Granted Patent B2

US 7,727,983 · App. 12/399,504 · Granted Jun 1, 2010

Abstract

Claims (602)

1. A compound of Formula (I):

wherein

R is —(CH 2 ) p -G 1 -L 1 -G 2 , wherein

L 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 16 )—, —C(O)—, —CON(R 16 )—, —N(R 16 )C(O)—, —N(R 16 )SO 2 —, —SO 2 N(R 16 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —C≡C—, wherein

R 16 is selected from the group consisting of: —hydrogen, —alkyl, —aryl, —alkylene-aryl;

G 1 is selected from the group consisting of: alkynylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G 1 is optionally substituted 1-4 times with substituents independently selected from R 10 , wherein

R 10 is R b ,

G 2 is selected from the group consisting of: —aryl, —heteroaryl, —fused arylcycloalkyl, —fused cycloalkylaryl, —fused cycloalkylheteroaryl, —fused heterocyclylaryl, and —fused heterocyclylheteroaryl, wherein G 2 is optionally substituted 1-4 times with substituents independently selected from R 11 , wherein

R 11 is R b ,

R 1 is selected from the group consisting of: —CO 2 H, —CO 2 R 12 , —C(O)NH 2 , —C(O)NHR 12 , —tetrazole, and acid isostere, wherein

R 12 is selected from the group consisting of: —C 1-10 alkyl, —cycloalkyl, and —aryl, wherein

R 12 is optionally substituted 1-4 times with a group independently selected from R c ;

R 2 is selected from the group consisting of: —hydrogen, —alkyl, —phenyl, —cycloalkyl, —alkylene-cycloalkyl, and —alkylene-phenyl, wherein alkyl, phenyl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c ;

R 3 is selected from R a ;

R 4 is selected from R a ; and

R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 and L 3 are independently selected from the group consisting of: a direct bond, CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 26 )SO 2 N(R 27 )—, wherein

R 26 and R 27 are independently selected from the group consisting of: hydrogen, —alkyl, —aryl, and —alkylene-aryl, wherein R 26 and R 27 are optionally substituted 1-4 times with R c , or R 26 and R 27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

Q 2 is selected from the group consisting of: a direct bond, C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene,

G 3 is selected from the group consisting of: —arylene, —cycloalkylene, —heterocyclylene, —heteroarylene, —fused arylcycloalkylene, —fused cycloalkylarylene, —fused cycloalkylheteroarylene, —fused heterocyclylarylene, and —fused heterocyclylheteroarylene, wherein

G 3 is optionally substituted 1-4 times with substituents independently selected from R 8 , wherein R 8 is selected from R b ,

G 4 is selected from the group consisting of: —aryl, —cycloalkyl, —heterocyclyl, —heteroaryl, —fused arylcycloalkyl, —fused cycloalkylaryl, —fused cycloalkylheteroaryl, —fused heterocyclylaryl, and —fused heterocyclylheteroaryl, wherein

G 4 is optionally substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b ,

Rings B and C are optionally substituted 1-4 times with substituents independently selected from the group consisting of R b ;

R a is selected from the group consisting of:

a) —hydrogen,

b) —S(O) m R d ,

c) —S(O) 2 OR d ,

d) —S(O) m NR d R e ,

e) —C(O)R d ,

f) —CO 2 R d ,

g) —C(O)NR d R e ,

h) —haloalkyl,

i) —cycloalkyl,

j) —heterocyclyl,

k) —C 1-10 alkyl,

l) —C 2-10 alkenyl,

m) —C 2-10 alkynyl,

n) —aryl,

o) —heteroaryl,

p) —C 1-10 alkylene-aryl,

q) —C 2-10 alkynylene-aryl,

r) —C 1-10 alkylene-heteroaryl,

s) —C 2-10 alkynylene-heteroaryl, and

t) —C(R f R g ) n -aryl,

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

R b is selected from the group consisting of:

a) —cycloalkyl,

b) —cyano,

c) —OR d ,

d) —NO 2 ,

e) —halogen,

f) —S(O) m R d ,

g) —SR d ,

h) —S(O) 2 OR d ,

i) —S(O) m NR d R e ,

j) —NR d R e ,

k) —O(CR f R g ) n NR d R e ,

l) —C(O)R d ,

m) —CO 2 R d ,

n) —CO 2 (CR f R g ) n CONR d R e ,

o) —OC(O)R d ,

p) —C(O)NR d R e ,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR e ,

t) —NR d C(O)NR d R e ,

u) —CF 3 ,

v) —OCF 3 ,

w) —haloalkyl,

x) —haloalkoxy,

y) —C 1-10 alkyl,

z) —C 2-10 alkenyl,

aa) —C 2-10 alkynyl,

ab) —C 1-10 alkylene-aryl,

ac) —C 1-10 alkylene-heteroaryl, and

ad) —heteroaryl,

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

R c is selected from the group consisting of:

a) —halogen,

b) —amino,

c) —carboxy,

d) —cyano,

e) —C 1-4 alkyl,

f) —O—C 1-4 alkyl,

g) —O—CF 3 ,

h) —cycloalkyl,

i) —O-cycloalkyl,

j) —aryl,

k) —C 1-4 alkylene-aryl,

l) —hydroxy,

m) —CF 3 ,

n) —haloalkyl,

o) —haloalkoxy,

p) —O-aryl,

q) —heteroaryl,

r) —heteroarylene-C 1-10 alkyl,

s) —heterocyclyl,

t) —CO 2 —C 1-10 alkyl,

u) —CO 2 —C 1-10 alkyl-aryl,

v) —fused arylcycloalkyl,

w) —alkynylene-heteroaryl,

x) —alkylene-aryl,

y) —alkynylene-aryl,

z) —nitro,

aa) —N(H)—C(O)—C 1-6 -alkyl, and

bb) —S—C 1-6 -alkyl;

R d and R e are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with R c ,

R f and R g are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, —carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to four substituents independently selected from R c ; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with R c ;

m is an integer from 1 to 2;

n is an integer from 1 to 10; and

p is an integer from 0 to 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of CO 2 H and CO 2 R 12 .

3. The compound of claim 1 , wherein R 1 is CO 2 H.

4. The compound of claim 1 , wherein R 2 is selected from the group consisting of: hydrogen and —C 1-10 alkyl.

5. The compound of claim 1 , wherein R 2 is hydrogen.

6. The compound of claim 1 , wherein p is 1.

7. The compound of claim 1 , wherein L 1 is a direct bond.

8. The compound of claim 1 , wherein:

p is 1;

G 1 is a substituted or unsubstituted phenyl;

L 1 is selected from the group consisting of a direct bond, —O—, and —N(H)C(O)—; and

G 2 is a phenyl group substituted 1-4 times with substituents independently selected from R 11 , and G 2 is substituted with at least one substituent selected from the group consisting of:

a) —C 1-10 alkyl,

b) —haloalkyl,

c) —haloalkoxy,

d) —CF 3 ,

e) —OCF 3 ,

f) —halogen,

g) —O—R d ,

h) —cyano,

i) —C(O)R d ,

j) —NR d R e ,

k) —cycloalkyl, and

l) —CO 2 R d ,

wherein alkyl and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c .

9. The compound of claim 1 , wherein:

p is 1;

G′ is —C≡C—;

L 1 is a direct bond; and

G 2 is a substituted or unsubstituted phenyl group substituted 1-4 times with substituents independently selected from R 11 , and G 2 is substituted with at least one substituent selected from the group consisting of:

a) —C 1-10 alkyl,

b) —haloalkyl,

c) —haloalkoxy,

d) —CF 3 ,

e) —OCF 3 ,

f) —halogen,

g) —O—R d ,

h) —cyano,

i) —C(O)R d ,

j) —NR d R e ,

k) —cycloalkyl,

l) —CO 2 R d ,

wherein the alkyl and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c .

10. The compound of claim 1 , wherein:

p is 1;

G 1 is a substituted or unsubstituted phenyl;

L 1 is a direct bond; and

G 2 is selected from the group consisting of: indole, pyridine, pyrimidine, quinoline, isoxazole, wherein G 2 is optionally substituted or unsubstituted.

11. The compound of claim 1 , wherein:

p is 1;

G 1 is an unsubstituted phenyl;

L 1 is a direct bond; and

G 2 is a phenyl, substituted with a cyano group.

12. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

a) —C 1-10 alkyl,

b) —phenyl,

c) —thiophenyl,

d) —furanyl,

e) —pyridyl,

f) —C 1-10 alkylene-pyridyl,

g) —C 1-10 alkylene-aminothiazolyl,

h) —C 1-10 alkylene-imidazolyl,

i) —C 1-10 alkylene-oxazolyl,

j) —C 1-10 alkylene-thiophenyl,

k) —C 2-10 alkynylene-phenyl,

l) —C 2-10 alkynylene-thiophenyl,

m) —C 2-10 alkynylene-pyridyl,

n) —C 2-10 alkynylene-pyrimidinyl,

o) —SO 2 -phenyl,

p) —CO 2 —C 1-10 alkyl,

q) —CO 2 -cycloalkyl,

r) —CO 2 -tetrahydrofuranyl,

s) —CO 2 -tetrahydropyranyl,

t) —CO 2 —C 1-10 alkylene-cycloalkyl,

u) —CO 2 —C 2-10 -alkynyl,

v) —CO 2 —CH 2 —C≡C-phenyl,

w) —C(O)—C 1-10 alkyl,

x) —C(O)-phenyl,

y) —C(O)-naphthyl,

z) —C(O)-cycloalkyl,

aa) —C(O)-furanyl,

bb) —C(O)-thiophenyl,

cc) —C(O)-isoxazolyl,

dd) —C(O)—C 1-10 alkylene-cycloalkyl,

ee) —C(O)—NH—C 1-10 alkyl,

ff) —C(O)—NH-phenyl, and

gg) —C(O)—N(cycloalkyl)-C 1-10 phenyl,

wherein the alkyl, alkynyl, cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, naphthyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, and isoxazolyl groups are optionally substituted 1-4 times with a group independently selected from R c .

13. The compound of claim 1 , wherein R 3 is —C 1-10 alkyl substituted with a phenyl group.

14. The compound of claim 1 , wherein R 3 is selected from the group consisting of —(R)-1-(phenyl)-propyl, and —(S)-1-(phenyl)-propyl.

15. The compound of claim 1 , wherein R 4 is selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted with one to four substituents independently selected from R c .

16. The compound of claim 1 , wherein R 4 is selected from the group consisting of —hydrogen, —C 1-6 alkyl, and —C(O)—C 1-6 alkyl.

17. The compound of claim 1 , wherein R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 is selected from the group consisting of: —CH 2 —, —O—, —N(R 26 )—, and —C(O)—,

wherein R 26 is selected from the group consisting of: hydrogen, —alkyl, —aryl, and —alkylene-aryl;

L 3 is a direct bond;

Q 2 is a C 1-10 alkylene group;

G 3 is a phenylene group,

wherein G 3 is optionally substituted 1-4 times with substituents independently selected from R 8 , wherein R 8 is selected from R b ; and

G 4 is selected from the group consisting of: cycloalkyl, phenyl, pyridinyl, benzothiophenyl, and benzothiazolyl, wherein G 4 is optionally substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b .

18. The compound of claim 1 , wherein R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 is —O—,

L 3 is a direct bond;

Q 2 is a C 1-10 alkylene group;

G 3 is a phenylene group, and

G 4 is a phenyl group, wherein G 4 is substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b , and wherein G 4 is substituted with at least one substituent selected from the group consisting of:

a) —C 1-6 alkyl,

b) —haloalkyl,

c) —halogen,

d) —alkoxy,

e) —haloalkoxy,

f) —CF 3 , and

g) —O—CF 3 .

19. The compound of claim 1 , having the formula (I-E)

or a pharmaceutically acceptable salt thereof.

20. A compound selected from the group consisting of a compound of Formula (II) and a compound of Formula (III)

R 3 is selected from R a ;

R 4 is selected from R a ; and

R 5 is G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 and L 3 are independently selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 26 )SO 2 N(R 27 )—, wherein

R 26 and R 27 are independently selected from the group consisting of: hydrogen, —alkyl, —aryl, and —alkylene-aryl, wherein R 26 and R 27 are optionally substituted 1-4 times with R c , or R 26 and R 27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

Q 2 is selected from the group consisting of: a direct bond, C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene,

G 3 is selected from the group consisting of: —arylene, —cycloalkylene, —heterocyclylene, —heteroarylene, —fused arylcycloalkylene, —fused cycloalkylarylene, —fused cycloalkylheteroarylene, —fused heterocyclylarylene, and —fused heterocyclylheteroarylene, wherein

G 3 is optionally substituted 1-4 times with substituents independently selected from R 8 , wherein R 8 is selected from R b ,

G 4 is selected from the group consisting of: —aryl, —cycloalkyl, —heterocyclyl, —heteroaryl, —fused arylcycloalkyl, —fused cycloalkylaryl, —fused cycloalkylheteroaryl, —fused heterocyclylaryl, and —fused heterocyclylheteroaryl, wherein

G 4 is optionally substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b ,

wherein R a is selected from the group consisting of:

a) —hydrogen,

b) —S(O) m R d ,

c) —S(O) 2 OR d ,

d) —S(O) m NR d R e ,

e) —C(O)R d ,

f) —CO 2 R d ,

g) —C(O)NR d R e ,

h) —haloalkyl,

i) —cycloalkyl,

j) —heterocyclyl,

k) —C 1-10 alkyl,

l) —C 2-10 alkenyl,

m) —C 2-10 alkynyl,

n) —aryl,

o) —heteroaryl,

p) —C 1-10 alkylene-aryl,

q) —C 2-10 alkynylene-aryl,

r) —C 1-10 alkylene-heteroaryl,

s) —C 2-10 alkynylene-heteroaryl, and

t) —C(R f R g ) n -aryl,

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

R b is selected from the group consisting of:

a) —cycloalkyl,

b) —cyano,

c) —OR d ,

d) —NO 2 ,

e) —halogen,

f) —S(O) m R d ,

g) —SR d ,

h) —S(O) 2 OR d ,

i) —S(O) m NR d R e ,

j) —NR d R e ,

k) —O(CR f R g ) n NR d R e ,

l) —C(O)R d ,

m) —CO 2 R d ,

n) —CO 2 (CR f R g ) n CONR d R e ,

o) —OC(O)R d ,

p) —C(O)NR d R e ,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR e ,

t) —NR d C(O)NR d R e ,

u) —CF 3 ,

v) —OCF 3 ,

w) —haloalkyl,

x) —haloalkoxy,

y) —C 1-10 alkyl,

z) —C 2-10 alkenyl,

aa) —C 2-10 alkynyl,

ab) —C 1-10 alkylene-aryl,

ac) —C 1-10 alkylene-heteroaryl, and

ad) —heteroaryl,

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

R c is selected from the group consisting of:

a) —halogen,

b) —amino,

c) —carboxy,

d) —cyano,

e) —C 1-4 alkyl,

f) —O—C 1-4 alkyl,

g) —O—CF 3 ,

h) —cycloalkyl,

i) —O-cycloalkyl,

j) —aryl,

k) —C 1-4 alkylene-aryl,

l) —hydroxy,

m) —CF 3 ,

n) —haloalkyl,

o) —haloalkoxy,

p) —O-aryl,

q) —heteroaryl,

r) —heteroarylene-C 1-10 alkyl,

s) —heterocyclyl,

t) —CO 2 —C 1-10 alkyl,

u) —CO 2 —C 1-10 alkyl-aryl,

v) —fused arylcycloalkyl,

w) —alkynylene-heteroaryl,

x) —alkylene-aryl,

y) —alkynylene-aryl,

z) —nitro,

aa) —N(H)—C(O)—C 1-6 -alkyl, and

bb) —S—C 1-6 -alkyl;

R d and R e are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with R c ,

R f and R g are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, —carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to four substituents independently selected from R c ; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with R c ;

m is an integer from 1 to 2;

n is an integer from 1 to 10; and

p is an integer from 0 to 2;

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , wherein R 4 is selected from the group consisting of —hydrogen, —C 1-6 alkyl, and —C(O)—C 1-6 alkyl.

22. The compound of claim 20 , wherein R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 is —O—,

L 3 is a direct bond;

Q 2 is a C 1-10 alkylene group;

G 3 is a phenylene group, and

G 4 is a phenyl group, wherein G 4 is substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b , and wherein G 4 is substituted with at least one substituent selected from the group consisting of:

a) —C 1-6 alkyl,

b) —haloalkyl,

c) —halogen,

d) —alkoxy,

e) —haloalkoxy,

f) —CF 3 , and

g) —O—CF 3 .

23. The compound of claim 20 , wherein R 3 is selected from the group consisting of:

a) —C 1-10 alkyl,

b) —phenyl,

c) —thiophenyl,

d) —furanyl,

e) —pyridyl,

f) —C 1-10 alkylene-pyridyl,

g) —C 1-10 alkylene-aminothiazolyl,

h) —C 1-10 alkylene-imidazolyl,

i) —C 1-10 alkylene-oxazolyl,

j) —C 1-10 alkylene-thiophenyl,

k) —C 2-10 alkynylene-phenyl,

l) —C 2-10 alkynylene-thiophenyl,

m) —C 2-10 alkynylene-pyridyl,

n) —C 2-10 alkynylene-pyrimidinyl,

o) —SO 2 -phenyl,

p) —CO 2 —C 1-10 alkyl,

q) —CO 2 -cycloalkyl,

r) —CO 2 -tetrahydrofuranyl,

s) —CO 2 -tetrahydropyranyl,

t) —CO 2 —C 1-10 alkylene-cycloalkyl,

u) —CO 2 —C 2-10 -alkynyl,

v) —CO 2 —CH 2 —C≡C-phenyl,

w) —C(O)—C 1-10 alkyl,

x) —C(O)-phenyl,

y) —C(O)-naphthyl,

z) —C(O)-cycloalkyl,

aa) —C(O)-furanyl,

bb) —C(O)-thiophenyl,

cc) —C(O)-isoxazolyl,

dd) —C(O)—C 1-10 alkylene-cycloalkyl,

ee) —C(O)—NH—C 1-10 alkyl,

ff) —C(O)—NH-phenyl, and

hh) —C(O)—N(cycloalkyl)-C 1-10 phenyl,

wherein the alkyl, alkynyl, cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, naphthyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, and isoxazolyl groups are optionally substituted 1-4 times with a group independently selected from R c .

24. A pharmaceutical composition comprising:

a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R is (CH 2 ) p -G 1 -L 1 -G 2 , wherein

L 1 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 16 )—, —C(O)—, —CON(R 16 )—, —N(R 16 )C(O)—, —N(R 16 )SO 2 —, —SO 2 N(R 16 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and wherein

R 16 is selected from the group consisting of: —hydrogen, —alkyl, —aryl, —alkylene-aryl;

G 1 is selected from the group consisting of: alkynylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G 1 is optionally substituted 1-4 times with substituents independently selected from R 10 , wherein

R 10 is R b ,

G 2 is selected from the group consisting of: —aryl, —heteroaryl, —fused arylcycloalkyl, —fused cycloalkylaryl, —fused cycloalkylheteroaryl, —fused heterocyclylaryl, and —fused heterocyclylheteroaryl, wherein G 2 is optionally substituted 1-4 times with substituents independently selected from R 11 , wherein

R 11 is R b ,

R 1 is selected from the group consisting of: —CO 2 H, —CO 2 R 12 , —C(O)NH 2 , —C(O)NHR 12 , —tetrazole, and acid isostere, wherein

R 12 is selected from the group consisting of: —C 1-10 alkyl, —cycloalkyl, and —aryl, wherein

R 12 is optionally substituted 1-4 times with a group independently selected from R c ;

R 2 is selected from the group consisting of: —hydrogen, —alkyl, —phenyl, —cycloalkyl, —alkylene-cycloalkyl, and —alkylene-phenyl, wherein alkyl, phenyl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from R c ;

R 3 is selected from R a ;

R 4 is selected from R a ; and

R 5 is G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 and L 3 are independently selected from the group consisting of: a direct bond, CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 26 )SO 2 N(R 27 )—, wherein

R 26 and R 27 are independently selected from the group consisting of: hydrogen, —alkyl, —aryl, and —alkylene-aryl, wherein R 26 and R 27 are optionally substituted 1-4 times with R c , or R 26 and R 27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

Q 2 is selected from the group consisting of: a direct bond, C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene,

G 3 is selected from the group consisting of: —arylene, —cycloalkylene, —heterocyclylene, —heteroarylene, —fused arylcycloalkylene, —fused cycloalkylarylene, —fused cycloalkylheteroarylene, —fused heterocyclylarylene, and —fused heterocyclylheteroarylene, wherein

G 3 is optionally substituted 1-4 times with substituents independently selected from R 8 , wherein R 8 is selected from R b ,

G 4 is selected from the group consisting of: —aryl, —cycloalkyl, —heterocyclyl, —heteroaryl, —fused arylcycloalkyl, —fused cycloalkylaryl, —fused cycloalkylheteroaryl, —fused heterocyclylaryl, and —fused heterocyclylheteroaryl, wherein

G 4 is optionally substituted 1-4 times with substituents independently selected from R 9 , wherein R 9 is selected from R b ,

Rings B and C are optionally substituted 1-4 times with substituents independently selected from the group consisting of R b ;

R a is selected from the group consisting of:

a) —hydrogen,

b) —S(O) m R d ,

c) —S(O) 2 OR d ,

d) —S(O) m NR d R e ,

e) —C(O)R d ,

f) —CO 2 R d ,

g) —C(O)NR d R e ,

h) —haloalkyl,

i) —cycloalkyl,

j) —heterocyclyl,

k) —C 1-10 alkyl,

l) —C 2-10 alkenyl,

m) —C 2-10 alkynyl,

n) —aryl,

o) —heteroaryl,

p) —C 1-10 alkylene-aryl,

q) —C 2-10 alkynylene-aryl,

r) —C 1-10 alkylene-heteroaryl,

s) —C 2-10 alkynylene-heteroaryl, and

t) —C(R f R g ) n -aryl,

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

R b is selected from the group consisting of:

a) —cycloalkyl,

b) —cyano,

c) —OR d ,

d) —NO 2 ,

e) —halogen,

f) —S(O) m R d ,

g) —SR d ,

h) —S(O) 2 OR d ,

i) —S(O) m NR d R e ,

j) —NR d R e ,

k) —O(CR f R g ) n NR d R e ,

l) —C(O)R d ,

m) —CO 2 R d ,

n) —CO 2 (CR f R g ) n CONR d R e ,

o) —OC(O)R d ,

p) —C(O)NR d R e ,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR e ,

t) —NR d C(O)NR d R e ,

u) —CF 3 ,

v) —OCF 3 ,

w) —haloalkyl,

x) —haloalkoxy,

y) —C 1-10 alkyl,

z) —C 2-10 alkenyl,

aa) —C 2-10 alkynyl,

ab) —C 1-10 alkylene-aryl,

ac) —C 1-10 alkylene-heteroaryl, and

ad) —heteroaryl,

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

R c is selected from the group consisting of:

a) —halogen,

b) —amino,

c) —carboxy,

d) —cyano,

e) —C 1-4 alkyl,

f) —O—C 1-4 alkyl,

g) —O—CF 3 ,

h) —cycloalkyl,

i) —O-cycloalkyl,

j) —aryl,

k) —C 1-4 alkylene-aryl,

l) —hydroxy,

m) —CF 3 ,

n) —haloalkyl,

o) —haloalkoxy,

p) —O-aryl,

q) —heteroaryl,

r) —heteroarylene-C 1-10 alkyl,

s) —heterocyclyl,

t) —CO 2 —C 1-10 alkyl,

u) —CO 2 —C 1-10 alkyl-aryl,

v) —fused arylcycloalkyl,

w) —alkynylene-heteroaryl,

x) —alkylene-aryl,

y) —alkynylene-aryl,

z) —nitro,

aa) —N(H)—C(O)—C 1-6 -alkyl, and

bb) —S—C 1-6 -alkyl;

R d and R e are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with R c ,

R f and R g are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, cycloalkyl, —C 1-10 alkylene-cycloalkyl, —carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to four substituents independently selected from R c ; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with R c ;

m is an integer from 1 to 2;

n is an integer from 1 to 10;

p is an integer from 0 to 2; and

a pharmaceutically acceptable carrier or diluent.

25. (S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25 , wherein the compound is (S)-2-({(S)-6-benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid.

27. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27 , wherein the compound is (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid.

29. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29 , wherein the compound is (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid.

31. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid or a pharmaceutically acceptable salt thereof.

32. The compound of claim 31 , wherein the compound is (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid.

33. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33 , wherein the compound is (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid.

35. A compound selected from the group consisting of:

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid 4-hydroxy-cyclohexyl ester,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid 3-hydroxy-cyclopentyl ester,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-3-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((S)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((R)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isobutyl ester,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid 2,2-dimethyl-propyl ester,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tetrahydro-pyran-4-yl ester,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-isobutyryl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid

(S)-2-({(S)-6-Benzenesulfonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(piperidine-1-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid cyclopropylmethyl ester,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid (R)-(tetrahydro-furan-3-yl) ester,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(furan-2-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-methyl-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-fluoro-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-methoxy-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-trifluoromethyl-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclohexanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(naphthalene-1-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tent-butyl ester,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(5-methyl-isoxazole-3-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-dimethylcarbamoyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-2-({(S)-6-Benzyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-phenethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(2,4,6-trifluoro-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(toluene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methyl-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-thiophen-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-fluoro-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-6-(2-Chloro-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methoxy-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(6-methyl-pyridin-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-6-(6-Bromo-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-(5-cyano-6-methylsulfanyl-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1-methyl-1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-6-(2-Cyano-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopropylmethyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-pyrimidin-2-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-thiophen-3-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(3-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tent-butyl ester,

(S)-2-({(S)-6-Benzoyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-3-[4-(3-Chloro-benzyloxy)-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-ethyl-benzyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclohexyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-cyclopentylmethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-ethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-({(S)-6-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionic acid,

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid,

(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid,

(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid,

(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3,5-dimethyl-isoxazole-4-sulfonyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid,

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid,

(R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, and

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid;

or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound of claim 33 and a pharmaceutically acceptable carrier or diluent.

37. A pharmaceutical composition comprising a compound of claim 26 and a pharmaceutically acceptable carrier or diluent.

38. A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable carrier or diluent.

39. A pharmaceutical composition comprising a compound of claim 28 and a pharmaceutically acceptable carrier or diluent.

40. A pharmaceutical composition comprising a compound of claim 29 and a pharmaceutically acceptable carrier or diluent.

41. A pharmaceutical composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier or diluent.

42. A pharmaceutical composition comprising a compound of claim 31 and a pharmaceutically acceptable carrier or diluent.

43. A pharmaceutical composition comprising a compound of claim 32 and a pharmaceutically acceptable carrier or diluent.

44. A pharmaceutical composition comprising a compound of claim 33 and a pharmaceutically acceptable carrier or diluent.

45. A pharmaceutical composition comprising a compound of claim 34 and a pharmaceutically acceptable carrier or diluent.

46. A pharmaceutical composition comprising a compound of claim 35 and a pharmaceutically acceptable carrier or diluent.

Assignments (12)