Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)

• US 6,906,053 B2
• Filed: 05/12/2004
• Issued: 06/14/2005
• Est. Priority Date: 05/25/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Sheppeck, James E., Duan, Jingwu, Xue, Chu-Biao, Wasserman, Zelda
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Patel, Sudhaker B.
• Application Number:
  US10/844,219
• Publication Number:
  US 20040209874A1
• Time in Patent Office: 398 Days
• Field of Search: 514/183, 514/311, 514/385, 514/396, 514/399, 514/409, 514/412, 514/422, 514/425, 548/300.1, 548/407, 548/317.1, 548/409, 546/112, 546/134, 546/16
• US Class Current: 514/183
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• 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: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/76 : with substituted hydrocarbon radicals attached to the third ring carbon atom
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : 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 409/14 : 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
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present application describes novel hydantoin derivatives of formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, and n 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):

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

R¹¹ is -W-U-X—

Y-Z-U^a-X^a—

Y^a-Z^a;

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

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, 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_3-8 cycloalkyl substituted with 0-5 R^c, a C_3-8 cycloalkenyl substituted with 0-5 R^b; and

phenyl substituted with 0-5 R^c;

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;

a C_3-8 cycloalkyl substituted with 0-5 R^c, a C_3-8 cycloalkenyl substituted with 0-5 R^b, phenyl substituted with 0-5 R^c, naphthyl substituted with 0-5 R^c, indanyl substituted with 0-5 R^c, and

a heterocycle substituted with 0-5 R^c and selected from the group;

benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, chromanyl, chromenyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, 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, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl;

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)_por S(O)_p—

S(O)_pgroup;

R¹ and R², together with the carbon atoms to which they are attached, combine to form a 6-membered heterocyclic ring consisting of carbon atoms, 1 ring heteroatoms selected from N, and NR¹⁰, 0-1 carbonyl groups, and 0-1 double bonds, and substituted with 0-3 R⁹;

R³ is selected from Q, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, C_2-6 alkynylene-Q, (CR^aR^a1)_rO(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)_rOC(O)O(CR^aR^a1)_s-Q, (CR^aR^a1)_rOC(O)NR^a(CR^aR^a1)_s-Q, (CR^aR^a1)_rNR^aC(O)O(CR^aR^a1)_s-Q, (CR^aR^a1)_rNR^aC(O)NR^a(CR^aR^a1)_s-Q, (CR^aR^a1)_rS(O)_p(CR^aR^a1)_s-Q, (CR^aR^a1)_rSO₂NR^a(CR^aR^a1)_s-Q, (CR^aR^a1)_rNR^aSO₂(CR^aR^a1)_s-Q, and (CR^aR^a1)_rNR^aSO₂NR^a(CR^aR^a1)_s-Q,

Q, at each occurrence, is selected from H, CHF₂, CH₂F, CF₃, a C_3-13 carbocycle substituted with 0-5 R^d, and

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^d;

R⁴ is 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,

R⁵ is 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;

n is 0 or 1;

alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom to which they are attached;

combine to form a 3-8 membered carbocyclic or heterocyclic ring consisting of carbon atoms, 0-2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_p, and 0-2 double bonds, and substituted with 0-3 R⁹;

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^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 consisting of carbon atoms and 0-2 ring heteroatoms selected from N, NR^a2, O, and S(O)_pand substituted with 0-3 R^c1;

alternatively, R^a and R^a1 when attached to a nitrogen, together with the nitrogen to which they are attached, combine to form a 5 or 6 membered heterocycle consisting of carbon atoms and 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 consisting of 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, 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, CH₂F, CHF₂, (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 consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_pand 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^c 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_1-4 alkyl, OR^a, Cl, F, Br, I, ═

O, CF₃, —

CN, NO₂, C(O)R^a, C(O)OR^a, C(O)NR^aR^a, and S(O)_pR^a;

R^d, at each occurrence, is independently selected from 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, C(S)NR^aR^a1, R^aNC(O)NR^aR^a1, OC(O)NR^aR^a1, R^aNC(O)O, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, NR^aS(O)₂NR^aR^a1, OS(O)₂NR^aR^a1, S(O)_pR^a3, CF₃, CF₂CF₃, C_3-10 carbocycle, and 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;

R^c, at each occurrence, is independently selected from H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, C_3-10 carbocycle substituted with 0-2 R^c1, and a 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;

R⁶ is H;

R⁷ is H;

R⁹, at each occurrence, is independently selected from 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(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-5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatorns selected from the group consisting of N, O, and S(O)_p, and substituted with 0-2 R^c1;

R¹⁰, at each occurrence, is independently selected from H, (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)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^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-5-10 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;

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 0, 1, 2, 3, and 4; and

,

t, at each occurrence, is selected from 1, 2, 3, and 4.

2. A compound according to claim 1, wherein;

W is (CR^aR^a1)_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), S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

X is absent or is C_1-3 alkylene;

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

U^a is absent or is selected from 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, and NR^a1S(O)_p;

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;

R³ is selected from Q, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, C_2-6 alkynylene-Q, (CR^aR^a1)_rO(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)_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(O)_p(CR^aR^a1)_s-Q (CR^aR^a1)_rSO₂NR^a(CR^aR^a1)_s-Q and (CR^aR^a1)_rNR^aSO₂(CR^aR^a1)_s-Q;

Q, at each occurrence, is selected from H, CHF₂, CH₂F, CF₃, a C_3-13 carbocycle substituted with 0-3 R^d, and 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 0-3 R^d,

R⁴ is 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;

R⁵ is 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, C_2-6 alkenyl, C_2-6 alkynyl, and —

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

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

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

O, —

CN, NO₂, CF₃, CH₂F, CHF₂, CF₂CF₃, (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;

(CH₂)_r—

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

(CH₂)_r-5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and 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;

R^d, at each occurrence, is independently selected from 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, C_3-6 carbocycle and 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

R⁹, at each occurrence, is independently selected from 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)_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

(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.

3. A compound according to claim 2, wherein;

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

X is absent or is methylene or ethylene;

Z is phenyl substituted with 0-4 R^b;

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

R³ is selected from 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, and (CH₂)_rNR^aSO₂(CH₂)_s-Q;

Q, at each occurrence, is selected from H, a C_3-8 carbocycle substituted with 0-3 R^d, and a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatorns selected from the group consisting of N, O, and S(O)_p, and substituted with 0-3 R^d;

R⁴ is selected from H and C_1-6 alkyl;

R⁵ is selected from H and C_1-6 alkyl;

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

(CH₂)_r-3-8 membered carbocyclic or heterocyclic ring consisting of 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^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, CF₃, CH₂F, CHF₂, (CR^aR^a1)_rNR^aR^a1, (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, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl;

C_3-6 cycloalkyl substituted with 0-1 R^c1;

phenyl substituted with 0-2 R^c1; and

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;

R^d, at each occurrence, is independently selected from 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 and phenyl;

R⁹, at each occurrence, is independently selected from H, (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)_rCO)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^c1;

(CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0-2 R^c1; and

(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;

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.

4. A compound according to claim 3, wherein;

Z^a is selected from;

phenyl substituted with 0-3 R^c;

naphthyl substituted with 0-3 R^c; and

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, benzthi azolyl, 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;

Q, at each occurrence, is selected from H,

a C₃₆ cycloalkyl substituted with 0-2 R^d;

phenyl substituted with 0-3 R^d; and

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 0-3 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_1-6 alkyl, phenyl, and benzyl;

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

O, CF₃, CH₂F, CHF₂, (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; and

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^c 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

,

R⁹, at each occurrence, is independently selected from H, (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;

(CR^aR^a1)_r—

C_3-7 carbocycle substituted with 0-2 R^c1; and

(CR^aR^a1)_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.

5. A compound according to claim 4, wherein;

X is absent or is methylene;

Y is absent or is O;

U^a is absent or is O;

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 O;

Z^a is selected from;

phenyl substituted with 0-3 R^c;

naphthyl substituted with 0-3 R^c; and

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;

R³ is selected from H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, phenyl, and benzyl;

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

R^a1, at each occurrence, is independently selected from H, and C_1-4 alkyl;

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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, CF₃, CH₂F, CHF₂, NR^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, and 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 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^e, at each occurrence, is independently selected from H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, C_3-6 carbocycle substituted with 0-2 R^c1, and 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;

R⁹, at each occurrence, is independently selected from H, (CH₂)_rC(O)(CH₂)_sR^e, (CH₂)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a, (CH₂)_rS(O)_pR^a3, (CH₂)_rSO₂NR^aR^a;

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_3-6 carbocycle substituted with 0-2 R^c1; and

(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; and

R¹⁰, at each occurrence, is independently selected from H, (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_1-6 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;

(CH₂)_r—

C_3-10 carbocycle substituted with 0-2 R^c1; and

(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.

6. A compound according to claim 5, wherein the compound is selected from:

R¹¹ is -W-U-X—

Y-Z-U^a-X^a—

Y^a-Z^a;

W is (CH₂)_m;

Y is absent;

R¹⁰, at each occurrence, is independently selected from H, (CH₂)_rC(O)(CH₂)_sR^e, (CH₂)_rC(O)OR^a1, (CR^aR^a1)_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;

(CH₂)_r—

C_3-6 cycloalkyl substituted with 0-2 R^c1;

(CH₂)_r-phenyl substituted with 0-2 R^c1; and

(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;

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

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

,

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

7. A compound according to claim 6, wherein the compound is selected from:

Z is phenyl substituted with 0-1 R^b;

Z^a is selected from;

phenyl substituted with 0-3 R^c;

naphthyl substituted with 0-3 R^c; and

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, at each occurrence, is independently selected from 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, and CF₃;

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

O, 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, and (CR^aR^a1)_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

,

R^e, at each occurrence, is independently selected from H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, phenyl substituted with 0-1 R^c1, and 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.

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

(cis,trans)-tert-butyl 6-({4-[2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate;

(cis,trans)-N-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-6-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

(cis,trans)-N-[8-acetyl-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-6-yl)]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide; and

(cis,trans)-tert-butyl 10-[2-{(4-[2-methyl-4-quinolinyl)methoxy]phenyl}amino)-2-oxoethyl]-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate;

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 inflammatory disorder, 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 a disease or condition in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, wherein the disease or condition is selected from acute infection, acute phase response, allergic asthma, anorexia, asthma, autoimmune disease, cachexia, cardiovascular effects, coagulation, fever, gingivitis, graft versus host disease, hemorrhage, multiple sclerosis, neovascular glaucoma, osteoarthritis, periodontitis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, shock, and solid tumor growth and tumor invasion by secondary metastases.

12. 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 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.

13. 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.

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

administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt form thereof.

15. A method of treating a disease or condition in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof, wherein the disease or condition is selected from acute infection, acute phase response, allergic asthma, anorexia, asthma, autoimmune disease, cachexia, cardiovascular effects, coagulation, fever, gingivitis, graft versus host disease, hemorrhage, multiple sclerosis, neovascular glaucoma, osteoarthritis, periodontitis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, shock, and solid tumor growth and tumor invasion by secondary metastases.

16. 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 6 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.

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 method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt form thereof.

19. A method of treating a disease or condition in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof, wherein the disease or condition is selected from acute infection, acute phase response, allergic asthma, anorexia, asthma, autoimmune disease, cachexia, cardiovascular effects, coagulation, fever, gingivitis, graft versus host disease, hemorrhage, multiple sclerosis, neovascular glaucoma, osteoarthritis, periodontitis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, shock, and solid tumor growth and tumor invasion by secondary metastases.

20. 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 7 in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p138 MAP kinase inhibitors, TNF-α

inhibitors, TNF-α

sequestration agents, and methotrexate.

21. 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.

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

administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt form thereof.

23. A method of treating a disease or condition in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof, wherein the disease or condition is selected from acute infection, acute phase response, allergic asthma, anorexia, asthma, autoimmune disease, cachexia, cardiovascular effects, coagulation, fever, gingivitis, graft versus host disease, hemorrhage, multiple sclerosis, neovascular glaucoma, osteoarthritis, periodontitis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, shock, and solid tumor growth and tumor invasion by secondary metastases.

24. 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 8 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.