Substituted 1,3-dihydro-imidazol-2-one and 1,3-dihydro-imidazol-2-thione derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)

• US 7,211,671 B2
• Filed: 09/21/2004
• Issued: 05/01/2007
• Est. Priority Date: 10/01/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gilmore, John L., Sheppeck, James, Chen, Xiao-Tao, He, Xiaohua
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US10/946,418
• Publication Number:
  US 20050075384A1
• Time in Patent Office: 952 Days
• Field of Search: 546/152, 548/325.1, 548/316.4
• US Class Current: 546/152
• CPC Class Codes: C04B 35/632 Organic additives
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention describes novel 1,3-dihydro-imidazol-2-one or 1,3-dihydro-imidazol-2-thione compounds of formula (I):

or a stereoisomer or pharmaceutically acceptable salt or solvate thereof, wherein A, L R¹, R², R³ and R⁴ are defined in the present specification, which are useful as selective inhibitors of MMP, TACE, aggrecanase or a combination thereof. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.

Claims

1. A compound of Formula (I):

2. A compound according to claim 1, wherein:

R¹ is Q, F, Cl, Br, I, CN, NO₂, —

CF₂CF₃, —

NR⁷R⁸, C_1-4 haloalkyl, —

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^aRa1)_sQ, -(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)_tSO₂NR^a(CR^aR^a1)_s—

Q, or —

(CR^aR^a1)_tNR^aSO₂(CR^aR^a1)_s—

Q;

R⁵ 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)_rNR^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)_rOC(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)_rNR^aC(O)(CR^aR^a1)_s—

Q, —

(CR^aR^a1)_rS(CR^aR^a1)_s—

Q, —

(CR^aR^a1)_rS(O)(CR^aR^a1)_s—

Q, —

(CR^aR^a1)_rS(O)₂(CR^aR^a1)_s—

Q, —

(CR^aR^a1)_rSO₂NR^a(CR^aR^a1)_s—

Q, or —

(CR^aR^a1)_rNR^aSO₂(CR^aR^a1)_s—

Q;

R⁶ is H, —

C_1-6 alkylene-Q, —

C_2-6 alkenylene-Q, or —

C_2-6 alkynylene-Q;

each R⁹ 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)_tNR^aC(O)NR^aR^a1, —

(CR^aR^a1)_tS(O)R^a3, —

(CR^aR^a1)_tS(O)R^a3, —

(CR^aR^a1)_rS(O)₂R^a3, —

(CR^aR^a1)SO₂NR^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;

or (CR^aR^a1)_r-5–

10 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1;

each R¹⁰ is, independently at each occurrence, H, —

(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)_rNR^aC(O)NR^aR^a1, —

(CR^aR^a1)_rS(O)R^a3, —

(CR^aR^a1)_rS(O)R^a3, —

(CR^aR^a1)_rS(O)₂R^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;

or —

(CR^aR^a1)_r-5–

10 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1;

each Q is, independently at each occurrence, H, CF₃, —

CH₂F, —

CHF₂, C_1-6 alkyl, a C_3-10 carbocycle substituted with 0–

5 R^d, or a 5–

10 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of NR⁹, O, and S(O)_p, and substituted with 0–

5 R^d;

each Q¹ is, independently at each occurrence, C_1-6 alkyl, a C_3-10 carbocycle substituted with 0–

5 R^d, or a 5–

12 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of NR⁹, O, and S(O)_p, and substituted with 0–

5 R^d;

Z⁰ is aryl or a 5–

6 membered heteroaryl consisting of carbon atoms and 0–

3 ring heteroatoms selected from O, N, NR⁹, and S, and substituted with 0–

3 R¹⁰; and

the aryl or heteroaryl is optionally fused to a 5–

6 membered carbocycle or heterocycle consisting of carbon atoms and 0–

2 ring heteroatoms selected from O, N, NR⁹, and S(O)_p, and 0–

2 double bonds, and substituted with 0–

3 R¹⁰;

W is (CR^aR^a1)_m, C_2-3 alkenylene, or C_2-3 alkynylene;

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

X is a bond or C_1-3 alkylene;

Y is a bond, O, NR^a1, S(O)_p, or C(O);

alternatively, Z⁰ is absent, and W—

U—

X—

Y forms S(O)_p;

Z is a C_3-8 cycloalkyl substituted with 0–

5 R^b, a C_3-8 cycloalkenyl substituted with 0–

5 R^b, phenyl substituted with 0–

5 R^b, naphthyl substituted with 0–

5 R^b or a 5–

14 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p and substituted with 0–

5 R^b;

U^a is a bond, 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 a bond, C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene;

Y^a is a bond, O, or NR^a1;

Z^a is a C_6-13 carbocycle substituted with 0–

5 R^c, or a 5–

14 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p and substituted with 0–

5 R^c;

provided that U, Y, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

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

O, CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂, —

(CR^aR^a1)_rOR^a, —

(CR^aR^a1)_rNR^aR^a1, —

(CR^aR^a1)_rC(O)NR^aOH, —

(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, —

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1, or —

(CH₂)_r-5–

6 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 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 or heterocyclic spiro ring C substituted with 0–

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

4 ring heteroatoms selected from O, N, and S(O)_p, and 0–

2 double bonds, provided that ring C contains other than a S—

S, O—

O, or S—

O bond;

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 or heterocyclic ring D substituted with 0–

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

2 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 0–

3 double bonds; and

each R^d is, independently at each occurrence, C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

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, C_3-6 carbocycle, or a 5–

6 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p.

3. A compound according to claim 2, wherein:

R¹ is Q, F, Cl, CN, —

NR⁷R⁸, C_1-4 haloalkyl, —

C_1-4 alkylene-Q, —

C_2-4 alkenylene-Q, —

C_2-4 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)_tSO₂NR^a(CR^aR^a1)_s—

Q, or —

(CR^aR^a1)_tNR^aSO₂(CR^aR^a1)_s—

Q;

R² is H or C_1-4 alkyl;

R³ is H or C_1-4 alkyl;

R⁵ is Q, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, —

(CH₂)_tO(CH₂)_s—

Q, —

(CH₂)_rNR^a(CH₂)_s—

Q, —

(CH₂)_rC(O)(CH₂)_s—

Q, —

(CH₂)_rC(O)O(CH₂)_s—

Q, —

(CH₂)_rOC(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(CH₂)_s—

Q, —

(CH₂)_rS(O)(CH₂)_s—

Q, —

(CH₂)_rS(O)₂(CH₂)_s—

Q, —

(CH₂)_rSO₂NR^a(CH₂)_s—

Q, or —

(CH₂)_rNR^aSO₂(CH₂)_s—

Q;

R⁶ is H, —

C_1-4 alkyl, C_2-4 alkenyl, or C_2-4 alkynyl;

R⁷ is H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, —

(CR^aR^a1)_rC(O)(CR^aR^a1)_s—

Q¹, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_s—

Q¹, —

(CR^aR^a1)_rC(O)O(CR^aR^a1)_tOC(O)_s—

Q¹, —

(CR^aR^a1)_rC(O)NH(CR^aR^a1)_s—

Q¹, or —

(CR^aR^a1)_rS(O)₂)(CR^aR^a1)_s—

Q¹;

R⁸ is H, C_1-4 alkyl, or —

(CH₂)_n-phenyl;

each R⁹ 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)_tS(O)R^a3, —

(CR^aR^a1)_tS(O)R^a3, —

(CR^aR^a1)_rS(O)₂R^a3, —

(CR^aR^a1)SO₂NR^aR^a1, —

(CR^aR^a1)_tNR^aSO₂R^a3, 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, —

(CH₂)_r—

C_3-10 carbocycle substituted with 0–

2 R^c1;

or —

(CH₂)_r-5–

10 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1;

each R¹⁰ is, independently at each occurrence, H, —

(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)_rS(O)R^a3, —

(CR^aR^a1)_rS(O)R^a3, —

(CR^aR^a1)_rS(O)₂R^a3, —

(CR^aR^a1)_rSO₂NR^aR^a1, —

(CR^aR^a1)_rNR^aSO₂R^a3, 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, —

(CH₂)_r—

C_3-10 carbocycle substituted with 0–

2 R^c1;

or —

(CH₂)_r-5–

10 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1;

Z⁰ is phenyl substituted with 0–

3 R¹⁰, or a 5–

6 membered heteroaryl substituted with 0–

3 R¹⁰ and selected from;

oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrazolyl;

W is (CH₂)_m;

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

X is a bond, or methylene or ethylene;

Y is a bond, O, NR^a1, S(O)_p, or C(O);

alternatively, Z⁰ is absent, and W—

U—

X—

Y forms S(O)_p;

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

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

O, CN, NO₂, 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, —

(CH₂)_r—

C_3-6 cycloalkyl substituted with 0–

1 R^c1, phenyl substituted with 0–

2 R^c1, or —

(CH₂)_r-5–

6 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 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 or heterocyclic ring D substituted with 0–

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

2 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 0–

3 double bonds;

each R^d is, independently at each occurrence, C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

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;

m is 0, 1, or 2;

n is 0, 1, or 2;

each r is, independently at each occurrence, 0, 1, 2, or 3;

each s is, independently at each occurrence, 0, 1, 2, or 3; and

each t is, independently at each occurrence, 2, or 3.

4. A compound according to claim 3, wherein:

A is O;

R¹ is Q, F, Cl, CN, —

NR⁷R⁸, C_1-4 haloalkyl, —

C_1-4 alkylene-Q, —

C_2-4 alkenylene-Q, —

C_2-4 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)_tSO₂NR^a(CH₂)_s—

Q, or —

(CH₂)_tNR^aSO₂(CH₂)_s—

Q;

R⁵ is H, C_1-4 alkyl, C_2-4 alkenyl, or C_2-4 alkynyl;

R⁷ is H, C_1-4 alkyl, or —

(CH₂)_n-phenyl;

R⁸ is H, C_1-4 alkyl, or —

(CH₂)_n-phenyl;

each R⁹ is, independently at each occurrence, H, —

(CH₂)_tNR^aR^a1, —

(CH₂)_rC(O)(CH₂)_sR^e, —

(CH₂)_rC(O)OR^a1, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_tNR^aC(O)R^a1, —

(CH₂)_tS(O)R^a3, —

(CH₂)_tS(O)R^a3, —

(CH₂)_rS(O)₂R^a3, —

(CH₂)SO₂NR^aR^a1, —

(CH₂)_tNR^aSO₂R^a3, C_1-4 alkyl, or —

(CH₂)_n-phenyl;

each R¹⁰ is, independently at each occurrence, H, —

(CH₂)_rNR^aR^a1, —

(CH₂)_rC(O)(CH₂)_sR^e, —

(CH₂)_rC(O)OR^a1, —

(CH₂)_rC(O)NR^aR^a1, —

(CH₂)_rNR^aC(O)R^a1, —

(CH₂)_rS(O)R^a3, —

(CH₂)_rS(O)R^a3, —

(CH₂)_rS(O)₂R^a3, —

(CH₂)_rSO₂NR^aR^a1, —

(CH₂)_tNR^aSO₂R^a3, C_1-4 alkyl, or —

(CH₂)_n-phenyl;

Z⁰ is phenyl substituted with 0–

2 R¹⁰, or pyridyl substituted with 0–

2 R¹⁰;

alternatively, Z⁰ is absent, and W—

U—

X—

Y forms S(O)_p;

U is O, C(O), CH(OH), C(O)NH, S(O)_p, S(O)_pNH, or NHS(O)_p;

Z is a C_4-8 cycloalkyl substituted with 0–

3 R^b, a C_4-8 cycloalkenyl substituted with 0–

3 R^b, phenyl substituted with 0–

4 R^b, naphthyl substituted with 0–

5 R^b, or a heterocycle substituted with 0–

3 R^b and selected from the group;

furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thienyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazolyl, pyrrolidinyl, pyrrolyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, methylenedioxyphenyl, and quinazolinyl;

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, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazolyl, pyrrolidinyl, pyrrolyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, methylenedioxyphenyl, 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;

each 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, or a 5–

6 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 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 or heterocyclic ring D substituted with 0–

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

2 heteroatoms selected from the group consisting of N, O, and S(O)_p, and 0–

3 double bonds; and

each R^d is, independently at each occurrence, C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

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.

5. A compound according to claim 4, wherein:

A is O;

L is a bond, CO or CH₂;

R¹ is H, C_1-4 haloalkyl, C_1-4 alkyl, or —

C(O)O(CH₂)_s—

H;

Z⁰ is phenyl;

alternatively, Z⁰ is absent, and W—

U—

X—

Y forms S(O)_p;

Z is phenyl substituted with 0–

2 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;

each 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;

each 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^al, —

(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 or heterocyclic ring consisting of;

carbon atoms and 0–

1 heteroatoms selected from the group consisting of N, O, and S(O)_p; and

each 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, or a 5–

6 membered heterocycle consisting of carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

1 R^c1.

7. A pharmaceutical composition, comprising:

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

8. A pharmaceutical composition, comprising:

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

9. A pharmaceutical composition, comprising:

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

10. A pharmaceutical composition, comprising:

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

11. A pharmaceutical composition, comprising:

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

6. A compound selected from the group:

4-(2-methyl-quinolin-4-yl methoxy)-N-[2-(2-oxo-2,3-dihydro-1H-imidazole-4-carbonyl)phenyl]benzamide;

4-(2-methyl-quinolin-4-yl methyl)-N-[2-(2-oxo-2,3-dihydro-1H-imidazole-4-carbonyl)phenyl]benzamide;

4-(2-methyl-quinolin-4-yl methoxy)-N-[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl methyl)phenyl]benzamide;

5-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylmethyl]-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester;

4-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylsulfanylmethyl]-1,3-dihydro-imidazol-2-one;

4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfinylmethyl]-1,3-dihydro-imidazol-2-one; and

4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylmethyl]-1,3-dihydro-imidazol-2-one;

or a stereoisomer or pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition, comprising:

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