IP Library › Granted Patent US 8,735,434

Granted Patent B2

US 8,735,434 · App. 12/120,969 · Granted May 27, 2014

Compounds as cannabinoid receptor ligands

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Patent No.: US 8,735,434
App. No.: 12/120,969
Granted: May 27, 2014
Kind: B2

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Abstract

The present application relates to thiazolylidene containing compounds of formula (I) wherein R 1 , R 2 , R 3 , and R 4 are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

Claims (135)

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl, wherein the phenyl 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, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c )—(CR e R f ) r —NO 2 , —(CR e R f )—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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, haloalkyl, —O—(CR e R f ) r —C(O)N(R b1 )(R c1 ), —O—(CR e R f ) r —C(S)N(R b1 )(R c1 ), —O—(CR e R f ) r —S(O) 2 N(R b1 )(R c1 ), —O—(CR e R f ) s —N(R b )(R c ), —O—(CR e R f ) s —N(R b )C(O)R a , —O—(CR e R f ) s —N(R b )S(O) 2 R d , and —O—(CR e R f ) r —CN;

two of the adjacent substituents T, together with the atoms to which they are attached optionally form a monocyclic ring selected from the group consisting of phenyl, heterocycle, and heteroaryl, wherein each ring is optionally further substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r —NO 2 , —(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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, and haloalkyl;

R 2 is —(CH 2 )-G 2 ;

R 3 and R 4 , together with the atoms to which they are attached, form a 5-membered monocyclic heterocycle; wherein said monocyclic heterocycle contains one oxygen atom, zero nitrogen atoms, zero additional double bonds, no alkenylene or alkylene bridge, and is unsubstituted or substituted with 1, 2, 3, or 4 C 1 -C 4 alkyl groups;

R a , R c , and R c1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R b and R b1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;

R b1 and R c1 , together with the nitrogen atom to which they are both attached optionally form a 4-7 membered monocyclic heterocycle; wherein said monocyclic heterocycle contains 0 or 1 additional heteroatom, 0 or 1 double bond, and is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, halo, hydroxy, and oxo;

R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R e and R f , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;

r, at each occurrence, is independently 1, 2, 3, 4, 5, or 6;

s, at each occurrence, is independently 2, 3, 4, 5, or 6;

G 1 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

G 2 , at each occurrence, is aryl;

wherein the rings as represented by G 1 or G 2 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, ═N—CN, ═N—OR n , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —SR m , —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 m ), —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —NO 2 , —(CR e R f ) r —OR m , —(CR e R f ) r —OC(O)R m , —(CR e R f ) r —OC(O)N(R m ) 2 , —(CR e R f ) r —SR m , —(CR e R f ) r —S(O) 2 R n , —(CR e R f ) r —S(O) 2 N(R m ) 2 , —(CR e R f ) r —C(O)R m , —(CR e R f ) r —C(O)OR m , —(CR e R f ) r —C(O)N(R m ) 2 , —(CR e R f ) r —N(R m ) 2 , —(CR e R f ) r —N(R m )C(O)R m , —(CR e R f ) r —N(R m )S(O) 2 R n , —(CR e R f ) r —N(R m )C(O)O(R m ), —(CR e R f ) r —N(R m )C(O)N(R m ), —(CR e R f ) r —CN, and haloalkyl;

R m , at each occurrence, is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl; two R m when attached to the same nitrogen atom optionally form a 4-7 membered monocyclic heterocycle; wherein said monocyclic heterocycle contains 0 or 1 additional heteroatom, 0 or 1 double bond, and is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, halo, hydroxy, and oxo; and

R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or cyanoalkyl,

wherein the compound is not a solvate.

2. The compound according to claim 1 , wherein the compound is 5-chloro-N-[(2Z)-3-(2,4-difluorobenzyl)-4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

3. 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.

4. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl, wherein the phenyl 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, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O)R d , —S(O)N(R b )(R c ), C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R), —N(R b )C(O)N(R b )(R c )—(CR e R f ) r —NO 2 , —(CR e R f , —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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) z R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, haloalkyl, —O—(CR e R f ) r —C(O)N(R b1 )(R c1 ), —O—(CR e R f ) r —C(S)N(R b1 )(R c1 ), —O—(CR e R f ) r —S(O) 2 N(R b1 )(R c ), —O—(CR e R f ) s —N(R b )(R c ), —O—(CR e R f ) s —N(R b )C(O)R a , —O—(CR e R f ) s —N(R b )S(O) 2 R d , and —O—(CR e R f ) r —CN;

R 2 is alkyl, alkenyl, alkynyl, G 2 , —C(O)R a , —S(O) 2 —R d , —O(G 1 ), —O—(CR e R f ) r -G 1 , —(CR e R f ) s —O-G 1 , —(CR e R f ) s —O—(CR e R f ) r -G 3 , —(CR e R f ) r —C(O)—R a , —(CR e R f ) r —SO 2 —R d , —(CR e R f ) s —N(R b )(R c ), —(CR e R f ) r -G 2 , —(CR e R f ) r -G 3 , —(CR e R f ) s —N(R b )SO 2 R d , —(CR e R f ) s —N(R b )COR a , —(CR e R f ) s —N(R b )CON(R b )(R c ), —(CR e R f ) s —N(R b ) SO 2 N(R b )(R c ), —(CR e R f ) r —SO 2 N(R b )(R c ), —(CR e R f ) r —C(O)N(R b )(R c ), —(CR e R f ) r —CN, haloalkyl, or haloalkoxyalkyl;

R 3 and R 4 , together with the atoms to which they are attached, form a 5-membered monocyclic heterocycle; wherein said monocyclic heterocycle contains one oxygen atom, zero nitrogen atoms, zero additional double bonds, no alkenylene or alkylene bridge, and is substituted with 1 oxo group and 0, 1 or 2 C 1 -C 4 alkyl groups;

R a , R c , and R c1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R b and R b1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R e and R f , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;

r, at each occurrence, is independently 1, 2, 3, 4, 5, or 6;

s, at each occurrence, is independently 2, 3, 4, 5, or 6;

G 1 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

G 2 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, or cycloalkenyl;

G 3 , is a monocyclic heterocycle containing 1 or 2 nitrogen atoms and 0 or 1 sulfur atom;

wherein the rings as represented by G 1 , G 2 , or G 3 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, ═N—CN, ═N—OR n , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —SR m , —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 m ), —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —NO 2 , —(CR e R f ) r —OR m , —(CR e R f ) r —OC(O)R m , —(CR e R f ) r —OC(O)N(R m ) 2 , —(CR e R f ) r —SR m , —(CR e R f ) r —S(O)R n , —(CR e R f ) r —S(O) 2 N(R m ) 2 , —(CR e R f ) r —C(O)R m , —(CR e R f ) r —C(O)OR m , —(CR e R f ) r —C(O)N(R m ) 2 , —(CR e R f ) r —N(R m ) 2 , —(CR e R f ) r —N(R m )C(O)R m , —(CR e R f ) r —N(R m )S(O) 2 R n , —(CR e R f ) r —N(R m )C(O)O(R m ), —(CR e R f ) r —N(R m )C(O)N(R m ), —(CR e R f ) r —CN, and haloalkyl;

R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or cyanoalkyl,

wherein the compound is not a solvate.

5. The compound according to claim 4 , wherein R 2 is C 3 -C 7 alkyl.

6. The compound according to claim 4 , wherein R 2 is —(CH 2 )-G 2 and G 2 is C 3 -C 6 cycloalkyl.

7. The compound according to claim 4 , wherein the compound is selected from the group consisting of:

N-[(2Z)-3-butyl-6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide, and

5-chloro-N-[(2Z)-3-(cyclobutylmethyl)-6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide,

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 4 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

9. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl, wherein the phenyl 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, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c )—(CR e R f ) r —NO 2 , —(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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, haloalkyl, —O—(CR e R f ) r —C(O)N(R b1 )(R c1 ), —O—(CR e R f ) r —C(S)N(R b1 )(R c1 ), —O—(CR e R f ) r —S(O) 2 N(R b1 )(R c1 ), —O—(CR e R f ) s —N(R b )(R c ), —O—(CR e R f ) s —N(R b )C(O)R a , —O—(CR e R f ) s —N(R b )S(O) 2 R d , and —O—(CR e R f ) r —CN;

two of the adjacent substituents T, together with the atoms to which they are attached optionally form a monocyclic ring selected from the group consisting of phenyl, heterocycle, and heteroaryl, wherein each ring is optionally further substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c ), —(CR e R f )—NO 2 , —(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 ), S(O) 2 N(R b )(R c ), —(CR e R f ) r —C(O)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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, and haloalkyl;

R 2 is alkyl, alkenyl, alkynyl, G 2 , —C(O)R a , —S(O) 2 —R d , —O(G 1 ), —O—(CR e R f ) r -G 1 , —(CR e R f ) s —O-G 1 , —(CR e R f ) s —O—(CR e R f ) r -G 1 , —(CR e R f ) r —C(O)—R a , —(CR e R f ) r —SO 2 —R d , —(CR e R f ) s —N(R b )(R c ), —(CR e R f ) r -G 2 , —(CR e R f ) r -G 3 , —(CR e R f ) s —N(R b )SO 2 R d , —(CR e R f ) s —N(R b )COR a , —(CR e R f ) s —N(R b )CON(R b )(R c ), —(CR e R f ) s —N(R b ) SO 2 N(R b )(R c ), —(CR e R f ) r —SO 2 N(R b )(R c ), —(CR e R f ) r —C(O)N(R b )(R c ), —(CR e R f ) r —CN, haloalkyl, or haloalkoxyalkyl;

R 3 and R 4 , together with the atoms to which they are attached, form a spiroheterocycle; said spiroheterocycle can be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halogen, —OH, —O(alkyl), and haloalkyl;

R a , R c , and R c1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R b and R b1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R e and R f , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;

r, at each occurrence, is independently 1, 2, 3, 4, 5, or 6;

s, at each occurrence, is independently 2, 3, 4, 5, or 6;

G 1 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

G 2 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, or cycloalkenyl;

G 3 , is a monocyclic heterocycle containing 1 or 2 nitrogen atoms and 0 or 1 sulfur atom;

wherein the rings as represented by G 1 , G 2 , or G 3 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, ═N—CN, ═N—OR n , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —SR m , —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)R n , —N(R m )C(O)O(R m ), —N(R m )C(O)N(R m ), —(CR e R f ) r —NO 2 , —(CR e R f ) r —OR m , —(CR e R f ) r —OC(O)R m , —(CR e R f ) r —OC(O)N(R m ) 2 , —(CR e R f ) r —SR m , —(CR e R f ) r —S(O) 2 R n , —(CR e R f ) r —S(O) 2 N(R m ) 2 , —(CR e R f ) r —C(O)R m , —(CR e R f ) r —C(O)OR m , —(CR e R f ) r —C(O)N(R m ) 2 , —(CR e R f , N(R m ) 2 , —(CR e R f ) r —N(R m )C(O)R m , —(CR e R f ), —N(R m )S(O) 2 R n , —(CR e R f ) r —N(R m )C(O)O(R m ), —(CR e R f ) r —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —CN, and haloalkyl;

R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or cyanoalkyl,

wherein the compound is not a solvate.

10. The compound according to claim 9 , wherein the compound is N-[(2′Z)-3′-butyl-4′-oxo-4′H-spiro[cyclobutane-1,6′-furo[3,4-d][1,3]thiazol]-2′(3′H)-ylidene]-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 9 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

12. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl, wherein the phenyl 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, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c )—(CR e R f ) r —NO 2 , —(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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, haloalkyl, —O—(CR e R f ) r —C(O)N(R b1 )(R c1 ), —O—(CR e R f ) r —C(S)N(R b1 )(R c1 ), —O—(CR e R f ) r —S(O) 2 N(R b1 )(R c1 ), —O—(CR e R f ) s —N(R b )(R c ), —O—(CR e R f ) s —N(R b )C(O)R a , —O—(CR e R f ) s —N(R b )S(O) 2 R d , and —O—(CR e R f ) r —CN;

R 2 is —(CR e R f ) r —CN;

R 3 and R 4 , together with the atoms to which they are attached, form a 6-membered monocyclic heterocycle; wherein said monocyclic heterocycle contains one oxygen atom, zero nitrogen atoms, zero additional double bonds, no alkenylene or alkylene bridge, and is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl and —OH;

R a , R c , and R c1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R b and R b1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R e and R f , at each occurrence, are each independently hydrogen or methyl;

r, at each occurrence, is independently 2, 3, or 4;

s, at each occurrence, is independently 2, 3, 4, 5, or 6;

G 1 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

wherein the rings as represented by G 1 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, ═N—CN, ═N—OR n , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —SR m , —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 m ), —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —NO 2 , —(CR e R f ) r —OR m , —(CR e R f ) r —OC(O)R m , —(CR e R f ) r —OC(O)N(R m ) 2 , —(CR e R f ) r —SR m , —(CR e R f ) r —S(O) 2 R n , —(CR e R f ) r —S(O) 2 N(R m ) 2 , —(CR e R f ) r —C(O)R m , —(CR e R f ) r —C(O)OR m , —(CR e R f ) r —C(O)N(R m ) 2 , —(CR e R f ) r —N(R m ), —(CR e R f ) r —N(R m )C(O)R m , —(CR e R f ) r —N(R m )S(O) 2 R n , —(CR e R f ) r —N(R m )C(O)O(R m ), —(CR e R f ) r —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —CN, and haloalkyl;

R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or cyanoalkyl,

wherein the compound is not a solvate.

13. The compound according to claim 12 , wherein the compound is 5-chloro-N-[(2Z)-1-(3-cyanopropyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 12 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

15. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl, wherein the phenyl 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, —CN, oxo, -G 1 , —NO 2 , —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —SR a , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R b )C(O)R a , —N(R b )S(O) 2 R d , —N(R b )C(O)O(R a ), —N(R b )C(O)N(R b )(R c )—(CR e R f ) r —NO 2 , —(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(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 b )C(O)R a , —(CR e R f ) r —N(R b )S(O) 2 R d , —(CR e R f ) r —N(R b )C(O)O(R a ), —(CR e R f ) r —N(R b )C(O)N(R b )(R c ), —(CR e R f ) r -G 1 , —(CR e R f ) r —CN, haloalkyl, —O—(CR e R f ) r —C(O)N(R b1 )(R c1 ), —O—(CR e R f ) r —C(S)N(R b1 )(R c1 ), —O—(CR e R f ) r —S(O) 2 N(R b1 )(R c1 ), —O—(CR e R f ) s —N(R b )(R c ), —O—(CR e R f ) s —N(R b )C(O)R a , —O—(CR e R f ) s —N(R b )S(O) 2 R d , and —O—(CR e R f ) r —CN;

R 2 is alkyl, alkenyl, alkynyl, G 2 , —C(O)R a , —S(O) 2 —R d , —O(G), —O—(CR e R f ) r -G 1 , —(CR e R f ) s —O-G 1 , (CR e R f ) s —O—(CR e R f ) r -G 1 , —(CR e R f ) r —C(O)—R a , —(CR e R f ) r —SO—R d , —(CR e R f ) s —N(R b )(R c ), —(CR e R f ) r -G 2 , —(CR e R f ) r -G 3 , —(CR e R f ) s —N(R b )SO 2 R d , —(CR e R f ) s —N(R b )COR a , —(CR e R f ) s —N(R b )CON(R b )(R c ), —(CR e R f ) s —N(R b ) SO 2 N(R b )(R c ), —(CR e R f ) r —SO 2 N(R b )(R c ), —(CR e R f , —C(O)N(R b )(R c ), —(CR e R f ) r —CN, haloalkyl, or haloalkoxyalkyl;

R 3 and R 4 , together with the atoms to which they are attached, form a 6-membered monocyclic heterocycle; wherein said monocyclic heterocycle contains one oxygen atom, zero or one nitrogen atom, and zero or one additional double bond; two non-adjacent atoms of said monocyclic heterocycle are linked by an alkenylene bridge of 2 carbon atoms, or are linked by an alkylene bridge of 2 carbon atoms, wherein one of the methylene groups of the alkenylene or the alkylene bridge can be optionally replaced by O, S, S(O), S(O) 2 , N(H), or N(alkyl); said monocyclic heterocycle can be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halogen, —OH, —O(alkyl), and haloalkyl;

R a , R c , and R c1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R b and R b1 , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, G 1 , or —(CR e R f ) r -G 1 ;

R e and R f , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;

r, at each occurrence, is independently 1, 2, 3, 4, 5, or 6;

s, at each occurrence, is independently 2, 3, 4, 5, or 6;

G 1 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

G 2 , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, or cycloalkenyl;

G 3 , is a monocyclic heterocycle containing 1 or 2 nitrogen atoms and 0 or 1 sulfur atom;

wherein the rings as represented by G 1 , G 2 , or G 3 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, ═N—CN, ═N—OR n , —CN, oxo, —NO 2 , —OR m , —OC(O)R m , —OC(O)N(R m ) 2 , —SR m , —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 m ), —N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —NO 2 , —(CR e R f ) r —OR m , —(CR e R f ) r —OC(O)R m , —(CR e R f ) r —OC(O)N(R m ) 2 , —(CR e R f ) r —SR m , —(CR e R f ) r —S(O) 2 R n , —(CR e R f ) r —S(O) 2 N(R m ) 2 , —(CR e R f ) r —C(O)R m , —(CR e R f ) r —C(O)OR m , —(CR e R f ) r —C(O)N(R m ) 2 , —(CR e R f ) r —N(R m ) 2 , —(CR e R f ) r —N(R m )C(O)R m , —(CR e R f ) r —N(R m )S(O) 2 R n , —(CR e R f ) r —N(R m )C(O)O(R m ), —(CR e R f )N(R m )C(O)N(R m ) 2 , —(CR e R f ) r —CN, and haloalkyl;

R n , at each occurrence, is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or cyanoalkyl,

wherein the compound is not a solvate.

16. The compound according to claim 15 , wherein

R 2 is C 3 -C 7 alkyl or —(CH 2 )-G 2 ; and

G 2 is C 3 -C 6 cycloalkyl.

17. The compound according to claim 15 , wherein the compound is selected from the group consisting of:

N-[(2Z)-3-butyl-3,4,7,8-tetrahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-ylidene]-5-chloro-2-methoxybenzamide, and

N-[(2Z)-3-butyl-3,4,5,6,7,8-hexahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-ylidene]-5-chloro-2-methoxybenzamide,

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 15 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

19. A compound selected from the group consisting of:

N-[(2Z)-3-butyl-4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide,

N-[(2Z)-1-butyl-4,4-dimethyl-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-5-chloro-2-methoxybenzamide,

5-chloro-N-[(2Z)-1-(cyclobutylmethyl)-4,4-dimethyl-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide,

N-[(2Z)-3-butyl-6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide,

5-chloro-N-[(2Z)-3-(cyclobutylmethyl)-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide,

N-[(2Z)-3-butyl-7-hydroxy-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide,

N-[(2Z)-3-butyl-7-hydroxy-7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide,

N-[(2Z)-3-butyl-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide,

5-chloro-N-[(2Z)-3-(cyclobutylmethyl)-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide,

5-chloro-N-[(2Z)-1-(cyclobutylmethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide,

N-[(2Z)-1-butyl-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-5-chloro-2-methoxybenzamide,

5-chloro-N-[(2Z)-1-isobutyl-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide,

N-[(2Z)-1-butyl-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-5-cyano-2-methoxybenzamide, and

N-[(2Z)-1-butyl-6,7-dihydro-5H-pyrano[3,2-d][1,3]thiazol-2(1H)-ylidene]-5-chloro-2-methoxybenzamide,

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 17, 2013

From: ABBOTT LABORATORIES

To: ABBVIE INC.

Reel/Frame 030235/0856 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 4, 2008

From: CARROLL, WILLIAM A.; DART, MICHAEL J.; FROST, JENNIFER M.; PEREZ-MEDRANO, ARTURO; PEDDI, SRIDHAR

To: ABBOTT LABORATORIES

Reel/Frame 021333/0582 →