Granted Patent B2

US 7,820,704 · App. 11/110,499 · Granted Oct 26, 2010

Abstract

Claims (267)

1. A compound of Formula I,

wherein

m is 0;

A is

R 1 is —C 1-5 alkylene-G 1 :

R 4 is selected from the group consisting of: -thienyl and —C 1-4 alkylene-thienyl;

R 6 and R 7 are independently selected from the group consisting of:

a) -hydrogen;

b) -halo;

c) -alkyl;

d) -L-D 1 -H;

e) -L-D 1 -alkyl;

f) -L-D 1 -aryl;

g) -L-D 1 -heteroaryl;

h) -L-D 1 -cycloalkyl;

i) -L-D 1 -heterocyclyl;

j) -L-D 1 -arylene-alkyl;

k) -L-D 1 -alkylene-arylene-alkyl;

l) -L-D 1 -alkylene-aryl;

m) -L-D 1 -arylene-aryl;

n) -L-D 2 -(aryl) 2 ; and

o) -L-D 2 -(arylene-alkyl) 2 ;

wherein at least one of R 6 and R 7 is not hydrogen;

W is S;

G 1 is —CO 2 H;

L is a direct bond, alkylene, alkenylene, alkynylene, or arylene;

D 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 8 )—, —C(O)—, —CON(R 8 )—, —CON(R 9 )SO 2 —, —N(R 9 )C(O)—, —N(R 9 )CON(R 8 )—, —N(R 8 )C(O)O—, —OC(O)N(R 8 )—, —N(R 8 )SO 2 —, —SO 2 N(R 8 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O 2 )—, or —N(R 8 )SO 2 N(R 9 )—, —N═N—, and —N(R 8 )—N(R 9 )—;

D 2 is N, alkylyne, or alkenylyne;

R 8 and R 9 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;

and

wherein the aryl, heteroaryl, heterocyclyl, cycloalkyl, and/or alkyl group(s) in R 1 , R 4 , R 6 , R 7 , R 8 , R 9 , and L may be optionally substituted 1-4 times with a substituent group selected from the group consisting of

a) -hydrogen;

b) halogen;

c) hydroxyl;

d) cyano;

e) carbamoyl;

f) —B-alkyl;

g) —B-perhaloalkyl;

h) —B-cycloalkyl;

i) —B-heterocyclyl;

j) —B-aryl;

k) —B-heteroaryl;

l) —B-alkylene-heteroaryl;

m) —B-alkylene-aryl;

n) —B-arylene-alkyl;

o) —B-perhaloalkyl;

p) —B-cycloalkylene-T-R 14 ;

q) —B-alkylene-N—R 14 R 15 ;

r) —B-cycloalkylene-alkyl; and

s) —B-alkylene-cycloalkyl;

wherein

B and T are independently selected from the group consisting of: direct bond, alkylene, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH, —O—S(O) 2 —, and —O—C(O)—;

wherein

R 14 and R 15 are independently selected from the group consisting of: hydrogen, heteroaryl, cycloalkyl, heterocyclyl, aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl, and alkylene-O-aryl; or

R 14 and R 15 may be taken together to form a ring having the formula —(CH 2 ) q -J-(CH 2 ) r — bonded to the nitrogen atom to which R 14 and R 15 are attached wherein q and r are independently equal to 1, 2, 3, or 4; J is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

R 17 and R 18 are independently selected from the group consisting of: hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl, -alkyene-heteroaryl, and -alkylene-aryl;

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

2. The compound of Formula (I) in claim 1 , having the formula (Ib)

or pharmaceutically acceptable salt, or solvate thereof.

3. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein R 6 is selected from the group consisting of: hydrogen, halo, alkyl, and phenyl.

4. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein R 6 is selected from the group consisting of: halo, alkyl, and phenyl.

5. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 7 is selected from the group consisting of:

a) -L-D 1 -alkyl;

b) -L-D 1 -aryl;

c) -L-D 1 -cycloalkyl;

d) -L-D 1 -heterocyclyl;

e) -L-D 1 -arylene-alkyl;

f) -L-D 1 -alkylene-arylene-alkyl;

g) -L-D 1 -alkylene-aryl;

h) -L-D 1 -arylene-aryl;

i) -L-D 2 -(aryl) 2 ; and

j) -L-D 2 -(arylene-alkyl) 2 ;

wherein

L is a direct bond, C 1-6 alkylene, or phenylene; and

D 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —C(O)—, —C(O)—O—, and —O—C(O)—.

6. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 7 is selected from the group consisting of:

a) -L-D 1 -alkyl;

b) -L-D 1 -aryl;

c) -L-D 1 -cycloalkyl;

d) -L-D 1 -heterocyclyl;

e) -L-D 1 -arylene-alkyl;

f) -L-D 1 -alkylene-arylene-alkyl;

g) -L-D 1 -alkylene-aryl; and

h) -L-D 1 -arylene-aryl;

i) -L-D 2 -(aryl) 2 ; and

j) -L-D 2 -(arylene-alkyl) 2 ;

wherein

L is a direct bond, C 1-6 alkylene, or phenylene; and

D 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —C(O)—, —C(O)—O—, and —O—C(O)—,

wherein the aryl, heterocyclyl, cycloalkyl, and/or alkyl group(s) in R 7 and L may be optionally substituted 1-4 times with a substituent group selected from the group consisting of

a) —H;

b) halogen;

c) hydroxyl;

d) cyano;

e) —B-alkyl;

f) —B-perhaloalkyl;

g) —B-cycloalkyl;

h) —B-heterocyclyl;

i) —B-aryl;

j) —B-heteroaryl;

k) —B-alkylene-heteroaryl;

l) —B-alkylene-aryl;

m) —B-arylene-alkyl;

n) —B-perhaloalkyl;

o) —B-cycloalkylene-T-R 14 ;

p) —B-cycloalkylene-alkyl; and

q) —B-alkylene-cycloalkyl;

wherein

B and T are independently selected from the group consisting of: direct bond, alkylene, —CH 2 —, and —O—;

wherein

R 14 is selected from the group consisting of: hydrogen, heteroaryl, cycloalkyl, heterocyclyl, aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl, and alkylene-O-aryl.

7. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 7 is selected from the group consisting of:

a) -L-D 1 -alkyl;

b) -L-D 1 -phenyl;

c) -L-D 1 -C 5-8 cycloalkyl;

d) -L-D 1 -tetrahydropyranyl;

e) -L-D 1 -phenylene-alkyl;

f) -L-D 1 -alkylene-phenylene-alkyl;

g) -L-D 1 -alkylene-phenyl;

h) -L-D 1 -phenylene-phenyl;

i) -L-D 2 -(phenyl) 2 ; and

j) -L-D 2 -(phenylene-alkyl) 2 ;

wherein

L is a direct bond, C 1-6 alkylene, or phenylene; and

D 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —C(O)—, —C(O)—O—, and —O—C(O)—,

wherein the aryl, cycloalkyl, and/or alkyl group(s) in R 7 and L may be optionally substituted 1-4 times with a substituent group selected from the group consisting of

a) —H;

b) halogen;

c) hydroxyl;

d) cyano;

e) —B-alkyl;

f) —B-perhaloalkyl;

g) —B-cycloalkyl; and

h) —B-aryl;

wherein

B is selected from the group consisting of: direct bond, alkylene, —CH 2 —, and —O—.

8. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 6 is selected from the group consisting of: hydrogen, halo, alkyl, and phenyl, and

R 7 is selected from the group consisting of:

phenyl,

benzyloxy-phenyl,

4-biphenyl-3-yl,

4-biphenyl-4-yl,

bromo-phenyl,

chloro-methyl-phenyl,

chloro-phenyl,

cyano-phenyl,

cyclohexylmethoxy-phenyl,

cyclohexyloxy-phenyl,

di-p-tolylmethyl,

methoxy-phenyl,

isobutoxy-phenyl,

trifluoromethoxy-phenyl,

phenethyloxy-phenyl,

phenoxy-phenyl,

methylphenyl,

isobutyl-phenyl,

isopropyl-phenyl,

tert-butyl-phenyl,

trifluoromethyl-phenyl,

dichloro-phenyl,

difluoro-phenyl,

dimethyl-phenyl,

dihydroxy-phenyl,

bis-trifluoromethyl-phenyl,

di-tert-butyl-hydroxy-phenyl,

benzoyl-phenyl,

(3-phenyl-propoxy)-phenyl,

(methyl-cyclohexyloxy)-phenyl,

(tert-butyl-cyclohexyloxy)-phenyl, and

(tetrahydropyran-4-yloxy)-phenyl.

9. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 6 is selected from the group consisting of: hydrogen, halo, alkyl, and phenyl, and

R 7 is selected from the group consisting of:

(tert-butyl-phenyl)-phenyl-methyl,

bis-(chloro-fluoro-phenyl)-methyl,

bis-(fluoro-phenyl)-methyl,

bis-(trifluoromethyl-phenyl)-methyl,

naphthalen-1-yl,

naphthalen-2-yl,

5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl, and

4-benzhydryl.

10. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 1 is

(CH 2 ) n -G 1 ; and

n is 1, 2, 3, or 4.

11. The compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 4 is selected from the group consisting of: thienyl, thien-2-yl-methyl, 3-thien-2-yl-propyl, and 2-thien-2-yl-ethyl.

12. A compound of Formula (Ib),

wherein

m is 0;

A is

R 2 is —C 1-5 alkylene-G 1 :

R 4 is selected from the group consisting of: -thien-2-yl and —C 1-4 thien-2-yl;

R 6 is selected from the group consisting of: hydrogen, halo, alkyl, and phenyl;

R 7 is selected from the group consisting of: phenyl, benzyloxy-phenyl, 4-biphenyl-3-yl, 4-biphenyl-4-yl, bromo-phenyl, chloro-methyl-phenyl, chloro-phenyl, cyano-phenyl, cyclohexylmethoxy-phenyl, cyclohexyloxy-phenyl, di-p-tolylmethyl, methoxy-phenyl, ethoxy-phenyl, isobutoxy-phenyl, trifluoromethoxy-phenyl, phenethyloxy-phenyl, phenoxy-phenyl, methylphenyl, isobutyl-phenyl, isopropyl-phenyl, tert-butyl-phenyl, trifluoromethyl-phenyl, dichloro-phenyl, difluoro-phenyl, dimethyl-phenyl, dihydroxy-phenyl, bis-trifluoromethyl-phenyl, di-tert-butyl-hydroxy-phenyl, benzoyl-phenyl, (3-phenyl-propoxy)-phenyl, (methyl-cyclohexyloxy)-phenyl, (tert-butyl-cyclohexyloxy)-phenyl, (tetrahydropyran-4-yloxy)-phenyl, (tert-butyl-phenyl)-phenyl-methyl, bis-(chloro-fluoro-phenyl)-methyl, bis-(fluoro-phenyl)-methyl, bis-(trifluoromethyl-phenyl)-methyl, naphthalen-1-yl, naphthalen-2-yl, 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl, and 4-benzhydryl;

W is —S—;

G 1 is —CO 2 H, and

wherein the aryl, heteroaryl, heterocyclyl, cycloalkyl, and/or alkyl group(s) in R 2 , R 4 , and R 6 may be optionally substituted 1-4 times with a substituent group selected from the group consisting of

a) -hydrogen;

b) halogen;

c) hydroxyl;

d) cyano;

e) carbamoyl;

f) —B-alkyl;

g) —B-perhaloalkyl;

h) —B-cycloalkyl;

i) —B-heterocyclyl;

j) —B-aryl;

k) —B-heteroaryl;

l) —B-alkylene-heteroaryl;

m) —B-alkylene-aryl;

n) —B-arylene-alkyl;

o) —B-perhaloalkyl;

p) —B-cycloalkylene-T-R 14 ;

q) —B-alkylene-N—R 14 R 15 ;

r) —B-cycloalkylene-alkyl; and

s) —B-alkylene-cycloalkyl;

wherein

B and T are independently selected from the group consisting of: direct bond, alkylene, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH, —O—S(O) 2 —, and —O—C(O)—;

wherein

R 14 and R 15 are independently selected from the group consisting of: hydrogen, heteroaryl, cycloalkyl, heterocyclyl, aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl, and alkylene-O-aryl; or

R 14 and R 15 may be taken together to form a ring having the formula —(CH 2 ) q -J-(CH 2 ) r — bonded to the nitrogen atom to which R 14 and R 15 are attached wherein q and r are independently equal to 1, 2, 3, or 4; J is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

R 17 and R 18 are independently selected from the group consisting of: hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl, -alkylene-heteroaryl, and -alkylene-aryl;

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

13. The compound of Formula (Ib) in claim 12 or pharmaceutically acceptable salt, or solvate thereof, wherein

R 7 is selected from the group consisting of: phenyl, bromo-phenyl, chloro-methyl-phenyl, chloro-phenyl, cyano-phenyl, di-p-tolylmethyl, methoxy-phenyl, ethoxy-phenyl, isobutoxy-phenyl, trifluoromethoxy-phenyl, methylphenyl, isobutyl-phenyl, isopropyl-phenyl, tert-butyl-phenyl, trifluoromethyl-phenyl, dichloro-phenyl, difluoro-phenyl, dimethyl-phenyl, dihydroxy-phenyl, bis-trifluoromethyl-phenyl, di-tert-butyl-hydroxy-phenyl, (tert-butyl-phenyl)-phenyl-methyl, bis-(chloro-fluoro-phenyl)-methyl, bis-(fluoro-phenyl)-methyl, bis-(trifluoromethyl-phenyl)-methyl, naphthalen-1-yl, naphthalen-2-yl, and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl.

14. A compound selected from the group consisting of:

3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid;

3-[(4-biphenyl-4-yl-thiazol-2-yl)-thiophen-2-ylmethylamino]-propionic acid;

3-({4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-thiophen-2-ylmethyl-amino)-propionic acid;

3-{[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-3-yl-amino}-propionic acid;

5-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid;

3-[[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amino]-propionic acid; and

3-[[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-(3-thiophen-2-yl-propyl)-amino]-propionic acid;

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

15. A pharmaceutical composition comprising a compound of Formula (I) in claim 1 , or a pharmaceutically salt, solvate, or prodrug thereof.

16. The pharmaceutical composition of claim 15 , wherein the compound of Formula (I) is in the form of a hydrochloric acid salt or a sodium salt.

17. The pharmaceutical composition of claim 15 further comprising one or more pharmaceutically acceptable carriers, excipients, or diluents.

18. A pharmaceutical composition comprising the compound of Formula (I) in claim 2 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

19. A pharmaceutical composition comprising the compound of Formula (I) in claim 3 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

20. A pharmaceutical composition comprising the compound of Formula (I) in claim 4 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

21. A pharmaceutical composition comprising the compound of Formula (I) in claim 5 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

22. A pharmaceutical composition comprising the compound of Formula (I) in claim 6 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

23. A pharmaceutical composition comprising the compound of Formula (I) in claim 7 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

24. A pharmaceutical composition comprising the compound of Formula (I) in claim 8 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

25. A pharmaceutical composition comprising the compound of Formula (I) in claim 9 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

26. A pharmaceutical composition comprising the compound of Formula (I) in claim 10 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

27. A pharmaceutical composition comprising the compound of Formula (I) in claim 11 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

28. A pharmaceutical composition comprising the compound of Formula (I) in claim 12 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

29. A pharmaceutical composition comprising the compound of Formula (I) in claim 13 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

30. A pharmaceutical composition comprising the compound of Formula (I) in claim 14 or a pharmaceutically acceptable salt, or solvate thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

31. 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid or a pharmaceutically acceptable salt, or solvate thereof.

32. The compound of claim 31 , wherein 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid is in the form of a hydrochloric acid salt or a sodium salt.

33. A pharmaceutical composition comprising the compound of claim 31 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

34. A pharmaceutical composition comprising the compound of claim 32 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

35. 3-{[4-(4-isobutyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid or a pharmaceutically acceptable salt, or solvate thereof.

36. The compound of claim 35 , wherein 3-{[4-(4-isobutyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid is in the form of a hydrochloric acid salt or a sodium salt.

37. A pharmaceutical composition comprising the compound of claim 35 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

38. A pharmaceutical composition comprising the compound of claim 36 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

39. 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid or a pharmaceutically acceptable salt thereof.

40. 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid.

41. A pharmaceutical composition comprising the compound of claim 39 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients, or diluents.

42. A pharmaceutical composition comprising the compound of claim 40 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

Assignments (11)