IP Library › Granted Patent US 7,148,236

Granted Patent B2

US 7,148,236 · App. 10/500,516 · Granted Dec 12, 2006

Modulators of acetylcholine receptors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,148,236
App. No.: 10/500,516
Granted: Dec 12, 2006
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to compounds that modulate neurotransmission by promoting the release of neurotransmitters such as acetylcholine, dopamine and norepinephrine. More particularly, the present invention relates to thio-bridged aryl compounds that are capable of modulating acetylcholine receptors and pharmaceutical compositions comprising such compounds. The compounds disclosed are useful for the treatment of dysfunctions of the central and autonomic nervous systems.

Claims (336)

1. A compound represented by Formula (I) or pharmaceutically acceptable salts thereof:

wherein:

R 1 is —H, C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or aryl-C 1-4 alkyl;

R 2 is

—OH,

—NH 2 ,

—NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —;

V is H, aryl, aryl-C 1-12 alkyl, diaryl-C 1-12 alkyl, lactonyl, or C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, —C(O)OC 1-4 alkyl, —OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy, aryloxy, or SO 2 C 1-4 alkyl; and T is H, halogen, C 1-5 alkyl, C 1-4 alkoxy, nitro, aryl, aryl-C 1-4 alkyl, or aryloxy unless V is H in which case T is absent,

aryl,

-(L) a -Z, wherein L is CH 2 , CO, O, NH or N(C 1-4 alkyl) and a is

0 or 1; and

Z is C 1-3 alkyl-F, C 0-3 alkyl-aryl-R 6 , C 0-3 alkyl-CO—R 6 , C 0-3 alkyl-CO—NR 6 2 , C 0-3 alkyl-CO 2 —R 6 , C 0-3 alkyl-SO 2 —R 6 , C 0-3 alkyl-SO 2 —NR 6 2 , C 1-3 alkyl-OR 6 , C 1-3 alkyl-CN or C 1-3 alkyl-NR 6 2 , wherein each C 0-3 alkyl or C 1-3 alkyl portion is optionally substituted with from 1 to 6 groups selected from F and C 1-5 alkyl,

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia)

wherein D is O or S; and

E is O, S, NR 5 , C(R 5 ) 2 , O—CR 5 2 , NR 5 —CR 5 2 , NR 5 —CO, CR 5 2 —O, CR 5 2 —S(O) r , CR 5 2 —NR 5 , CR 5 2 —CR 5 2 , CO—NR 5 , or CR 5 ═CR 5 ; or

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib)

wherein G is CR 5 or N; and

J is CR 5 or N;

unless X is N in which case R 2 is absent

R 3 is H, halogen, C 1-4 alkyl optionally substituted with from 1 to 3 fluorine atoms, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkyl, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH;

R 4 is H, halogen, C 1-4 alkyl optionally substituted with from 1 to 3 fluorine atoms, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkyl, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH;

R 5 is each independently H or C 1-4 alkyl;

R 6 is each independently H, C 1-6 alkyl, aryl or arylC 1-4 alkyl, each of which (except H) may be optionally substituted with from 1 to 3 fluorine atoms;

X is C or N;

W is C or N;

W′ is C or N;

Y is C or N;

Y′ is C or N;

provided that there are no more than two N atoms in the aryl ring;

A is (CH 2 ) q ;

m, n are both 1;

o and p are both 0;

q 2;

r is 0, 1 or 2;

provided that when X, W, W′, Y and Y′ are all C, R 3 is H, R 4 is H or Cl positioned meta to the sulphur atom, A is (CH 2 ) Q and R 1 is selected from H, unsubstituted C 1-4 alkyl and unsubstituted C 3-4 cycloalkyl; then R 2 may not be H or —OH, and that

when one of X, Y and Y′ is N, R 3 is H, R 4 is H or Cl positioned meta to the sulphur atom, A is (CH 2 ) Q and R 1 is selected from H, unsubstituted C 1-4 alkyl and unsubstituted C 3-4 cycloalkyl; the R 2 may not be H or —OH.

2. A compound as claimed in claim 1

wherein:

R 1 is

—NH 2 ,

—NH-Q-V-T,

aryl,

-(L) a -Z,

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia), or

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib);

unless X is N in which case R 2 is absent.

3. A compound as claimed in claim 1 or claim 2

wherein:

R 2 is —NH-Q-V-T,

aryl,

-(L) a -Z,

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia), or

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib);

unless X is N in which case R 2 is absent.

4. A compound as claimed in claim 3

wherein:

R 2 is —NH-Q-V-T wherein Q is —C(O)—NH—, or —C(O)O—;

V; and

aryl,

-(L) a -Z,

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia), or

linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib);

unless X is N in which case R 2 is absent.

5. A compound as claimed in claim 1

wherein:

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is

—OH,

—NH 2 ,

—NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —;

V is aryl, aryl-C 1-12 alkyl, diaryl-C 1-12 alkyl, lactonyl, or C 1-8 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, —C(O)OC 1-4 alkyl, —OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy, aryloxy, or SO 2 C 1-4 alkyl; and

T is H, halogen, aryl, aryl-C 1-4 alkyl, or aryloxy,

unless X is N in which case R 2 is absent

R 3 is H, halogen, C 1-4 alkyl, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH,

R 4 is H, halogen, C 1-4 alkyl, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH,

X is C or N,

W is C or N, provided that both X and Y are not N,

W′ is C

Y is C or N

Y′ is C

q is optionally 1, 2 or 3

r is 0.

6. A compound as claimed in claim 5 wherein R 1 is H, C 1-6 alkyl optionally substituted with 1 or 2 hydroxyl groups, or aryl-C 1-4 alkyl.

7. A compound as claimed in claim 6 wherein R 1 is benzyl, p-methoxybenzyl, furanylmethyl, imidazolylmethyl, pyridinylmethyl, thienylmethyl, pyridylmethyl, N-hydroxypyridylmethyl or thiazolylmethyl.

8. A compound as claimed in claim 7 wherein R 2 is R 3 is carbonamido (—CONH 2 ) or C 1-4 alkyl-OH, and R 4 is H, C 1-4 alkyl, CF 3 , halogen or cyano.

9. A compound as claimed in claim 7 wherein R 2 is OH, and R 3 and R 4 each independently represent H, C 1-4 alkyl, CF 3 , cyano or halogen.

10. A compound as claimed in claim 7 wherein R 2 is of formula —NH-Q-V-T; T is H and R 3 and R 4 each independently represent H, methyl, CF 3 , chloro- or cyano-.

11. A compound as claimed in claim 7 wherein R 2 is of formula —NH—SO2-V-T; V is aryl, —C 1-12 alkyl or aryl-C 1-12 alkyl; R 3 is H, methyl, CF 3 , Cl or cyano and R 4 is H.

12. A compound as claimed in claim 7 wherein R 2 is of formula —NH—SO 2 -V-T, V is selected from C 1-12 alkyl, phenyl, naphthyl, thienyl, oxazolyl, isoxazolyl, or phenyl(CH═CH)—, optionally substituted with 1, 2, 3 or 4 substituents selected from:

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkoxy;

C 1-12 alkylthio;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)OC 1-4 alkyl;

—OCH 2 CF 3 ;

—NHC(O)C 1-4 alkyl.

13. A compound as claimed in claim 7 wherein R 2 is of formula —NH—SO 2 -V-T, T is selected from H; or diazole, oxazole, isoxazole, phenyl or phenoxy, optionally substituted with 1, 2, 3 or 4 substituents selected from

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkoxy;

C 1-12 alkylthio;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)OC 1-4 alkyl;

—OCH 2 CF 3 ;

—NHC(O)C 1-4 alkyl.

14. A compound as claimed in claim 7 wherein R 2 is of formula —NH—SO 2 -V-T, V is selected from 3-chloro-4-methylphenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, naphthyl, 2,4,6-trimethylphenyl, phenyl(CH═CH)—, 4-chlorophenyl, 2-chlorophenyl, 2,5-dichlorothien-3-yl, 2,5,6-trimethyl-4-methoxyphenyl, 4-methoxyphenyl, 2,3,4-trifluorophenyl, 3-cyanophenyl, 2-methoxycarbonylthien-3-yl or 4-pentylphenyl and T is H.

15. A compound as claimed in claim 7 wherein R 2 is of formula —NH—SO 2 -V-T, T is 2-chloro-5-nitrophenoxy and V is phenyl.

16. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)-V-T wherein V is selected from aryl; aryl-C 1-12 alkyl; diaryl-C 1-12 alkyl; lactonyl; or C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, C(O)OC 1-4 alkyl, OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy or aryloxy.

17. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)-V-T, and V is selected from C 1-2 alkyl, phenyl, phenyl-C 1-12 alkyl, diphenylmethyl, naphthyl, furanyl, thienyl, diazolyl, pyridinyl, thiazolyl, benzothienyl, fluorenyl, oxazolyl or isoxazolyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkoxy;

C 1-12 alkylthio;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)O—C 1-4 alkyl;

—OCH 2 CF 3 .

18. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)-V-T, T is selected from H; halogen; or diazole, oxazole, isoxazole, phenyl, phenoxy or benzodioxanyl optionally substituted with 1, 2, 3 or 4 substituents selected from

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkylthio;

C 1-12 alkoxy;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)O—C 1-4 alkyl.

19. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)NH-V-T wherein V is selected from C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, C(O)OC 1-4 alkyl, OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy or aryloxy; aryl; or aryl-C 1-12 alkyl.

20. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)NH-V-T, V is selected from phenyl, phenyl-C 1-12 alkyl or naphthyl optionally substituted with 1, 2, 3 or 4 substituents selected from

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkylthio;

C 1-12 alkoxy;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)O—C 1-4 alkyl.

21. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)O-V-T, wherein V is selected from C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, C(O)OC 1-4 alkyl, OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy or aryloxy; aryl; or aryl-C 1-12 alkyl.

22. A compound as claimed in claim 7 wherein R 2 is of formula —NH—C(O)O-V-T, preferably V is selected from phenyl or phenyl-C 1-12 alkyl optionally substituted with 1, 2, 3 or 4 substituents selected from

—NO 2 ;

halogen;

—CF 3 ;

C 1-12 alkylthio;

C 1-12 alkoxy;

C 1-12 alkyl;

C 1-4 alkylsulfonyl;

—CN;

—OCF 3 ;

—C(O)O—C 1-4 alkyl; or

—OCH 2 CF 3 .

23. A compound as claimed in claim 1 wherein R 2 is of formula —NH—C(O)-V-T

wherein

V is H, C 1-6 alkyl, C 3-6 cycloalkyl, aryl or aryl-C 1-12 alkyl; and

T is H, halogen, C 1-5 alkyl, C 1-4 alkoxy, nitro, aryl, aryl-C 1-4 alkyl, or aryloxy unless V is H in which case T is absent.

24. A compound as claimed in claim 23

wherein

V is H, C 1-6 alkyl or C 3-6 cycloalkyl; and

T is H unless V is H in which case T is absent.

25. A compound as claimed in claim 23

wherein

V is aryl or aryl-C 1-12 alkyl; and

T is H, halogen, C 1-5 alkyl, C 1-4 alkoxy, nitro, aryl, aryl-C 1-4 alkyl, or aryloxy.

26. A compound as claimed in claim 25

wherein

V is phenyl, pyridyl, thienyl, thiazolyl, thiadiazolyl, or phenyl-C 1-6 alkyl; and

T is H, halogen, C 1-5 alkyl, C 1-4 alkoxy, nitro, aryl, aryl-C 1-4 alkyl, or aryloxy.

27. A compound as claimed in claim 1

wherein

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is —NH 2 , or

—NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —;

T is H, halogen, aryl, aryl-C 1-4 alkyl, or aryloxy unless V is H in which case T is absent,

X is C;

W is C or N;

W′ is C or N;

Y is C or N;

Y′ is C or N;

provided that there are not more than two N atoms in the aryl ring and provided that at least one of W, W′, Y or Y′ is N;

A is optionally a CH═CH double bond, (CH 2 ) q or (CH 2 )O(CH 2 );

r is 0, 1 or 2.

28. A compound as claimed in claim 27 wherein

W is C;

W′ is C;

Y′ is C; and

Y is N.

29. A compound as claimed in claim 27

wherein

W is N;

W′ is C;

Y′ is C; and

Y is C.

30. A compound as claimed in claim 29

wherein

R 2 is —NH 2 .

31. A compound as claimed in claim 29

wherein

R 2 is —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —;

T is H, halogen, aryl, aryl-C 1-4 alkyl, or aryloxy unless V is H in which case T is absent.

32. A compound as claimed in claim 31

wherein

Q is —SO 2 —or —CO—.

33. A compound as claimed in claim 1

wherein

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is aryl,

X is C,

W is C or N;

W′ is C or N;

Y is C or N;

Y′ is C or N;

provided that there are no more than two N atoms in the aryl ring;

r is 0, 1 or 2.

34. A compound as claimed in claim 33 wherein R 2 is a C 3 to C 12 aromatic or heteroaromatic group optionally substituted with one or more substituents selected from C 1-12 alkyl, C 1-12 alkoxy, thio, C 1-12 alkylthio, carboxy, carboxy(C 1-6 alkyl), formyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonylalkoxy, nitro, trihalomethyl, trihaloalkoxy, trihalomethoxy, trihalomethyl(C 1-6 alkyl), hydroxy, hydroxy(C 1-6 )alkyl, (C 1-6 alkoxy)carbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, aminocarboxy, C 1-6 alkylaminocarboxy, di(C 1-6 alkyl)aminocarboxy, aminocarboxy(C 1-6 )alkyl, C 1-6 alkylaminocarboxy(C 1-6 alkyl), di(C 1-6 alkyl)aminocarboxy(C 1-6 alkyl), C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl(C 1-6 alkyl)amino, halo, C 1-6 alkylhalo, sulphamoyl, tetrazolyl and cyano.

35. A compound as claimed in claim 33 wherein R 2 is phenyl, naphthyl, fluorenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl, imidazolinyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, azabenzimidazolyl, carbazolyl benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, benzodioxolyl, benzodioxanyl, cinnolinyl or carbolinyl optionally substituted with one or more substituents selected from C 1-2 alkyl, C 1-12 alkoxy, thio, C 1-12 alkylthio, carboxy, carboxy(C 1-6 alkyl), formyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonylalkoxy, nitro, trihalomethyl, trihaloalkoxy, trihalomethoxy, trihalomethyl(C 1-6 alkyl), hydroxy, hydroxy(C 1-6 )alkyl, (C 1-6 alkoxy)carbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, aminocarboxy, C 1-6 alkylaminocarboxy, di(C 1-6 alkyl)aminocarboxy, aminocarboxy(C 1-6 )alkyl, C 1-6 alkylaminocarboxy(C 1-6 alkyl), di(C 1-6 alkyl)aminocarboxy(C 1-6 alkyl), C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl(C 1-6 alkyl)amino, halo, C 1-6 alkylhalo, sulphamoyl, tetrazolyl and cyano.

36. A compound as claimed in claim 33 wherein R 2 is phenyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, or quinolinyl, optionally substituted with one or more substituents selected from C 1-2 alkyl, C 1-12 alkoxy, thio, C 1-12 alkylthio, carboxy, carboxy(C 1-6 alkyl), formyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonylalkoxy, nitro, trihalomethyl, trihaloalkoxy, trihalomethoxy, trihalomethyl(C 1-6 alkyl), hydroxy, hydroxy(C 1-6 )alkyl, (C 1-6 alkoxy)carbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, aminocarboxy, C 1-6 alkylaminocarboxy, di(C 1-6 alkyl)aminocarboxy, aminocarboxy(C 1-6 )alkyl, C 1-6 alkylaminocarboxy(C 1-6 alkyl), di(C 1-6 alkyl)aminocarboxy(C 1-6 alkyl), C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl(C 1-6 alkyl)amino, halo, C 1-6 alkylhalo, sulphamoyl, tetrazolyl and cyano.

37. A compound as claimed in claim 1

wherein:

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is (L) a -Z, wherein L is 0, CO, CH 2 , NH or N(C 1-4 alkyl) and a is 0 or 1; and

Z is C 1-3 alkyl-F, C 0-3 alkyl-aryl-R 6 , C 0-3 alkyl-CO—R 6 , C 0-3 alkyl-CO—NR 6 2 , C 0-3 alkyl-CO 2 —R 6 , C 0-3 alkyl-SO 2 —R 6 , C 0-3 alkyl-SO 2 —NR 6 2 , C 1-3 alkyl-OR 6 , C 1-3 alkyl-CN or C 1-3 alkyl-NR 6 2 wherein each C 0-3 alkyl or C 1-3 alkyl portion is optionally substituted with from 1 to 6 groups selected from F and C 1-5 alkyl,

R 6 is each independently H, C 1-6 alkyl, aryl, or arylC 1-4 alkyl, each of which (except H) may be optionally substituted with from 1 to 3 fluorine atoms;

X is C;

W is C or N,

Y is C or N,

W′ is C or N,

Y′ is C or N,

provided that there are no more than two N atoms in the aryl ring,

r is 0, 1 or 2.

38. A compound as claimed in claim 37 wherein L is O, CO or CH 2 .

39. A compound as claimed in claim 37 wherein L is NH or N(C 1-4 alkyl).

40. A compound as claimed in claim 39 wherein Z is C 0-3 alkyl-aryl-R 6 , C 0-3 alkyl-CO—NR 6 2 , C 03 alkyl-CO 2 —R 6 , C 1-3 alkyl-OR 6 or C 1-3 alkyl-NR 6 2 wherein each C 0-3 alkyl or C 1-3 alkyl portion is optionally substituted with from 1 to 6 groups selected from F and C 1-5 alkyl.

41. A compound as claimed in claims 38 or 39 wherein Z is C 0-3 alkyl-aryl-R 6 , wherein aryl is selected from phenyl, naphthyl, fluorenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl, imidazolinyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, azabenzimidazolyl, carbazolyl benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, benzodioxolyl, benzodioxanyl, cinnolinyl or carbolinyl optionally, be substituted with one or more substituents selected from C 1 to C 12 alkyl (preferably C 1 to C 6 alkyl), C 1 to C 12 alkoxy (preferably C 1 to C 6 alkoxy), thio, C 1 to C 12 alkylthio (preferably C 1 to C 6 alkylthio), carboxy, carboxy(C 1 to C 6 )alkyl, formyl, C 1 to C 6 alkylcarbonyl, C 1 to C 6 alkylsulfonyl, C 1 to C 6 alkylcarbonylalkoxy, nitro, trihalomethyl, trihalo(C 1 to C 6 alkoxy), trihalomethoxy, trihalomethyl(C 1 to C 6 alkyl), hydroxy, hydroxy(C 1 to C 6 )alkyl, (C 1 to C 6 alkoxy)carbonyl, amino, C 1 to C 6 alkylamino, di(C 1 to C 6 alkyl)amino, aminocarboxy, C 1 to C 6 alkylaminocarboxy, di(C 1 to C 6 alkyl)aminocarboxy, aminocarboxy(C 1 to C 6 )alkyl, C 1 to C 6 alkylaminocarboxy(C 1 to C 6 )alkyl, di(C 1 to C 6 alkyl)aminocarboxy(C 1 to C 6 )alkyl, C 1 to C 6 alkylcarbonylamino, C 1 to C 6 alkylcarbonyl(C 1 to C 6 alkyl)amino, halo, C 1 to C 6 alkylhalo, sulphamoyl, tetrazolyl and cyano and wherein each C 0-3 alkyl portion is optionally substituted with from 1 to 3 groups selected from F and C 1-3 alkyl.

42. A compound as claimed in claims 38 or 39 wherein Z is C 1-3 alkyl-CO—NR 6 2 , wherein each C 1-3 alkyl portion is optionally substituted with from 1 to 3 groups selected from F and C 1-3 alkyl.

43. A compound as claimed in claims 38 or 39 wherein Z is C 1-3 alkyl-CO 2 —R 6 , wherein each C 1-3 alkyl portion is optionally substituted with from 1 to 3 groups selected from F and C 1-3 alkyl.

44. A compound as claimed in claims 38 or 39 wherein Z is C 1-3 alkyl-OR 6 wherein each C 1-3 alkyl portion is optionally substituted with from 1 to 3 groups selected from F and C 1-3 alkyl.

45. A compound as claimed in claims 38 or 39 wherein Z is C 0-3 alkyl-NR 6 2 wherein each C 1-3 alkyl portion is optionally substituted with from 1 to 3 groups selected from F and C 1-3 alkyl.

46. A compound as claimed in any one of claims 37 to 39 wherein R 6 is/are each independently H, C 1-6 alkyl, phenyl, or phenylC 1-4 alkyl, each of which (except H) may be optionally substituted with from 1 to 3 fluorine atoms.

47. A compound as claimed in any one of claims 37 to 39 wherein R 6 is/are each independently H, methyl, ethyl, propyl, cyclohexyl, or benzyl, each of which (except H) may be optionally substituted with 1, 2 or 3 fluorine atoms.

48. A compound as claimed in claim 1

wherein:

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia)

wherein D is O or S; and

E is O, S, NR 5 , or C(R 5 ) 2 ,

R 5 is each independently H or C 1-4 alkyl;

X is C;

W is C or N;

Y is C or N;

Y′ is C or N;

provided that there are no more than two N atoms in the aryl ring,

r is 0, 1 or 2.

49. A compound as claimed in claim 48 wherein E is O or NR 5 .

50. A compound as claimed in claim 48 or 49 wherein R 5 is/are each independently H or C 1-4 alkyl.

51. A compound as claimed in claim 1

wherein:

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia)

wherein D is O or S; and

E is O—CR 5 2 , NR 5 —CR 5 2 , NR 5 —CO, CR 5 2 —O, CR 5 2 —S(O) r , CR 5 2 —NR 5 , CR 5 2 —CR 5 2 , CO—NR 5 , or CR 5 ═CR 5 ;

R 5 is each independently H, C 1-4 alkyl;

X is C;

W is C or N;

Y is C or N;

Y′ is C or N;

provided that there are no more than two N atoms in the aryl ring;

r is 0, 1 or 2.

52. A compound as claimed in claim 51 wherein E is O—CR 5 2 , NR 5 —CR 5 2 , NR 5 —CO, CR 5 2 —CR 5 2 , or CR 5 ═CR 5 .

53. A compound as claimed in claim 51 or 52 wherein E is O—CR 5 2 , NR 5 —CO, or CR 5 ═CR 5 .

54. A compound as claimed in claim 53 wherein R 5 is/are each independently H or C 1-4 alkyl.

55. A compound as claimed in claim 1

wherein:

R 1 is —H,

C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or

aryl-C 1-4 alkyl;

R 2 is linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib)

wherein G is CR 5 or N; and

J is CR 5 or N;

R 5 is each independently H or C 1-4 alkyl;

X is C;

W is C or N;

Y is C or N;

Y′ is C or N

provided that there are no more than two N atoms in the aryl ring;

r is 0, 1 or 2.

56. A compound as claimed in claim 55 wherein each R 5 is H.

57. A compound as claimed in claims 1 , 48 , 51 or 55 wherein r is 0.

58. A compound as claimed in claims 1 , 48 , 51 or 55 wherein r is 2.

59. A compound as claimed in any one of claims 1 , 48 , 51 or 55 wherein R 1 is H or C 1-3 alkyl.

60. A compound as claimed in any one of claims 1 , 48 , 51 or 55

wherein

R 3 is H, halogen, C 1-4 alkyl, CF 3 , or OC 1-4 alkyl, and

R 4 is H, halogen, C 1-4 alkyl, CF 3 , or OC 1-4 alkyl.

61. A compound as claimed in any one of claims 1 , 48 , 51 or 55 wherein one or both of R 3 and R 4 are positioned ortho to the S(O) r moeity.

62. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1 , 48 , 51 or 55 with a pharmaceutically acceptable diluent or carrier.

Assignments (3)

CHANGE OF NAME Recorded Jan 28, 2010

From: MERCK & CO., INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 023861/0349 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2006

From: ELI LILLY AND COMPANY

To: MERCK & CO., INC.

Reel/Frame 017279/0723 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2004

From: ASTLES, PETER CHARLES; BAKER, STEPHEN RICHARD; KEENAN, MARTINE; VERNIER, JEAN MICHEL; SANDERSON, ADAM JAN; CUBE, ROWENA VILLANUEVA; PEREZ, JOSE ANTONIO MARTINEZ; HERRANZ, ANA ISABEL MATEO; DELL, COLIN PETER; SANFELICIANO, SONIA GUTIERREZ; PRIETO, LOURDES; SMITH, COLIN WILLIAM

To: ELI LILLY AND COMPANY

Reel/Frame 016410/0370 →