Granted Patent B2

US 7,723,369 · App. 11/699,780 · Granted May 25, 2010

Abstract

Claims (128)

1. A compound of Formula IId:

wherein

R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen and R b ,

wherein R 20 is hydrogen, and one or more of R 23 , R 24 , R 25 , R 26 and R 27 are independently selected from the group consisting of:

hydrogen,

—C 1-10 alkyl,

-cycloalkyl,

-heterocyclyl,

-trifluoroalkyl,

-halogen,

-carboxy,

—CO 2 — 1-10 alkyl

—C 1-10 alkylene—CO 2 —C 1-10 alkyl,

—C 2-10 alkenylene—CO 2 —C 1-10 alkyl,

—C 1-10 alkylene—CO 2 H,

—C 1-10 alkenylene—CO 2 H,

—O—C 1-10 alkylene—C(O)NH—C 1-10 alkyl,

—C(O)—C 1-10 alkyl,

—C(O)—NH—C 1-10 alkyl,

—O—heterocyclyl,

—O—C 1-10 haloalkyl,

—O—C 1-10 perhaloalkyl,

—O-cycloalkyl,

—O-phenyl,

—hydroxy,

—O—C 1-10 alkylene-cycloalkyl,

—O—C 1-10 alkylene-phenyl,

—S-heterocyclyl,

—S—C 1-10 alkyl,

—S—C 1-10 haloalkyl,

—S—C 1-10 perhaloalkyl,

—S-cycloalkyl,

—S-phenyl,

—S—C 1-10 alkylene-cycloalkyl,

—S—C 1-10 alkylene-phenyl,

—C 1-10 alkylene-cycloalkyl,

—C 1-10 alkylene-phenyl,

-amino

—NH(C 1-10 alkyl),

—N(C 1-10 alkyl) 2 ,

—N(C 1-10 alkyl)(C 1-10 alkylene-cycloalkyl),

—NHCO 2 —C 1-10 alkyl,

—NH(C 1-10 alkylene-cycloalkyl),

—S(O) 2 —C 2-10 alkyl,

—SO 2 -cycloalkyl,

—SO 2 —C 1-10 alkylene-cycloalkyl,

—S(O)—C 1-10 alkyl,

—S(O)-cycloalkyl, and

—S(O)—C 1-10 alkylene-cycloalkyl,

wherein alkyl, alkenyl, aryl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R C ;

G is

wherein q is 2, D is C(R 7 )(R 8 ), E is N, and side f is a sincile bond

wherein R 7 and R 8 are selected from the group consisting of:

hydrogen and C 1-4 alkyl

M is hydrogen or a counter ion selected from the group consisting of: Na + , K + , and other pharmaceutically acceptable counter ions;

R C is

a) -halogen,

b) -amino,

c) -carboxy,

d) —C 1-4 alkyl,

e) —O—C 1-4 alkyl,

f) -cycloalkyl,

g) —O-cycloalkyl,

h) -aryl,

i) —C 1-4 alkylene-aryl,

j) -hydroxy,

k) —CF 3 ,

l) —O-aryl,

m) -heteroaryl,

n) -heteroaryl-C 1-10 alkyl,

o) heterocyclyl,

p) —CO 2 —C 1-10 alkyl, or

q) —CO 2 —C 1-10 alkyl-aryl,

r is 1,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 20 is hydrogen, and one or more of R 23 -R 27 is independently selected from the group consisting of: methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-ethyl-propyl, 1-propyl-butyl, 3,3-dimethyl-butyl, 4-methyl-pentyl, 4,4-dimethyl-pentyl, 1-(3,3-dimethyl-butyl)-4,4-dimethyl-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl, trifluoromethyl, 4,4,4-trifluorobutoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, isobutoxy, isopropoxy, tert-butoxy, 2-phenethoxy, 2,2-dimethylpropoxy, 3-methyl-butoxy, 3,3-dimethyl-butoxy, 3′-phenethyloxy, 2-cyclohexyl-ethanesulfonyl, 3,3-dimethyl-butane-1-sulfonyl, cyclohexanesulfonyl, cyclohexylmethanesulfonyl, cyclohexylmethylsulfonyl, 2-cyclohexyl-ethanesulfinyl, 3,3-dimethyl-butane-1-sulfinyl, cyclohexylmethylsulfinyl, 2-cyclohexyl-ethylsulfanyl, 3,3-dimethyl-butylsulfanyl, phenethylsulfanyl, cyclohexylmethylsulfanyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopentylethoxy, 2-cyclohexylethoxy, 2-cyclohexyl-vinyl, 3-ethyl-cyclobutyl, chloro, fluoro, and phenyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of:

a) -hydrogen;

b) -fluoro;

c) -chloro;

d) trifluoromethyl;

e) trifluoromethoxy;

f) —SO 2 —C 1 —C 6 alkyl

g) -cyano;

h) nitro; and

i) -phenyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, fluoro, and chloro, wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is not hydrogen.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIe):

6. A pharmaceutical composition comprising a compound of Formula (IId) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient, or a mixture thereof.

7. A compound selected from the group consisting of:

5-{3-[2-(4′-Cyclohexyo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(4′-Tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3′-Cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-[3′-(2-Cyclohexyl-ethoxy)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide

5-(3-[4-(2,4-Dichloro-phenyl)-2-(3′-phenethyloxy-bibhenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5(3-{4-(2,4Dichloro-phenyl)-2-[3′-(3,3-dimethyl-butylsulfanyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Dichloro-phenyl)-2-[3′-(3,3-dimethyl-butane-1-sulfonyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3′-CyclohexylmethylsuIfanyl-bipheflyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3′-Cyclohexylmethylsulfonyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3′-(2-Cyclohexyl-ethylsulfanyl)-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3′-(2-Cyclohexyl-theanesulfonyl)-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Difluoro-phenyl)-2-[3′-(3,3-dimethyl-butylsulfanyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Difluoro-phenyl)-2-[3′-(3,3-dimethyl-butane-1-sulfonyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{5-[2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{5-[2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methoxy-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(4′-Cyclohexyl-bipheflyl-4-ylmethyl)-4-(2,6-dichloro-phenyl)-imidazol-1yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,6-Dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(3-Cyclohexylmethoxy-biphenyl-4-(2,6-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Dichloro-phenyl)-2-[4′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(4′-Cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,3-Dichloro-phenyl)-2-[4′-(3,3-dimethyl-butysulfanyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(4′-Cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-(4′-Cyclohexylmethysulfanyl-biphenyl-4-ylmethyl_-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-[4′-(2-Cyclohexyl-ehtoxy)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-{3-[2-[4′-(2-Cyclohexyl-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dixhloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide;

5-(3-{4-(2,4-Dichloro-phenyl)-2-[4′-(4,4-dimethyl-pent-1-enyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide, and

5-{3-[2-[3′-(2-cyclohexylethyl)-biphenyl-4-y;-methyl]-4-(2,4-dichloro-phenyl}-imkdazol-1yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a mixture thereof.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of: hydrogen, sodium, or potassium.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein M is hydrogen.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein M is sodium or potassium.

12. The compound of claim 7 or a sodium or potassium salt thereof.

13. 5-{3-[2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide or a pharmaceutically acceptable salt thereof.

14. A sodium or potassium salt of the compound of claim 13 .

15. 5-{3-[2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.

16. A pharmaceutical composition comprising the compound of claim 13 , and a pharmaceutically acceptable carrier, diluent, excipient, or a mixture thereof.

17. A pharmaceutical composition comprising 5-{3-[2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide or a sodium or potassium salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a mixture thereof.

Assignments (11)