(O)N(R m ) 2 , —(CR i R j ) w —OR m , —(CR i R j ) w —OC(O)R m , —(CR i R j ) w —OC(O)N(R m ) 2 , —(CR i R j ) w —S(O) 2 R n , —(CR i R j ) w —S(O) 2 N(R m ) 2 , —(CR i R j ) w —C(O)R m , —(CR i R j ) w —C(O)OR m , —(CR i R j ) w —C(O)N(R m ) 2 , —(CR i R j ) w —N(R m ) 2 , —(CR i R j ) w —N(R m )C(O)R m , —(CR i R j ) w —N(R m )S(O) 2 R n , —(CR i R j ) w —N(R m )C(O)O(R m ), —(CR i R j ) w —N(R m )C(O)N(R m ) 2 , and —(CR i R j ) w —CN;
R p and R q , at each occurrence, are each independently hydrogen or alkyl;
r and u, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6;
t, at each occurrence, is independently 2, 3, 4, 5, or 6;
v is 1 or 2;
each occurrence of w is independently 1, 2 or, 3;
G 4 is monocyclic heterocycle, monocyclic heteroaryl, or monocyclic cycloalkyl;
G 5 and G 6 , are each a monocyclic ring independently selected from the group consisting of cycloalkyl, heterocycle, heteroaryl, and phenyl;
R a and R c , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G′, or —(CR e R f ) r -G 1 ;
R b , at each occurrence, is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;
R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G′, or —(CR e R f ) r -G 1 ;
R e , R f , R g , R h , R i , and R j , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;
R k is hydrogen, alkyl, haloalkyl, alkoxyalkyl, or haloalkoxyalkyl;
R z is alkoxyalkyl, hydroxyalkyl, cyanoalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;
R m , at each occurrence, is independently hydrogen, alkyl, haloalkyl, —(CR e R f ) q —OR m1 , or monocyclic cycloalkyl;
R m1 , at each occurrence, is independently hydrogen, alkyl, haloalkyl, or monocyclic cycloalkyl;
R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl; and
the cycloalkyl, heterocycle, heteroaryl, and phenyl, by itself of as part of a substituent, of R 3 , R 3a , R 4 , G 4 , G 5 , G 6 , R b , R m , R m1 , and R m1 , are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, halo, oxo, cyano, and hydroxy.
2. The compound according to claim 1 having formula (II), or a pharmaceutically acceptable salt thereof,
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 3 is hydrogen, alkyl, monocyclic cycloalkyl, or haloalkyl;
R 3a is alkyl or haloalkyl;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, monocyclic cycloalkyl, haloalkyl, or monocyclic heterocycle; and
R 5 is hydrogen, alkyl, haloalkyl, or halo.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl substituted by 1, 2, 3, 4, or 5 substituents as represented by T.
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CN.
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
Y is OR y ; and
R y is alkyl.
7. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR g R h ) t —OR k , —(CR g R h ) t —O-G 2 , —(CR g R h ) t —O—(CR g R h ) u -G 2 , —(CR g R h ) u —C(O)—R a , —(CR g R h ) u —C(═NOR m1 )R a , —(CR g R h ) u -G 3 , —(CR g R h ) t —N(R b )SO 2 R d , —(CR g R h ) t —N(R b )COR a , —(CR g R h ) t —N(R b )CON(R b )(R c ), —(CR g R h ) t —N(R b )SO 2 N(R b )(R c ), —(CR g R h ) u —SO 2 N(R b )(R c ), —(CR g R h ) u —C(O)N(R b )(R c ), —(CR g R h ) u —OC(O)N(R b )(R c ), or —(CR g R h ) u —CN;
R g and R h are each independently hydrogen or C 1 -C 4 alkyl;
G 2 and G 3 , at each occurrence, are each independently monocyclic heteroaryl, monocyclic cycloalkyl, or monocyclic heterocycle;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, monocyclic cycloalkyl, haloalkyl, or monocyclic heterocycle;
R 1 is phenyl substituted by 1, 2, or 3, substituents as represented by T; and
Y is CN.
8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, —(CR g R h ) u -G 3 , or —(CR g R h ) u —CN; and
R 4 is alkyl, monocyclic cycloalkyl, or haloalkyl.
9. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR g R h ) t —OR k , —(CR g R h ) t —O-G 2 , —(CR g R h ) t —O—(CR g R h ) u -G 2 , —(CR g R h ) u —C(O)—R a , —(CR g R h ) u —C(═NOR m1 )R a , —(CR g R h ) u -G 3 , —(CR g R h ) t —N(R b )SO 2 R d , —(CR g R h ) t —N(R b )COR a , —(CR g R h ) t —N(R b )CON(R b )(R c ), —(CR g R h ) t —N(R b )SO 2 N(R b )(R c ), —(CR g R h ) u —SO 2 N(R b )(R c ), —(CR g R h ) u —C(O)N(R b )(R c ), —(CR g R h ) u —OC(O)N(R b )(R c ), or —(CR g R h ) u —CN;
R g and R h are each independently hydrogen or C 1 -C 4 alkyl;
G 2 and G 3 , at each occurrence, are each independently monocyclic heteroaryl, monocyclic cycloalkyl, or monocyclic heterocycle;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, monocyclic cycloalkyl, haloalkyl, or monocyclic heterocycle;
R 1 is phenyl substituted by 1, 2, or 3 substituents as represented by T;
Y is OR y ; and
R y is alkyl.
10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, —(CR g R h ) u -G 3 , or —(CR g R h ) u —CN; and
R 4 is alkyl, monocyclic cycloalkyl, or haloalkyl.
11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR g R h ) t —OR k , —(CR g R h ) t —O-G 2 , —(CR g R h ) t —O—(CR g R h ) u -G 2 , —(CR g R h ) u —C(O)—R a , —(CR g R h ) u —C(═NOR m1 )R a , —(CR g R h ) u -G 3 , —(CR g R h ) t —N(R b )SO 2 R d , —(CR g R h ) t —N(R b )COR a , —(CR g R h ) t —N(R b )CON(R b )(R c ), —(CR g R h ) t —N(R b )SO 2 N(R b )(R c ), —(CR g R h ) u —SO 2 N(R b )(R c ), —(CR g R h ) u —C(O)N(R b )(R c ), —(CR g R h ) u —OC(O)N(R b )(R c ), or —(CR g R h ) u —CN;
R g and R h are each independently hydrogen or C 1 -C 4 alkyl;
G 2 and G 3 , at each occurrence, are each independently monocyclic heteroaryl, monocyclic cycloalkyl, or monocyclic heterocycle;
R 3 is hydrogen, alkyl, monocyclic cycloalkyl, or haloalkyl;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, monocyclic cycloalkyl, haloalkyl, or monocyclic heterocycle;
R 1 is phenyl substituted by 1, 2, or 3, substituents as represented by T; and
Y is CN.
12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, —(CR g R h ) u -G 3 , or —(CR g R h ) u —CN;
R 3 is hydrogen, alkyl, or haloalkyl; and
R 4 is alkyl, monocyclic cycloalkyl, or haloalkyl.
13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR g R h ) t —OR k , —(CR g R h ) t —O-G 2 , —(CR g R h ) t —O—(CR g R h ) u -G 2 , —(CR g R h ) u —C(O)—R a , —(CR g R h ) u —C(═NOR m1 )R a , —(CR g R h ) u -G 3 , —(CR g R h ) t —N(R b )SO 2 R d , —(CR g R h ) t —N(R b )COR a , —(CR g R h ) t —N(R b )CON(R b )(R c ), —(CR g R h ) t —N(R b )SO 2 N(R b )(R c ), —(CR g R h ) u —SO 2 N(R b )(R c ), —(CR g R h ) u —C(O)N(R b )(R c ), —(CR g R h ) u —OC(O)N(R b )(R c ), or —(CR g R h ) u —CN;
R g and R h are each independently hydrogen or C 1 -C 4 alkyl;
G 2 and G 3 , at each occurrence, are each independently monocyclic heteroaryl, monocyclic cycloalkyl, or monocyclic heterocycle;
R 3a is alkyl or haloalkyl;
R 4 is hydrogen, alkyl, alkenyl, alkynyl, monocyclic cycloalkyl, haloalkyl, or monocyclic heterocycle;
R 5 is hydrogen, alkyl, haloalkyl, or halo;
R 1 is phenyl substituted by 1, 2, or 3, substituents as represented by T; and
Y is CN.
14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein
R 2 is alkyl, —(CR g R h ) u -G 3 , or —(CR g R h ) u —CN;
R 3a is alkyl;
R 4 is alkyl, monocyclic cycloalkyl, or haloalkyl; and
R 5 is hydrogen.
15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of
N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-N′-cyano-2-methoxybenzenecarboximidamide;
N-[(2Z)-5-tert-butyl-3-isobutyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-N′-cyano-2-methoxybenzenecarboximidamide;
N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-N′-cyano-2-methoxybenzenecarboximidamide;
N-[(2Z)-5-tert-butyl-3-(3-cyanopropyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-N′-cyano-2-methoxybenzenecarboximidamide; and
N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-N,2-dimethoxybenzenecarboximidamide.
16. 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.