Glutamate aggrecanase inhibitors

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

W is —C(O)—;

R 1 is biphenyl optionally substituted with one or more of R 5 or R 6 , and when R 1 is substituted with more than one of R 5 or R 6 , the substituents can be identical or different;

R 2 is hydrogen;

R 3 is —CO 2 H;

R 4 is —CONR 9 R 10 ;

R 5 is aryl, heteroaryl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, —O-aryl, —O-heteroaryl, —S-aryl, —S-heteroaryl, —NH-aryl, —NH-heteroaryl, —CO—(C 1 -C 6 ) alkyl, —CO-aryl, —CO-heteroaryl, —SO 2 (C 1 -C 6 ) alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —NHSO 2 (C 1 -C 6 ) alkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHCO-aryl, —NHCO-heteroaryl, —CONH-aryl, —CONH-heteroaryl, (C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —S—(C 1 -C 6 ) alkyl, —NH—(C 1 -C 6 ) alkyl, —NHCO—(C 1 -C 6 ) alkyl, —CONH—(C 1 -C 6 ) alkyl, —O—(C 3 -C 6 ) cycloalkyl, —S—(C 3 -C 6 ) cycloalkyl, —NH—(C 3 -C 6 ) cycloalkyl, —NHCO—(C 3 -C 6 ) cycloalkyl, or —CONH—(C 3 -C 6 cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R 6 , and when R 5 is substituted with more than one R 6 the substituents can be identical or different;

R 6 is hydrogen, halogen, —CN, —OCF 3 , —CF 3 , —OH, —SH, —NR 7 R 8 , —CONR 7 R 8 —NR 8 COR 7 —NR 8 CO 7 R 7 —CO 7 R 7 —SO 2 (C 1 -C 6 ) alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, —SO 2 R 7 —NR 7 SO 2 R 8 , —SO 7 NR 7 R 8 ; (C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —S—(C 1 -C 6 ) alkyl, —NH—(C 1 -C 6 ) alkyl, —NHCO—(C 1 -C 6 ) alkyl, —CONH—(C 1 -C 6 ) alkyl, —O—(C 3 -C 6 ) cycloalkyl, —S—(C 3 -C 6 ) cycloalkyl, —NH—(C 3 -C 6 ) cycloalkyl, —NHCO—(C 3 -C 6 ) cycloalkyl, —CONH—(C 3 -C 6 ) cycloalkyl, heterocycloalkyl, —(C 1 -C 6 ) (C 7 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, —O—(C 1 -C 6 ) alkyl-(C 3 -C 6 ) cycloalkyl, —O-alkenyl, —O—(C 1 -C 6 ) alkyl substituted with aryl, aryl, heteroaryl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, —O-aryl, —O-heteroaryl, —S-aryl, or —S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of R 13 ;

R 12 is —SO 2 -heteroaryl, heterocycloalkyl, heteroaryl, —(CH 2 ) n -heteroaryl, —O-heteroaryl, or —S-heteroaryl; each heterocycloalkyl, or heteroaryl optionally substituted with one or more of R 13 ;

R 7 and R 8 are each independently hydrogen, (C 1 -C 6 ) alkyl, aryl, heteroaryl, (C 2 -C 6 alkenyl, (C 7 -C 6 ) alkynyl, cycloalkyl, —(CH 2 ) n -heteroaryl; or R 7 and R 8 together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R 9 and R 10 are each independently hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl-OH, (C 1 -C 6 ) alkyl-O—(C 1 -C 6 ) alkyl, aryl, cycloalkyl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R 12 ; or R 9 and R 10 together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R 11 is aryl, heteroaryl, or cycloalkyl;

R 13 is halogen, —O—(C 1 -C 6 ) alkyl, —CO 2 H, —OH, —CF 3 , hydrogen, (C 1 -C 6 ) alkyl, aryl, heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, cycloalkyl, cycloalkyl substituted with —OH, aryl substituted with —NH 2 , aryl substituted with —O—(C 1 -C 6 ) alkyl, —(CH 2 ) n -aryl, or —(CH 2 ) n -heteroaryl;

m is 0;

n is 0-4; and

p is 2.

2. The compound of claim 1 of the formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein

R 1 , R 2 , and R 4 are defined as in claim 1 .

3. The compound of claim 1 of the formula (Id):

or a pharmaceutically acceptable salt thereof,

wherein

ring A and ring B are each independently optionally substituted with one or more of R 5 and R 6 ; and

R 2 , R 4 , R 5 , and R 6 are defined as in claim 1 .

4. The compound of claim 3 of the formula (Id-1):

or a pharmaceutically acceptable salt thereof, wherein

ring A and ring B are defined as in claim 3 ,

Het is —SO 2 -heteroaryl, heterocycloalkyl, heteroaryl, —(CH 2 ) n -heteroaryl, —O-heteroaryl, or —S-heteroaryl, and

R 2 , R 4 , R 5 , R 6 , R 9 and R 13 are defined as in claim 3 .

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein

R 2 is hydrogen;

R 4 is

and

R 13 is defined as in claim 3 .

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 13 is halogen.

7. A compound selected from:

N 2 -(1,1′-biphenyl-4-ylcarbonyl)-N 1 -(2-furylmethyl)-L-α-glutamine,

N 2 -biphenyl-4-ylcarbonyl)-N 1 -(pyridin-4-ylmethyl)-L-α-glutamine,

N 2 -biphenyl-4-ylcarbonyl)-N 1 -(2-morpholin-4-ylethyl)-L-α-glutamine

N 2 -(biphenyl-4-ylcarbonyl)-N 1 -[2-(2-thienyl)ethyl]-L-α-glutamine,

N-[2-(5-chloro-2-thienyl)-1,1-dimethylethyl]-N 2 -[(3-fluorobiphenyl-4-yl)carbonyl]-L-α-glutamine,

N-[2-(5-chloro-2-thienyl)-1,1-dimethylethyl]-N 2 -[(3′,4′-difluorobiphenyl-4-yl)carbonyl]-L-α-glutamine, and

N 2 -(biphenyl-4-ylcarbonyl)-N-[2-(5-chloro-2-thienyl)-1,1-dimethylethyl]-L-α-glutamine,

or a pharmaceutically acceptable salt thereof.

8. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier.

9. The composition of claim 8 , wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.

10. A method for treating a disorder, in an animal in need thereof, wherein the disorder is osteoarthritis, wherein the method comprises administering an effective dose of the compound of claim 1 , or a pharmaceutically acceptable salt.