Uracil derivatives as inhibitors of TNF-alpha converting enzyme (TACE) and matrixmetalloproteinases

• US 20030229081A1
• Filed: 03/14/2003
• Published: 12/11/2003
• Est. Priority Date: 03/18/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Maduskuie, Thomas P.
• Granted Patent: US 7,101,883 B2
• Time in Patent Office: Days
• US Class Current: 514/224.2
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 239/545 with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/69 Benzenesulfonamido-pyrimidines
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present application describes novel uracil derivatives of formula I:

A-W-U-X-Y-Z-U^a-X^a-Y^a-Z^a  I

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, W, U, X, Y, Z, U^a, X^a, Y^a, and Z^a are defined in the present specification, which are useful as inhibitors of TNF-α converting enzyme (TACE), matrix metalloproteinases (MMP), aggrecanase or a combination thereof.

Claims

1. A compound of formula I:

A-W-U-X-Y-Z-U^a-X^a-Y^a-Z^a 

 

I

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;

A is selected from the group;

W is (CHR^a) m;

U is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), OC(O)O, OC(O)NR^a1, NR^a1C(O)O, NR^a1C(O)NR^a1, OS(O)₂, S(O)₂O, S(O)_p, S(O)_pNR^a1, NR^a1S (O)_p, and NR^a1SO₂NR^a1;

X is absent or is selected from C_1-3 alkylene, C_2-3 alkenylene, and C_2-3 alkynylene;

Y is absent or is selected from O, NR^a1, S(O)_p and C(O);

Z is selected from;

a C_3-13 carbocycle substituted with 0-5 R^b; and

a 5-14 membered heterocycle comprising 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;

provided that Z is other than 2-oxo-1,4-pyridinylene;

U^a is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), OC(O)O, OC(O)NR^a1, NR^a1C(O)O, NR^a1C(O)NR^a1, S(O)_p, S(O)_pNR^a1, NR^a1S(O)_p, and NR^a1SO₂NR^a1;

X^a is absent or is selected from C_1-10 alkylene, C_2-10 alkenylene, and C_2-10 alkynylene;

Y^a is absent or is selected from O, NR^a1, S(O)_p, and C(O);

Z^a is selected from H, a C_3-13 carbocycle substituted with 0-5 R^c, and a 5-14 membered heterocycle comprising 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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, C_2-6 alkynyl substituted with 0-1 R^b, (CR^aR^a1)_sOR^a1, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0-5 R^d, and (CR^aR^a1)_r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-5 R^d;

R², at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b;

R³, at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b;

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

R^a1, at each occurrence, is independently selected from H, C_1-6 alkyl substituted with 0-1 R^e, C_2-6 alkenyl substituted with 0-1 R^e, C_2-6 alkynyl substituted with 0-1 R^e, and —

(CH₂)_r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^a2, O, and S(O)_p and substituted with 0-3 R^e;

alternatively, R^a and R^a1, when attached to a nitrogen, are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle comprising carbon atoms and from 0-1 additional heteroatoms selected from N, NR^a2, O, and S(O)_p;

R^a2, at each occurrence, is independently selected from C_1-4 alkyl, phenyl, and benzyl;

R^a3, at each occurrence, is independently selected from H, 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, and —

(CH₂)_r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^a2, O, and S(O)_p, and substituted with 0-3 R^c1;

R^b, at each occurrence, is independently selected from C_1-6 alkyl substituted with 0-1 R^c1, OR^a, SR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, C(S)NR^aR^a1, NR^aC(O)NR^aR^a1, OC(O)NR^aR^a1, NR^aC(O)OR^a, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, NR^aS(O)₂NR^aR^a1, OS(O)₂NR^aR^a1, NR^aS(O)₂R^a3, S(O)_pR^a3, CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, CF₃, CF₂CF₃, OCF₃, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(═

NCN)NR^aR^a1, (CR^aR^a1)_rC(═

NR^a)NR^aR^a1, (CR^aR^a1)_rC(═

NOR^a)NR^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(S)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rC(S)NR^aR^a1, (CR^aR^a1)_rOC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)OR^a1, (CR^aR^a1)_rNR^aC(O)NR^aR^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3, (CR^aR^a1)_rNR^aSO₂NR^aR^a1;

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

(CR^aR^a1)_r-5-14 membered heterocycle comprising 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 spiro ring C that is a 3-11 membered carbocycle or heterocycle substituted with 0-2 R^c1 and comprising;

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;

R^c1, at each occurrence, is independently selected from H, 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, R^aNC(O)NR^aR^a1, OC(O)NR^aR^a1, R^aNC(O)OR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a2, NR^aS(O)₂NR^aR^a1, OS(O)₂NR^aR^a1, NR^aS(O)₂R^a2, S(O)_pR^a2, CF₃, OCF₃, CF₂CF₃, CH₂F, and CHF₂;

R^d, at each occurrence, is independently selected from C_1-6 alkyl substituted with 0-2 R^e, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a1, C(O)R^a1, C(O)OR^a, C(O)NR^aR^a1, C(S)NR^aR^a1, R^aNC(O)NR^aR^a1, OC(O)NR^aR^a1, R^aNC(O)OR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, NR^aS(O)₂NR^aR^a1, OS(O)₂NR^aR^a1, NR^aS(O)₂R^a3, S(O)_pR^a3, CF₃, and CF₂CF₃;

R^e, at each occurrence, is independently selected from H, C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a, C(O)R^a, C(O)OR^a, C(O)NR^aR^a, R^aNC(O)NR^aR^a, OC(O)NR^aR^a, R^aNC(O)OR^a, S(O)₂NR^aR^a, NR^aS(O)₂R^a2, NR^aS(O)₂NR^aR^a, OS(O)₂NR^aR^a, NR^aS(O)₂R^a2, S(O)_pR^a2, CF₃, OCF₃, CF₂CF₃, CH₂F, and CHF₂;

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

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

r, at each occurrence, is selected from 0, 1, 2, 3, and 4;

s, at each occurrence, is selected from 1, 2, 3, and 4; and

provided that

i) when Z is phenylene or naphthylene, then U^a-X^a-Y^a-Z^a forms a group other than H, C_1-6 alkyl, NH₂, NHCOCH₃, or naphthyl;

ii) when W-U-X-Y forms —

NHSO₂—

, Z is naphthylene, then Z^a is a group other than phenyl substituted with 0-5 R^c;

iii) when W-U-X-Y forms —

NHSO₂—

, Z is phenylene, U^a-X^a-Y^a forms a bond, then Z^a is a group other than phenyl substituted with 0-5 R^c;

iv) when W-U-X-Y forms —

NR^a1SO₂—

, Z is phenylene, then Z^a is a group other than phenyl substituted with one 5-6 membered carbocycle or heterocycle substituted with 0-2 R^c1;

v) when R¹ is (CR^aR^a1)_rNR^aR^a1 or (CR^aR^a1)_rC(O)NR^aR^a1, Z is phenylene or naphthylene, then U^a-X^a-Y^a forms a group other than a bond and Z^a is other than H; and

vi) when W-U-X-Y forms —

NHSO₂CH₂—

or —

NHCOCH₂—

, Z is naphthyl, then U^a-X^a-Y^a forms other than CH₂CH₂NR^1a.

2. A compound according to claim 1, wherein;

W is (CHR^a)_m;

U is absent or is selected from;

CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), OC(O)NR^a1, NR^a1C(O)O, NR^a1C(O)NR^a1, OS(O)₂, S(O)₂O, S(O)₂, S(O)_pNR^a1, NR^a1S(O)_p, and NR^a1SO₂NR^a1;

X is absent or is C_1-3 alkylene;

Y is absent;

U^a is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), OC(O)O, OC(O)NR^a1, NR^a1C (O)O, NR^a1C (O)NR^a1, S(O)_p, S(O)_pNR_a1, NR^a1S(O)_p, and NR^a1SO₂NR^a1;

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

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_3-13 carbocycle substituted with 0-5 R^c, and a 5-14 membered heterocycle comprising 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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, C_2-6 alkynyl substituted with 0-1 R^b, (CR^aR^a1)_sOR^a1, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0-3 R^d, and (CR^aR^a1)_r-5--10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-3 R^d;

R², at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

R³, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

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

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

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

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (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;

C2-6 alkynyl substituted with 0-1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0-2 R^c1; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

3. A compound according to claim 2, wherein;

W is absent or is CH₂;

U is selected from;

C(O)NH, NHC(O), OS(O)₂, S(O)₂O, S(O)₂, S(O)₂NH, and NHS(O)₂;

X is absent;

Y is absent;

Z is selected from;

phenylene substituted with 0-5 R^b;

naphthylene substituted with 0-5 R^b; and

a 5-14 membered heterocycle comprising 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 absent or is selected from;

O, NR^a1, and CR^a(OH);

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

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_5-10 carbocycle substituted with 0-5 R^c, and a 5-14 membered heterocycle comprising 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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b, (CH₂)_nOR^a1, and (CH₂)_rNR^aR^a1;

R², at each occurrence, is independently selected from H and C_1-4 alkyl;

R³, at each occurrence, is independently selected from H and C_1-4 alkyl;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H and C_1-6 alkyl;

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

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (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 RC¹;

C_2-6 alkynyl substituted with 0-1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0-2 R^c1; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

4. A compound according to claim 3, wherein;

W is absent or is CH₂;

U is selected from;

NHC(O), OS(O)₂, S(O)₂, and NHS(O)₂;

X is absent;

Y is absent;

Z is selected from;

phenylene substituted with 0-5 R^b; and

naphthylene substituted with 0-5 R^b;

U^a is absent or is O;

X^a is absent or is CH₂ or CH₂CH₂;

Y^a is absent or is O;

Z^a is a 5-10 membered 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, and pyrazolyl;

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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (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, (CH₂)_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; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

5. A compound according to claim 1, wherein the compound is of formula Ia:

6. A compound according to claim 5, wherein;

U^a is absent or is selected from;

O, NR^a1, and CR^a(OH)

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

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_3-13 carbocycle substituted with 0-5 R^c, and a 5-14 membered heterocycle comprising 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^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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, C_2-6 alkynyl substituted with 0-1 R^b, (CR^aR^a1)_sOR^a1, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0-3 R^d, and (CR^aR^a1)_r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-3 R^d;

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

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

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

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)C(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; and

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; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

7. A compound according to claim 6, wherein;

Z is selected from;

phenylene substituted with 0-5 R^b;

naphthylene substituted with 0-5 R^b; and

a 5-14 membered heterocycle comprising 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 absent or is selected from;

O, NR^a1, and CR^a(OH);

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

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_5-10 carbocycle substituted with 0-5 R^c, and a 5-14 membered heterocycle comprising 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;

R¹, at each occurrence, is independently selected from H, CF₃′

, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H and C_1-6 alkyl;

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

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (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; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

8. A compound according to claim 7, wherein;

Z is selected from;

phenylene substituted with 0-3 R^b; and

naphthylene substituted with 0-3 R^b;

U^a is absent or is O;

X^a is absent or is CH₂ or CH₂CH₂;

Y^a is absent or is O;

Z^a is a 5-10 membered 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, and pyrazolyl;

provided that 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;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0-1 R^b, C_2-6 alkenyl substituted with 0-1 R^b, and C_2-6 alkynyl substituted with 0-1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (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, (CH₂)_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; and

(CH₂)_r-5-6 membered heterocycle comprising 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.

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

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-6-[(2-methyl-4-quinolinyl)methoxy]-2-naphthalenesulfonamide;

N-(6-amino-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonate;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

N-(2,4-dioxohexahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

N-(2,4-dioxohexahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

N-[(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}thio)-2,4(1H,3H) -pyrimidinedione;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-phenoxybenzenesulfonamide;

or a pharmaceutically acceptable salt form thereof.

10. A pharmaceutical composition, comprising:

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

11. A method for treating an inflammatory disorder, comprising:

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

12. A method, comprising:

administering a compound of claim 1 or a pharmaceutically acceptable salt form thereof in an amount effective to treat an inflammatory disorder.

13. A method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising:

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

14. A method of treating a condition or disease according to claim 13, wherein the disease or condition is selected from acute infection, acute phase response, age related macular degeneration, alcoholic liver disease, allergy, allergic asthma, aneurism, anorexia, 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, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'"'"'s granulomatosis.

17. A method for treating inflammatory disorders, comprising:

administering, to a host in need of such treatment, a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-α

inhibitors, TNF-α

sequestration agents, and methotrexate.

18. A medical device for implanting into a mammalian body wherein the medical device has a coating material comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, effective for reducing inflammation or restinosis.