Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)

• US 7,041,693 B2
• Filed: 10/02/2003
• Issued: 05/09/2006
• Est. Priority Date: 10/04/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sheppeck, James
• Primary Examiner(s): Solola, Taofiq
• Assistant Examiner(s): SHIAO, REI TSANG
• Application Number:
  US10/677,988
• Publication Number:
  US 20040067996A1
• Time in Patent Office: 950 Days
• Field of Search: 548/300.1, 548/311.1, 548/315.1, 548/315.4, 546/135, 546/192, 514/317, 514/385, 514/396, 514/397, 514/306, 514/307
• US Class Current: 514/385
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present application describes novel hydantoin derivatives of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein L, Z⁰, R¹, R⁴, R⁵, and R¹¹ are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), aggrecanase, or a combination thereof.

Claims

1. A compound of formula (I):

2. A compound according to claim 1, wherein:

R¹ is Q, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, —

C_2-6 alkynylene-Q, —

(CR^aR^a1)_tO(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tNR^a(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tOC(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rC(O)NR^a(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tNR^aC(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tS(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tS(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rS(O)₂(CR^aR^a1)_s-Q, —

(CR^aR^a1)SO₂NR^a(CR^aR^a1)_s-Q, or —

(CR^aR^a1)_tNR^aSO₂(CR^aR^a1)_s-Q;

R² is Q¹, —

C_1-6 alkylene-Q¹, —

C_2-6 alkenylene-Q¹, —

C_2-6 alkynylene-Q¹, —

(CR^aR^a1)_rO(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rNR^a(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rOC(O)(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rC(O)NR^a(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rNR^aC(O)(CR_aR^a1)_s-Q¹, —

(CR^aR^a1₂)_rS(O)_p(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rSO₂NR^a(CR^aR^a1)_s-Q¹, or —

(CR^aR^a1)_rNR^aSO₂(CR^aR^a1)_s-Q¹;

W is (CR^aR^a1)_m;

X is absent or is C_1-3 alkylene;

U^a is absent or is O, NR^a1, C(O), CR^a(OH), C(O)O, C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, or NR^a1S(O)_p;

X^a is absent or is C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene;

Y^a is absent or is O or NR^a1;

R^a is, independently at each occurrence, H, C_1-6 alkyl, phenyl, or benzyl;

R^a1 is, independently at each occurrence, H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or —

(CH₂)_r-3–

8 membered carbocyclic ring;

R^c is, independently at each occurrence, H, Cl, F, Br, ═

O, CN, NO₂, CF₃, CH₂F, CHF₂, —

CF₂CF₃, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)R^a1, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR_aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl substituted with 0–

1 R^c1, C_2-6 alkenyl substituted with 0–

1 R^c1, C_2-6 alkynyl substituted with 0–

1 R^c1, or —

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1;

alternatively, when two R^c groups are attached to the same carbon atom, they form a 3–

8 membered carbocyclic spiro ring C substituted with 0–

2 R^c1 and consisting of carbon atoms and 0–

2 double bonds;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–

7 membered carbocyclic ring D substituted with 0–

2 R^c1 and consisting of carbon atoms and 0–

3 double bonds;

R^d is, independently at each occurrence, C_1-6 alkyl, —

OR^a, Cl, F, Br, ═

O, CN, NO₂, —

NR^aR^a1, —

C(O)R^a, —

C(O)OR^a, —

C(O)NR^aR^a1, —

S(O)₂NR^aR^a1, —

NR^aS(O)₂R^a3, —

S(O)_pR^a3, CF₃, or C_3-6 carbocycle;

R⁴ is H or C_1-4 alkyl;

R⁵ is H or C_1-4 alkyl;

R⁶ is, independently at each occurrence, H, Cl, F, Br, I, ═

O, CN, NO₂, CF₃, —

CF₂CF₃, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)NR^aOH, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_sR^e, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rOC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)OR^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl substituted with 0–

2 R^c1, C_2-6 alkenyl substituted with 0–

2 R^c1, C_2-6 alkynyl substituted with 0–

2 R^c1, —

(CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0–

2 R^c1; and

R⁷ is, independently at each occurrence, H, —

(CR^aR^a1)_tNR^aR^a1, —

(CR^aR^a1)_rC(O)NR^aOH, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_sR^e, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_tNR^aC(O)R^a1, —

(CR^aR^a1)_tOC(O)NR^aR^a1, —

(CR^aR^a1)_tNR^aC(O)OR^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_tNR^aSO₂R^a3, C_1-6 alkyl substituted with 0–

2 R^c1, C_2-6 alkenyl substituted with 0–

2 R^c1, C_2-6 alkynyl substituted with 0–

2 R^c1, —

(CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0–

2 R^c1.

3. A compound according to claim 2, wherein:

R¹ is Q, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, —

C_2-6 alkynylene-Q, —

(CR^aR^a1)_tO(CR^aR^a1)_s-Q —

(CR^aR^a1)_tNR^a(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rC(O)NR^a(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tS(CR^aR^a1)_s-Q, —

(CR^aR^a1)_tS(O)(CR^aR^a1)_s-Q, —

(CR^aR^a1)_rS(O)₂(CR^aR^a1)_s-Q, —

(CR^aR^a1)SO₂NR^a(CR^aR^a1)_s-Q, or —

(CR^aR^a1)_tNR^aSO₂(CR^aR^a1)_s-Q;

R² is Q¹, —

C_1-6 alkylene-Q¹, —

C_2-6 alkenylene-Q¹, —

C_2-6 alkynylene-Q¹, —

(CR^aR^a1)_rO(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rNR^a(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rOC(O)(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rC(O)NR^a(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rNR^aC(O)(CR^aR^a1)_s-Q¹, —

(CR^aR^a1₂)_rS(O)_p(CR^aR^a1)_s-Q¹, —

(CR^aR^a1)_rSO₂NR^a(CR^aR^a1)_s-Q¹, or —

(CR^aR^a1)_rNR^aSO₂(CR^aR^a1)_s-Q¹;

R³ is Q, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, —

C_2-6 alkynylene-Q, —

(CH₂)_rO(CH₂)_s-Q, —

(CH₂)_rNR^a(CH₂)_s-Q, —

(CH₂)_rC(O)(CH₂)_s-Q, —

(CH₂)_rC(O)O(CH₂)_s-Q, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_rC(O)NR^a(CH₂)_s-Q, —

(CH₂)_rNR^aC(O)(CH₂)_s-Q, —

(CH₂)_rS(O)_p(CH₂)_s-Q, —

(CH₂)_rSO₂NR^a(CH₂)_s-Q, or —

(CH₂)_rNR^aSO₂(CH₂)_s-Q;

Q is, independently at each occurrence, H, a C_3-10 carbocycle substituted with 0–

3 R^d;

Q¹ is, independently at each occurrence, H, a C_3-10 carbocycle substituted with 0–

3 R^d;

U is absent or is O, NR^a1, C(O), C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, or NR^a1S(O)_p;

X is absent or is methylene or ethylene;

U^a is absent or is O, NR^a1, C(O), C(O)NR^a1, NR^a1C(O), S(O)_p, S(O)_pNR^a1, or NR^a1S(O)_p;

R^a3 is, independently at each occurrence, H, C_1-6 alkyl, C_2-6 alkenyl, or —

(CH₂)_r-3–

8 membered carbocyclic cyclic ring consisting of carbon atoms and substituted with 0–

3 R^c1;

R^c is, independently at each occurrence, H, Cl, F, Br, ═

O, CF₃, CH₂F, CHF₂, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)R^a1, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl substituted with 0–

1 R^c1, or phenyl substituted with 0–

2 R^c1;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–

7 membered carbocyclic ring D substituted with 0–

2 R^c1 and consisting of carbon atoms and 0–

3 double bonds;

R^d is, independently at each occurrence, C_1-6 alkyl, —

OR^a, Cl, F, Br, ═

O, —

NR^aR^a1, —

C(O)R^a, —

C(O)OR^a, —

C(O)NR^aR^a1, —

S(O)₂NR^aR^a1, —

NR^aS(O)₂R^a3, —

S(O)_pR^a3, CF₃ or phenyl;

R⁴ is H;

R⁵ is H;

R⁶ is, independently at each occurrence, H, Cl, F, Br, I, ═

O, CN, NO₂, CF₃, —

CF₂CF₃, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_sR^e, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl substituted with 0–

2 R^c1, C_2-6 alkenyl substituted with 0–

2 R^c1, C_2-6 alkynyl substituted with 0–

2 R^cl, —

(CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0–

2 R^c1;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, 2, and 3; and

t, at each occurrence, is selected from 1, 2, and 3;

provided that;

(i) when L is a bond, CHR² or CHR³, and Z is phenyl, then Z^a is other than phenyl;

(ii) when L is a bond or CH₂, and Z is phenyl, then Z^a is other than furanyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyranyl, pyrazinyl, or pyrazolyl;

or

(iii) when L is a bond, Z is phenyl, —

U^a—

X^a—

Y^a—

forms C_1-2 alkylene, and Z^a is benzimidazolyl, then R^c is other than C(O)OR^a1.

4. A compound according to claim 3, wherein:

R¹ is Q, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, —

C_2-6 alkynylene-Q, —

(CH₂)_tO(CH₂)_s-Q, —

(CH₂)_tNR^a(CH₂)_s-Q, —

(CH₂)_rC(O)(CH₂)_s-Q, —

(CH₂)_rC(O)O(CH₂)_s-Q, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_rC(O)NR^a(CH₂)_s-Q, —

(CH₂)_tS(CH₂)_s-Q, —

(CH₂)_tS(O)(CH₂)_s-Q, —

(CH₂)_rS(O)₂(CH₂)_s-Q, —

(CH₂)SO₂NR^a(CH₂)_s-Q, or —

(CH₂)_tNR^aSO₂(CH₂)_s-Q;

R² is Q¹, —

C_1-6 alkylene-Q¹, —

C_2-6 alkenylene-Q¹, —

C_2-6 alkynylene-Q¹, —

(CH₂)_rO(CH₂)_s-Q¹, —

(CH₂)_rNR^a(CH₂)_s-Q¹, —

(CH₂)_rC(O)(CH₂)_s-Q¹, —

(CH₂)_rC(O)O(CH₂)_s-Q¹, —

(CH₂)_rC(O)NR^a(CH₂)_s-Q¹, —

(CH₂)_rNR^aC(O)(CH₂)_s-Q¹, —

(CH₂)_rS(O)_p(CH₂)_s-Q¹, —

(CH₂)_rSO₂NR^a(CH₂)_s-Q¹, or —

(CH₂)_rNR^aSO₂(CH₂)_s-Q¹;

R³ is H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, phenyl, or benzyl;

Q is, independently at each occurrence, H, a C_3-6 cycloalkyl substituted with 0–

2 R^d, or phenyl substituted with 0–

3 R^d;

Q¹ is, independently at each occurrence, H, a C_3-6 cycloalkyl substituted with 0–

2 R^d, phenyl substituted with 0–

3 R^d;

R^a is, independently at each occurrence, H, C_1-6 alkyl, phenyl, or benzyl;

R^a1 is, independently at each occurrence, H, C_1-6 alkyl, phenyl, or benzyl;

R^a3 is, independently at each occurrence, H, C_1-6 alkyl, phenyl, or benzyl;

R^c is, independently at each occurrence, H, Cl, F, Br, ═

O, CF₃, CH₂F, CHF₂, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)R^a1, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, phenyl substituted with 0–

2 R^c1;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–

6 membered carbocyclic ring D substituted with 0–

2 R^c1 and consisting of carbon atoms and 0–

3 double bonds; and

R⁶ is, independently at each occurrence, H, Cl, F, Br, I, ═

O, CN, NO₂, CF₃, —

CF₂CF₃, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_sR^e, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or —

(CR^aR^a1)_r—

C_3-7 carbocycle substituted with 0–

2 R^c1;

provided that;

(i) when L is a bond, CHR² or CHR³, and Z is phenyl, then Z^a is other than phenyl;

(ii) when L is a bond or CH₂, and Z is phenyl, then Z^a is other than furanyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyranyl, pyrazinyl, or pyrazolyl;

or

(iii) when L is a bond, Z is phenyl, —

U^a—

X^a—

Y^a—

forms C_1-2 alkylene, and Z^a is benzimidazolyl, then R^c is other than C(O)OR^a1.

5. A compound according to claim 4, wherein:

R¹ is H, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, or —

C_2-6 alkynylene-Q;

Q is, independently at each occurrence, H, phenyl substituted with 0–

2 R^d;

L is a bond, CO or CH₂;

X is absent or is methylene;

Y is absent or is O;

Z is phenyl substituted with 0–

4 R^b, thienyl substituted with 0–

2 R^b, furanyl substituted with 0–

2 R^b, pyridyl substituted with 0–

2 R^b, pyrazinyl substituted with 0–

2 R^b, pyrimidinyl substituted with 0–

2 R^b, thiazolyl substituted with 0–

1 R^b, oxazolyl substituted with 0–

1 R^b, isoxazolyl substituted with 0–

1 R^b, or imidazolyl substituted with 0–

1 R^b;

U^a is absent or is O;

X^a is absent or is C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene;

Y^a is absent or is O;

Z^a is phenyl substituted with 0–

3 R^c, naphthyl substituted with 0–

3 R^c, or a heterocycle substituted with 0–

3 R^c and selected from the group;

furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazolyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, imidazolyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, quinazolinyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, and pyrazolo[1,5-a]pyridinyl;

R^a is, independently at each occurrence, H, or C_1-4 alkyl;

R^a1 is, independently at each occurrence, H, or C_1-4 alkyl;

R^a3 is, independently at each occurrence, H, C_1-4 alkyl, phenyl, or benzyl;

R^c is, independently at each occurrence, H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cl, F, Br, ═

O, CF₃, CH₂F, CHF₂, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)R^a1, —

(CR^aR^a1)_rC(O)OR^a1, —

(CR^aR^a1)_rC(O)NR^aR^a1, —

(CR^aR^a1)_rNR^aC(O)R^a1, —

(CR^aR^a1)_rS(O)_pR^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, or phenyl;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–

6 membered carbocyclic ring D substituted with 0–

2 R^c1 and consisting of carbon atoms and 0–

3 double bonds;

R^e is, independently at each occurrence, H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, or C_3-6 carbocycle substituted with 0–

2 R^c1; and

R⁶ is, independently at each occurrence, H, Cl, F, Br, I, ═

O, CN, NO₂, CF₃, —

CF₂CF₃, —

(CH₂)_rOR^a, —

(CH₂)_rNR^aR^a1, —

(CH₂)_rC(O)R^a, —

(CH₂)_rC(O)(CH₂)_sR^e, —

(CH₂)_rC(O)OR^a1, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_rS(O)_pR^a3, —

(CH₂)_rSO₂NR^aR^a1, C_1-4 alkyl substituted with 0–

1 R^c1, C_2-4 alkenyl substituted with 0–

1 R^c1, C_2-4 alkynyl substituted with 0–

1 R^c1, or —

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1;

provided that;

(i) when L is a bond or CH₂, and Z is phenyl, then Z^a is other than phenyl;

(ii) when L is a bond or CH₂, and Z is phenyl, then Z^a is other than furanyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyranyl, pyrazinyl, or pyrazolyl;

or

(iii) when L is a bond, Z is phenyl, —

U^a—

X^a—

Y^a—

forms C_1-2 alkylene, and Z^a is benzimidazolyl, then R^c is other than C(O)OR^a1.

6. A compound according to claim 5, wherein the compound, or a stereoisomer or pharmaceutically acceptable salt form thereof, is selected from:

7. A compound according to claim 6, wherein:

Z is phenyl substituted with 0–

1 R^b;

Z^a is phenyl substituted with 0–

3 R^c, naphthyl substituted with 0–

3 R^c, or a heterocycle substituted with 0–

3 R^c and selected from the group;

pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, pyrazolyl, and pyrazolo[1,5-a]pyridinyl;

R^b is, independently at each occurrence, C_1-6 alkyl, —

OR^a, Cl, F, Br, —

NR^aR^a1, —

C(O)R^a, —

C(O)OR^a, —

C(O)NR^aR^a1, —

S(O)₂NR^aR^a1, —

NR^aS(O)₂R^a3, —

S(O)_pR^a3, or CF₃;

R^c is, independently at each occurrence, H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cl, F, Br, ═

O, CF₃, —

(CH₂)_rOR^a, —

(CH₂)_rNR^aR^a1, —

(CH₂)_rC(O)R^a1, —

(CH₂)_rC(O)OR^a1, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_rNR^aC(O)R^a1, —

(CH₂)_rS(O)_pR^a3, —

(CH₂)_rSO₂NR^aR^a1, or —

(CH₂)_rNR^aSO₂R^a3;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5–

6 membered carbocyclic ring and

R^e is, independently at each occurrence, H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, phenyl substituted with 0–

1 R^c1;

provided that;

(i) when Z is phenyl, then Z^a is other than phenyl, pyridyl, or pyrazolyl; and

(ii) when Z is phenyl, —

U^a—

X^a—

Y^a—

forms C_1-2 alkylene, and Z^a is benzimidazolyl, then R^c is other than C(O)OR^a1.

8. A compound according to claim 1, wherein the compound is selected from the group:

N-[2-(2,5-dioxoimidazolidin-4-yl)phenyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide;

4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-[2-(2,5-dioxoimidazolidin-4-yl)phenyl]benzamide;

N-[2-(2,5-dioxoimidazolidin-4-yl)benzyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide;

5-[2-({4-[(2-methylquinolin-4-yl)methoxy]benzyl}thio)phenyl]imidazolidine-2,4-dione;

5-[3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-2-furyl]imidazolidine-2,4-dione;

5-[3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)-2-furyl]imidazolidine-2,4-dione;

5-[3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-2-thienyl]imidazolidine-2,4-dione;

5-[3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfinyl)-2-thienyl]imidazolidine-2,4-dione;

5-[3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)-2-thienyl]imidazoldine-2,4-dione;

N-[2-(2,5-dioxo-imidazolidin-4-yl)-3-thienyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide;

5-methyl-5-(3-{4-[(2-methylquinolin-4-yl)methoxy]phenoxy}-2-thienyl)imidazolidine-2,4-dione;

2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-N-(4-phenoxybenzyl)thiophene-3-carboxamide;

5-methyl-5-[3-({4-[(2-methylquinolin-4-yl)methoxy]piperidin-1-yl}carbonyl)-2-thienyl]imidazolidine-2,4-dione; and

2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-N-{4-[(2-methylquinolin-4-yl)methoxy]benzyl}thiophene-3-carboxamide;

or a stereoisomer or a pharmaceutically acceptable salt form thereof.

9. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt form thereof.

10. A method for treating an inflammation, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt form thereof.

11. A method of treating according to claim 10, wherein the disease or condition is selected from to as acute infection, acute phase response, age related macular degeneration, alcoholic liver disease, allergy, allergic asthma, anorexia, aneurism, aortic aneurism, asthma, atherosclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, Bechet'"'"'s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn'"'"'s disease, enteropathic arthropathy, Felty'"'"'s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter'"'"'s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still'"'"'s disease, shock, Sjogren'"'"'s syndrome, skin inflammatory diseases, periodontis, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'"'"'s granulomatosis.

12. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt form thereof.

13. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt form thereof.

14. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt form thereof.

15. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt form thereof.

16. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt form thereof.

17. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt form thereof.

18. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt form thereof.