CYCLIC SULFONE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-aCONVERTING ENZYME (TACE) FIELD OF THE INVENTION This invention relates generally to novel cyclic sulfone derivatives as inhibitors of matrix metalloproteinases (MMP), TNF-a converting enzyme (TACE), aggrecanase or a combination thereof, pharmaceutical compositions containing the same, and methods of using the same.

BACKGROUND OF THE INVENTION There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis; corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease; and, bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloprotease), which form inactive complexes with the MP's.

Osteo-and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled

sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al.

J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA.

Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum.

1978, 21, 761-766, Woessner et al. Arthritis Rheum. 1983, 26, 63-68 and Woessner et al. Arthritis Rheum. 1984, 27, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al.

Arthritis Rheum. 1993, 36, 1214-22).

Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990,25, 175-184, AP, San Diego).

Tumor necrosis factor-a (TNF-a) is a cell-associated cytokine that is processed from a 26kd precursor form to a 17kd active form. TNF-a has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-a has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-a with specific antibodies can

be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet 1994,344, 1105), non-insulin dependent diabetes melitus (Lohmander, L. S. et al. Arthritis Rheum.

1993, 36, 1214-22), and Crohn's disease (MacDonald et al.

Clin. Exp. Immunol. 1990, 81, 301).

Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-a converting enzyme (TACE), the enzyme responsible for TNF-a release from cells, were purified and sequenced (Black et al Nature 1997, 385, 729; Moss et al Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, and non-insulin dependent diabetes melitus.

Since excessive TNF-a production has been noted in several disease conditions also characterized by MMP- mediated tissue degradation, compounds which inhibit both MMPs and TNF-a production may also have a particular advantage in diseases where both mechanisms are involved.

Prostaglandins (PG) play a major role in the inflammation process and the inhibition of PG production has been a common target of anti-inflammatory drug

discovery. Many NSAIDS have been found to prevent the production of PG by inhibiting the enzyme cyclooxygenase (COX). Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2 is an inducible isozyme associated with inflammation. Selective COX-2 inhibitor was believed to maintain the efficacy of traditional NSAIDs, which inhibit both isozymes, and produce fewer and less drastic side effects. As a result, development of selective COX-2 inhibitors has attracted major interest in the pharmaceutical industry. Because of the significant roles of PGs and TNF-a in inflammation, combined use of COX-2 and TACE inhibitors may have superior efficacy to either therapy alone in some inflammatory diseases.

WO00/40576 depicts inhibitors of MMP and TNF-a of the formula: wherein RI can be optionally substituted aryl or heterocyclic group; X is O or a single bond; Ar is optionally substituted aryl or heterocyclic group; R2 is carboxy, protected carboxy or amidated barboxy; Y can be sulfonyl; A is lower alkylene; Z is methylene, thia, sulfinyl or sulfonyl; and, m and n are each an interger of 0 to 6, and 1 < m+n < 6. These compounds are not considered to be part of the present invention.

WO01/60808 discloses inhibitors of MMP and TNF-a of the formula:

wherein R1 can be optionally substituted aryl, aryloxy, or heterocyclic group; Ar is aryl or heterocyclic group; R2 is amidated barboxy; X can be sulfonyl; Y and Z are each lower alkylene; Z is methylene, thia, sulfinyl or sulfonyl ; R3 is hydrogen or acyl ; and, m and n are each an interger of 0 to 2. These compounds are not considered to be part of the present invention.

The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti- inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and/or other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.

SUMMARY OF THE INVENTION Accordingly, the present invention provides novel cyclic sulfone derivatives useful as MMP, TACE, and/or aggrecanase inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides 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 of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.

The present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, 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-a inhibitors, TNF-a sequestration agents, and methotrexate.

The present invention provides novel compounds of the present invention for use in therapy.

The present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors'discovery that compounds of formula I:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, X, Ua, Xa, ya, Za, RI, R, Rb, and q are defined below, are effective MMP, TACE, and/or aggrecanase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [1] Thus, in an embodiment, the present invention provides a novel compound of formula I: or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein; A is selected from :-CoR5,-CO2H,-CO2R6,-C (O) NHOH, - C (O) NHOR5,-C (O) NHOR6,-NHRa,-N (OH) COR5,-N (OH) CHO, -SH, -CH2SH, -S(O) (=NH) Ra,-S (=NH) 2Ra,-SC (O) Ra, -PO (OH) 2, and-PO (OH) NHRa ; ring B, including the shown carbon and sulfonyl groups, is a 4-8 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-2 heteroatoms selected from O, N, NRLO, and S (O) p, provided that ring B contains other than a S-S, O-O, or S-0 bond;

ring B consists of 0-1 double bonds and is substituted with 0-2 Rb ; X is absent or is CR3R4 ; Ua is absent or is selected from: 0, NRa1, C (0), C (0) 0, OC (0), C (0) NRal, NRa1C (O), OC (0) O, OC (O) NRal, NRalC (0) O, NRalC (O) NRal, S (O) p, S (O) pNRal, NRa1S (O) p, and NRaISO2NRal ; Xa is absent or is selected from: C1_4 alkylene, C2_4 alkenylene, and C2_4 alkynylene; ya is absent or is selected from : 0, NRa1, S (O) p, and C (O); provided that Ua-Xa-ya form other than a bond or 0 ; Za is a C3-13 carbocycle substituted with 0-5 Rc or a 5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-5 Ré ; provided that Ua, Ya, and Za do not combine to form a N-N, N-0, O-N, 0-0, S (O) p-0, O-S (O) p or S (O) p-S (O) p group; RI is selected from: H, C1-6 alkyl substituted with 0-1 Rb, C2-6 alkenyl substituted with 0-1 Rb, and 3-6 alkynyl substituted with 0-1 Rb ; R2 is selected from: Q, -C1-6 alkylene-Q, C2-6 alkenylene-Q, -C2-6 alkynylene-Q,

-(CRaRal) rl° (cRaRal) r-Qt -(CRaRa1)r1NRa(CRaRa1)r-Q, -(CRaRa1)r1C(O)(CRaRa1)r-Q, -(CRaRa1)r1C(O)O(CRaRa1)r-Q, -(CRaRa1)r1OC(O)(CRaRa1)r-Q, -(CRaRa1)r1C(O0NRaRa1, -(CRaRa1)r1C(O)NRa(CRaRa1)r-Q, -(CRaRa1r1NRaC(O)(CRaRa1)r-Q, -(CRaRa1)r1OC(O)O(CRaRa1)r-Q, - (CRaRal) rlOC (0) NRa (CRaRal) r-Q, -(CRaRa1)r1NRaC(O)O(CRaRa1)r-Q, -(CRaRa1)r1NRaC(O)NRa(CRaRa1)-r-Q, -(CRaRa1)r1S(O)p(CRaRa1)r-Q, - (CRaRal) rlS02NRa (CRaRal) r-Q.

-(CRaRa1)r1NRaSO2(CRaRa1)r-Q, and -(CRaRa1)r1NRaSO2NRa(CRaRa1) r-Q ; Q, at each occurrence, is independently selected from: H, a C3-13 carbocycle substituted with 0-5 Rd, and a 5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-5 Rd ; alternatively, R1 and R2, together with the carbon atom to which they are attached, combine to form a 3-10 membered heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from 0, N, NR10, and S (O) p, and substituted with 0-3 Ré ; R3 is H or C1_4 alkyl ; R4 is H or C1_4 alkyl ;

alternatively, R3 and R4 combine to form a 3-6 membered carbocyclic ring; R5, at each occurrence, is independently selected from: C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re; R6, at each occurrence, is independently selected from: phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-io alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1_6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-5 alkyl)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, [5-(Ra)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyl, -C1-10 alkyl-NR7R7a, -CH(R8) OC (=O) R9, and - CH (R8) OC (=O) OR9; R7 is selected from: H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ; R7a is selected from: H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ; R8 is selected from: H and C1_4 alkyl ;

R9 is selected from: H, C1_8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb; RIO, at each occurrence, is independently selected from: H, C1-6 alkyl substituted with 0-2 Rc1, C2-6 alkenyl substituted with 0-2 RC1, C2-6 alkynyl substituted with 0-2 Rc1, -(CRaRa1)sNRaRa1, -(CRaRa1)r1C(O)NRaOH, - (CRaRal) r1C (0) Rai,- (CRaRal) riC (0) ORal, - (CRaRal) riC (S)ORa1, -(CRaRa1)r1C(O)NRaRa1, - (CRaRal) sNRaC (0) Ral,- (CRaRal) rlC (S) NRaRal, - (CRaRal) SOC (0) NRaRa1, - (CRaRal) SNRaC (0) ORal, -(CRaRa1)sNRaC(O)NRaRa1, -(CRaRa1)r1S(O)pRa3, - (CRaRal) r1S02NRaRal,- (CRaRal) SNRaS02Ra3, -(CRaRa1)sNRaSO2NRaRa1, -(CRaRa1)r1-C3-10 carbocycle substituted with 0-2 Rd, and -(CRaRa1)r1-5-14 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 0-2 Rc1; Ra, at each occurrence, is independently selected from: H, C1-6 alkyl, phenyl, and benzyl; Ral, at each occurrence, is independently selected from: H, C1-6 alkyl substituted with 0-1 Rg, C2_6 alkenyl substituted with 0-1 Rg, C2-6 alkynyl substituted with 0-1 Rg, and- (CH2) r-3-8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from N, NR2a, O, and S (O) p and substituted with 0-3 Rg ;

alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle consisting of carbon atoms and 0-1 additional heteroatoms selected from N, NRa2, 0, and S (O) p; Ra2, at each occurrence, is independently selected from: C1_4 alkyl, phenyl, and benzyl; Ra3, at each occurrence, is independently selected from: H, C1_6 alkyl substituted with 0-1 RC1, C2-6 alkenyl substituted with 0-1 RC1, C2-6 alkynyl substituted with 0-1 Rc, and- (CH2) r-3-8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from N, NR2a, 0, and S (O) p, and substituted with 0-3 Rcl ; Rb, at each occurrence, is independently selected from: C1_6 alkyl substituted with 0-1 Rcl,-ORa, Cl, F, Br, I, =O, -CN, NO2, -NRaRa1, -C (O) Ra,-C (O) ORa, -C(O)NRaRa1, -C (S) NRaRal,-NRaC (O) NRaRal-OC (O) NRaRa -NRaC(O)ORa, -S(O)2NRaRa1, -NRaS(O)2Ra3, -NRaS(O)2NRaRa1, -OS(O)2NRaRa1, -NRaS(O)2Ra3, -S(O)pRa3 CF3,-CF2CF3,-CHF2,-CH2F, and phenyl; RC, at each occurrence, is independently selected from: H, C1_6 alkyl substituted with 0-2 RC1, C2-6 alkenyl substituted with 0-2 Rc3-, C2_6 alkynyl substituted with 0-2 Rc1, -ORa, Cl, F, Br, I, =O, -CN, N02, CF3,-OCF3, -CF2CF3, -CH2F, -CHF2, -(CRaRa1)r1NRaRa1, -(CRaRa1)r1C(=NCN)NRaRa1, -(CRaRa1)r1C (=NRa) NRaRa1,

- (CRaRal) rlC (=NORa) NRaRa1, - (CRaRal) riC (0) NRaOH, - (CRaRa1)r1C(O)Ra1, -(CRaRa1)r1C(O)ORa1, - (CRaRal) rlC (S) ORal,- (CRaRal) rlC (O) NRaRal, - (CRaRa1)r1NRaC(O)Ra1, -(CRaRa1)r1C(S)NRaRa1, - (CRaRal) r1OC (O)NRaRa1, -(CRaRa1)r1NRaC(O)ORa1, - (CRaRal) r1NRaC(O)NRaRa1, -(CRaRa1)r1S(O)pRa3, - (CRaRal) rlS02NRaRal,- (CRaRal) rlNRaS02Ra3, - (CRaRa1) rlNRaSO2NRaRal,- (CRaRa1) rl-C3-10 carbocycle substituted with 0-2 Rd, and- (CRaRa1) rl-5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-2 Rcl ; alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-11 membered carbocycle substituted with 0-2 RC1 or a 3-13 membered heterocycle consisting of: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 1-5 ring heteroatoms selected from O, N, and S (O) p, and substituted with 0-2 RC1, provided that ring C contains other than a S-S, O-O, or S-0 bond ; alternatively, when two Rc 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 consisting of: carbon atoms, 0-2 heteroatoms selected from the group consisting of N, 0, and S (O) p, and 0-3 double bonds, and substituted with 0-2 Rc1;

Rc1, at each occurrence, is independently selected from: H, C1-6 alkyl,-ORa, Cl, F, Br, I, =O, -CN, NO2, -NRaRa1, -C(O)Ra, -C(O) ORa, -C (O) NRaRal,-NRaC (O) NRaRal, -OC(O)NRaRa1, -NRaC(O)ORa1, -S(O)2NRaRa1, -NRaS(O)2Ra2, -NRaS(O)2NRaRa1, -OS (0) 2NRaRal,-NRaS (0) 2Ra2,-S (O) pRa2, CF3,-OCF3,-CF2CF3,-CH2F, and-CHF2; RD, at each occurrence, is independently selected from: C1-6 alkyl,-ORa, Cl, F, Br, I, =O, -CN, NO2, -NRaRa1, -C(O)Ra, -C(O)ORa, -C(O)NRaRa1, -C (S) NRaRal, -NRaC(O)NRARa1, -OC(O)NRaRa1, -NRaC(O)ORa1, -S(O)2NRaRa1, -NRaS(O)2Ra3, -NRaS(O)2NRaRa1, -OS (0) 2NRaRal,-NRaS (0) 2Ra3,-S (O) pria3, CF3, -CF2CF3, C3-10 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 (0) p ; Re, at each occurrence, is independently selected from: phenyl substituted with 0-2 Rb, and biphenyl substituted with 0-2 Rb ; Rf, at each occurrence, is independently selected from: C1_4 alkyl, C3_g cycloalkyl, Cul-5 alkoxy, and phenyl substituted with 0-2 Rb ; Rg, at each occurrence, is independently selected from: H, C1_6 alkyl,-ORa, Cl, F, Br, I, =O, -CN, NO2, -NRaRa, -C(O)Ra, -C(O)ORa, -C(O)NRaRa, -NRaC(O)NRaRa, - OC (0) NRaRa,-NRaC (0) ORa,-S (0) 2NRaRa,-NRaS (0) 2Ra2, -NRaS(O)2NRaRa, -OS (0) 2NRaRa, -NRaS (0) 2Ra2,-S (O) pRa2, CF3, -OCF3, -CF2CF3, -CH2F, and-CHF2 ;

p, at each occurrence, is selected from 0,1, and 2; q is selected from 0,1, and 2; r, at each occurrence, is selected from 0,1, 2,3, and 4; rl, at each occurrence, is selected from 0,1, 2,3, and 4; and, s, at each occurrence, is selected from 1,2, 3, and 4.

[2] In a preferred embodiment, the present invention provides a novel compound, wherein; A is selected from: COR5,-C02H,-C (O) NHOH, -C (O) NHOR5, - C (0) NHOR6, -N (OH) COR5,-N (OH) CHO,-SH, and-CH2SH ; ring B, including the shown carbon and sulfonyl groups, is a 5-7 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-2 heteroatoms selected from 0, N, NR10, and S (O) p, provided that ring B contains other than a S-S, 0-0, or S-0 bond; ring B consists of 0-1 double bonds and is substituted with 0-2 Rb ; Ua is absent or is selected from: 0, NRa1, C (O), C (O) 0, C (O) NRa1, NRaIC (O), S (O) p, and S (O) pNRa1; Xa is absent or is selected from: C1_2 alkylene, C2 alkenylene, and C2 alkynylene;

ya is absent or is selected from: 0 and NRa1 ; provided that Ua-Xa-Ya form a linker with 2 atoms in length; Za is a C3-10 carbocycle substituted with 0-5 Rc or 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 0-5 RC ; provided that Ua, Ya, and Za do not combine to form a N-N, N-0, O-N, 0-0, S (O) p-0, O-S (O) p or S (O) p-S (O) p group; R1 is selected from: H and C1-6 alkyl ; R2 is selected from: Q, -C1-6 alkylene-Q, -C1-6 alkenylene-Q, -(CRaRa1)r1O(CRaRa1)r-Q, -(CRaRa1)r1NRa(CRaRa1)r-Q, -(CRaRa1)r1C(O)(CRaRa1)r-Q, -(CRaRa1)r1C(O)O(CRaRa1)r-Q, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1) rlc (o) NRa (cRaRal) r-Q, -(CRaRa1)r1S(O) p (CRaRa1)r-Q, and -(CRaRa1)r1SO2NRa(CRaRa1)r-Q; Q, at each occurrence, is independently selected from: H, a C3-6 carbocycle substituted with 0-5 Rd, and a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p and substituted with 0-5 Rd ; alternatively, R1 and R2, together with the carbon atom to which they are attached combine to form a 3-10

membered heterocyclic ring consisting of carbon atoms and 0-1 ring heteroatoms selected from 0, N, NRIO, and S (O) p, and substituted with 0-1 RC ; R5, at each occurrence, is independently selected from: C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re; R6, at each occurrence, is independently selected from: phenyl, naphthyl, C1_6 alkyl-phenyl-C1_6 alkyl-, C3_g cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2_6 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1_6 alkoxy-C1_6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-4 alkyl)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, [5- (Ra)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyl, -C1-6 alkyl-NR7R7a, -CH (R8) OC (=O) R9, and -CH(R8) OC (=O) OR9 ; R7 is selected from: H, C1-6 alkyl, 3-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ; R7a is selected from: H, Cl-6 alkyl, 2-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ;

R8 is selected from: H and C1_4 linear alkyl ; R9 is selected from: H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb ; RIO, at each occurrence, is independently selected from: H, C1-6 alkyl substituted with 0-1 Rcl, 2-6 alkenyl substituted with 0-1 Rc1, 2-6 alkynyl substituted with 0-1 Rc1, -(CRaRa1)sNRaRa1, -(CRaRa1)r1C(O)Ra1, - (CRaRa1) r1C(O)ORa1, -(CRaRa1)r1C(O)NRaRa1, - (CRaRal) rl (O)pRa3, -(CRaRa1)r1SO2NRaRa1, -(CRaRa1) rl-C3-6 carbocycle substituted with 0-1 Rc1, and-(CRaRa1) rl-5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-1 Rcl ; Ra, at each occurrence, is independently selected from: H and C1_4 alkyl ; Ra, at each occurrence, is independently selected from: H, C1_4 alkyl, phenyl, and benzyl; alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle consisting of carbon atoms and 0-1 additional heteroatoms selected from N, NRa2, O, and S (O) p ;

Rb, at each occurrence, is independently selected from: CI-6 alkyl,-ORa, Cl, F, Br, =0,-CN,-NRaRal,-C (O) Ra, -C(O)ORa, -C(O)NRaRa1, -S(O)2NRaRa1, -S(O)pRa3, and Ces ; Rc, at each occurrence, is independently selected from: C1-6 alkyl substituted with 0-1 RC1, C2_6 alkenyl substituted with 0-1 RC1, C2-6 alkynyl substituted with 0-1 RCl,-ORa, Cl, F, Br, =0,-CN,-NRaRal, CF3, - (CRaRa1) riC (O)Ra1, -(CRaRa1)r1C(O)ORa1, -(CRaRa1)r1C(O)NRaRa1, -(CRa1Ra1)r1S(O)pRa3, - (CRaRa1) rlSO2NRaRal, C3-6 carbocycle, and a 5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p; alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-8 membered carbocycle substituted with 0-2 RC1 or a 3-8 membered heterocycle consisting of: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 1-5 ring heteroatoms selected from 0, N, and S (O) p, and substituted with 0-2 RC1, provided that ring C contains other than a S-S, O-O, or S-O bond; alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered saturated, partially saturated and unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S (0) p, and 0-3 double bonds, and substituted with 0-2 pel ;

Rd, at each occurrence, is independently selected from: C1-6 alkyl,-ORa, Cl, F, Br, =0,-CN,-NRaRal,-C (O) Ra, -C(O)ORa, -C(O)NRaRa1, -S(O)2NRaRa1, -S(O)pRa3, CF3, C3-6 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; Rf, at each occurrence, is independently selected from: C1_4 alkyl, C3-6 cycloalkyl, Cul-5 alkoxy, and phenyl substituted with 0-2 Rb ; p, at each occurrence, is selected from 0,1, and 2; q is 0 or 1; r, at each occurrence, is selected from 0,1, 2,3, and 4; rl, at each occurrence, is selected from 0,1, 2,3, and 4; and, s, at each occurrence, is selected from 1,2, 3, and 4.

[3] In a more preferred embodiment, the present invention provides a novel compound, wherein; A is-C (0) NHOH; ring B, including the shown carbon and sulfonyl groups, is a 5-6 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-1 heteroatoms selected from 0, N, NR10, and S (O) p,

provided that ring B contains other than a S-S, O-O, or S-0 bond; ring B consists of 0-1 double bonds and is substituted with 0-2 Rb; X is absent or is CR3R4; Ua is absent or is selected from : 0, NRa1, C (O), C (O) NRa1, S (O) p, and S (O) pNRa1; Xa is absent or is selected from: C1-2 alkylene, C2 alkenylene, and C2 alkynylene; ya is absent or is selected from: 0 and NRa1; provided that Ua-Xa-ya form a linker with 2 atoms in length; Za is a 5-6 carbocycle substituted with 0-3 Rc or a 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O) p, and substituted with 0-3 RC ; alternatively, Za is substituted with 0-4 Rc and is selected from the group:

W is S, SO, SO2, 0, or NR11, provided that Ua, Ya, and Za do not combine to form a N-N, N-0, O-N, 0-0, S (O) p-0, O-S (O) p or S (O) p-S (O) p group; RI is selected from: H and Cul-4 alkyl ; R2 is selected from: Q,-C1_6 alkylene-Q, -(CHaRa1)r1C(O)(CRaRa1)r-Q, -(CRaRa1)r1C(O)O(CRaRa1)r-Q, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)r1C(O)NRa(CRaRa1)r-Q, and -(CRaRa1)r1S(O)p(CRaRa1) r-Q ; Q, at each occurrence, is independently selected from: H, a C3-6 carbocycle substituted with 0-3 Rd, and a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p and substituted with 0-3 Rd ; R10 at each occurrence, is independently selected from: H, C1-6 alkyl, 2-6 alkenyl, C2_6 alkynyl, - (CRaRal) sNRaRa1, -(CRaRa1)r1C(O)Ra1, - (CRaRal) riC (O)ORa1, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)r1S(O)pRa3, -(CRaRa1)r1SO2NRaRa1, phenyl, and benzyl; R11, at each occurrence, is independently selected from: H, C1_4 alkyl, phenyl, and benzyl; Ra, at each occurrence, is independently selected from: H and C1_4 alkyl ;

Ra, at each occurrence, is independently selected from: H, C1-4 alkyl, phenyl, and benzyl; Rb, at each occurrence, is independently selected from: C1-4 alkyl,-ORa, Cl, F, =O,-NRaRal,-C (O) Ra, -C(O) ORa, -C (O) NRaRa1,-S (O) 2NRaRa1,-S (o) pRa3, and CF3 ; Rc, at each occurrence, is independently selected from: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,-ORa, Cl, F, Br, =O,-NRaRa1, CF3, -(CRaRa1)r1C(O)Ra1, - (CRaRa1) r1C (0) ORa,- (CRaRal) rlC (0) NRaRal, -(CRaRa1)r1S(O)pRa3, -(CRaRa1)r1SO2NRaRa1, and phenyl ; alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-8 membered carbocycle substituted with 0-1 Razor a 3-8 membered heterocycle consisting of: carbon atoms, 0-2 carbonyl groups, 0-4 double bonds, and from 1-4 ring heteroatoms selected from O, N, and S (O) p, and substituted with 0-1 RC1, provided that ring C contains other than a S-S, 0-0, or S-0 bond; alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered saturated, partially saturated and unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S (O) p, and 0-3 double bonds, and substituted with 0-2 Rcl ; and, Rd, at each occurrence, is independently selected from: C1-6 alkyl,-ORa, Cl, F, Br, =O, -NRaRa1, -C(O)Ra,

-C(O)NRaRa1, -S(O)2NRaRa1, -S(O)pRa3, CF3, and phenyl.

[4] In an even more preferred embodiment, the present invention provides a novel compound, wherein; X is absent or is CH2 ; Ua is absent or is 0 ; Xa, is absent or is CH2 or CH2CH2 ; Ya is absent or is 0 ; provided that Ua-Xa-ya form a linker with 2 atoms in length; Za is selected from phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 RC ; provided that Ua, Ya, and Za do not combine to form a N-N, N-0, O-N, or 0-0 group; R1 is selected from: H, CH3, and CH2CH3 ; R2 is selected from: Q, -C1-6 alkylene-Q, -C (O) (CRaRa1) r-Qt -C(O)O(CRaRa1)r-Q, -C(O) NRa (CRaRal) r-Q, and - S p(CRaRa1)r-Q; Q, at each occurrence, is independently. selected from: H, cyclopropyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with

0-1 Rd, phenyl substituted with 0-2 Rd, and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl; Ra, at each occurrence, is independently selected from: H, CH3, and CH2CH3 ; Rai, at each occurrence, is independently selected from: H, CH3, and CH2CH3 ; Ra2, at each occurrence, is independently selected from: H, CH3, and CH2CH3 ; Rc, at each occurrence, is independently selected from: C1-6 alkyl, C2-6 alkenyl, 2-6 alkynyl,-ORa, Cl, F, Br, =0,-NRaRal, CF3, -(CRaRa1)r1C(O)Ra1, - (CRaRa1)r1C(O)ORa, -(CRaRa1)r1C(O)NRaRa1, -(CRaRal) rlS (o) pRa3 and - (CRaRal) rlS02NRaRal ; Rd, at each occurrence, is independently selected from: C1-6 alkyl,-ORa, Cl, F, Br, =0,-NRaRal,-C (O) Ra, -C(O)NRaRa1, -S(O)2NRaRa1, -S(O)pRa3, CF3 and phenyl; p, at each occurrence, is selected from 0,1, and 2; r, at each occurrence, is selected from 0,1, 2, and 3; and, rl, at each occurrence, is selected from 0,1, 2, and 3.

[5] In another preferred embodiment, the present invention provides a novel compound selected from the group: N-hydroxy-2- (4-isopropyl-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetamide; <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-hydroxy-2-(2-{4-[(2-methyl-4-quinolinyl) methOxy] phenyl}- 1, 1-dioxido-2-thiomorpholinyl) acetamide; N-hydroxy-2- (4-methyl-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetamide; 2-(4-ethyl-2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-2-thiomorpholinyl)-N-hydroxyacetamide ; 2-(4-allyl-2-{4-[(2-methyl-4-quinolinyl) methoxy] phenyl}- 1, 1-dioxido-2-thiomorpholinyl)-N-hydroxyacetamide ; N-hydroxy-2-[2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-4-(2-propynyl)-2- thiomorpholinyl) acetamide; 2- (4- (2-butynyl)-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl)-N-hydroxyacetamide ; 2-(4-benzyl-2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-2-thiomorpholinyl)-N-hydroxyacetamide ;

N-hydroxy-2-[2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-4- (2-pyridinylmethyl)-2- thiomorpholinyl) acetamide; N-hydroxy-2-[2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-4- (3-pyridinylmethyl)-2- thiomorpholinyl) acetamide ; N-hydroxy-2-[2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-4- (4-pyridinylmethyl)-2- thiomorpholinyl) acetamide; 2-(4-acetyl-2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxido-2-thiomorpholinyl)-N-hydroxyacetamide ; N-hydroxy-2- (4-isobutyryl-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetamide; N-hydroxy-2- (4- (3-methylbutanoyl)-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetamide ; isopropyl 2-[2-(hydroxyamino)-2-oxoethyl]-2-{4-[(2-methyl- 4-quinolinyl) methoxy] phenyl}-4-thiomorpholinecarboxide 1,1-dioxide ; <BR> <BR> <BR> <BR> <BR> N-hydroxy-2-[2-{4-[(2-methyl-4-quinolinyl) methOxy] phenyl}-<BR> <BR> <BR> <BR> 4- (methylsulfonyl)-1, 1-dioxido-2- thiomorpholinyl] acetamide; N-hydroxy-2- (3- {4- [ (2-methyl-4-quinolinyl) methoxy] phenyl} - 4, 4-dioxido-1, 4-oxathian-3-yl) acetamide;

N-hydroxy-2-(2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1,1-dioxoidotetrahdyro-2H-thiopyran-2-yl)acetamide; and, N-hydroxy-2-(2-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl}- 1, 1-dioxidotetrahydro-2-thienyl) acetamide ; or a pharmaceutically acceptable salt form thereof.

In another preferred embodiment, the present invention provides a novel compound, wherein; A is selected from COR5,-C02H,-C (O) NHOH, -C (O) NHOR5, - C (0) NHOR6, -N (OH) COR5,-N (OH) CHO,-SH, and-CH2SH.

In another preferred embodiment, the present invention provides a novel compound, wherein; A is-C (O) NHOH.

In another preferred embodiment, the present invention provides a novel compound, wherein; ring B, including the shown carbon and sulfonyl groups, is a 5-7 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-2 heteroatoms selected from 0, N, NR10, and S (O) p, provided that ring B contains other than a S-S, O-O, or S-O bond; and, ring B consists of 0-1 double bonds and is substituted with 0-2 Rb.

In another preferred embodiment, the present invention provides a novel compound, wherein; ring B, including the shown carbon and sulfonyl groups, is a 5-6 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-1 heteroatoms selected from 0, N, NR10, and S (O) p, provided that ring B contains other than a S-S, 0-0, or S-O bond; and, ring B consists of 0-1 double bonds and is substituted with 0-2 Rb.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ua is absent or is selected from: O, NRa1, C (O), C (O) O, C (O) NRa1, NRa1C (O), S (O) p, and S(O)pNRa1; Xa is absent or is selected from: C1_2 alkylene, C2 alkenylene, and C2 alkynylene; Ya is absent or is selected from: O and NRa1 ; and, provided that Ua-Xa-Ya form a linker with 2 atoms in length.

In another preferred embodiment, the present invention provides a novel compound, wherein;

Ua is absent or is selected from : 0, NRa1, C (0), C (0) NRal, S (0) p, and S (0) pNRal; Xa is absent or is selected from C1-2 alkylene, C2 alkenylene, and C2 alkynylene; ya is absent or is selected from 0 and NRa1 ; and, provided that Ua-Xa-Ya form a linker with 2 atoms in length.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ua is absent or is 0 ; Xa is absent or is CH2 or CH2CH2 ; ya is absent or is 0 ; and, provided that Ua-Xa-ya form a linker with 2 atoms in length.

In another preferred embodiment, the present invention provides a novel compound, wherein; Za is a 3-10 carbocycle substituted with 0-5 Rc or a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-5 RC.

In another preferred embodiment, the present invention

provides a novel compound, wherein; za is a C5-6 carbocycle substituted with 0-3 Rc or a 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-3 RC.

In another preferred embodiment, the present invention provides a novel compound, wherein; Za is substituted with 0-4 Rc and is selected from the group: W is S, SO, SO2, 0, or NR11 ; and, R1l, at each occurrence, is independently selected from H, C1_4 alkyl, phenyl, and benzyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; Za is selected from phenyl substituted with 0-3 RC, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 RC.

In another preferred embodiment, the present invention provides a novel compound, wherein; R1 is selected from: H and C1_6 alkyl ; R2 is selected from: Q,-C1_6 alkylene-Q, -C1-6 alkenylene-Q, -(CRaRa1)r1O(CRaCRa1)r-Q, - (CRaRal) rl_NRa (CRaRal) r-Q,- (CRaRal) ri-C (0) (CRaRal) r-Q, -(CRaRa1)r1C(O)O(CRaRa1)r-Q, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)r1C(O) NRa (CRaRal) r-Q, -(CRaRa1)r1S(O) p (CRaRal) r-Q, and -(CRaRa1)r1SO2NRa(CRaRa1)r-Q; Q is selected from: H, a C3-6 carbocycle substituted with 0-5 Rd, and a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p and substituted with 0-5 Rd ; and, alternatively, R1 and R2 together with the carbon atom to which they are attached combine to form a 3-10 membered heterocyclic ring consisting of carbon atoms and 0-1 ring heteroatoms selected from 0, N, NRLO, and S (O) p, and substituted with 0-1 Rc.

In another preferred embodiment, the present invention provides a novel compound, wherein; R1 is selected from : H and C1-4 alkyl ; R2 is selected from : Q,-C1_6 alkylene-Q,

-(CRaRa1)r1C(O)(CRaRa1)r-Q, -(CRaRa1)r1C(O)O(CRaRa1)r-Q, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)r1C(O)NRa(CRaRa1)r-Q, and -(CRaRa1)r1S(O) p (CRaRal) r-Q ; and, Q is selected from: H, a C3-6 carbocycle substituted with 0-3 Rd, and a 5-10 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p and substituted with 0-3 Rd.

In another preferred embodiment, the present invention provides a novel compound, wherein; RI is selected from H, CH3, and CH2CH3 ; R2 is selected from Q,-C1_6 alkylene-Q, -C (0) (CRaRa1) r-Q, -C(O)O(CRaRa1)r-Q, -C(O)NRa(CRaRa1)r-Q, and -S (O) p (CRaRa1) r-Q ; and, Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; R2 is selected from Q,-C1_6 alkylene-Q, -C (O) (CRaRa1) r-Q, - C(O0O(CRaRa1)r-Q, -C(O)NRa(CRaRa1)r-Q, and -S (O) p (CRaRa1) r-Q ; and,

Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ra, at each occurrence, is independently selected from: H and C1_4 alkyl ; Rai, at each occurrence, is independently selected from: H, C1_4 alkyl, phenyl, and benzyl; and, alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle consisting of carbon atoms and 0-1 additional heteroatoms selected from N, NRa2, O, and S (O) p.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ra, at each occurrence, is independently selected from: H and CI-4 alkyl ; and, Rai, at each occurrence, is independently selected from: H, CI-4 alkyl, phenyl, and benzyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ra, at each occurrence, is independently selected from: H, CH3, and CH2CH3 ; and, Ra1 at each occurrence, is independently selected from: H, CH3, and CH2CH3.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ra2, at each occurrence, is independently selected from: C1_4 alkyl, phenyl, and benzyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; Ra2, at each occurrence, is independently selected from: H, CH3, and CH2CH3.

In another preferred embodiment, the present invention provides a novel compound, wherein; Rb, at each occurrence, is independently selected from: C1_6 alkyl,-ORa, Cl, F, Br, =0,-CN,-NRaRal,-C (O) Ra, - C (0) ORa,-C (0) NRaRal,-S (0) 2NRaRa1,-S (0) pRa3, and CF3.

In another preferred embodiment, the present invention provides a novel compound, wherein;

Rc, at each occurrence, is independently selected from: C-6 alkyl substituted with 0-1 Rcl, 2-6 alkenyl substituted with 0-1 Rcl, C2-6 alkynyl substituted with 0-1 RClZ-ORa, Cl, F, Br, =O,-CN,-NRaRal, CF3, - (CRaRal) riC (O) Ral,- (CRaRal) rlC (O) ORal, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)r1S(O)pRa3, -(CRaRa1)r1SO2NRaRa1, C3-6 carbocycle, and a 5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (0) p; alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-8 membered carbocycle substituted with 0-2 Rd or a 3-8 membered heterocycle consisting of: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 1-5 ring heteroatoms selected from O, N, and S (O) p, and substituted with 0-2 RC1, provided that ring C contains other than a S-S, 0-0, or S-0 bond; and, alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered saturated, partially saturated and unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, 0, and S (O) p, and 0-3 double bonds, and substituted with 0-2 Rcl.

In another preferred embodiment, the present invention provides a novel compound, wherein;

Rc, at each occurrence, is independently selected from: C1-6 alkyl, C2-6 alkenyl, 2-6 alkynyl,-ORa, Cl, F, Br, =0,-NRaRa1, CF3,- (CRaRal) rlC (0) Ral, -(CRaRa1)r1C(O)ORa, -(CRaRa1)r1C(O)NRaRa1, -(CRaRa1)R1S(O)pRa3, -(CRaRa1)r1SO2NRaRa1, and phenyl ; alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-8 membered carbocycle substituted with 0-1 Rcl or a 3-8 membered heterocycle consisting of: carbon atoms, 0-2 carbonyl groups, 0-4 double bonds, and from 1-4 ring heteroatoms selected from 0, N, and S (O) p, and substituted with 0-1 Rcl, provided that ring C contains other than a S-S, O-O, or S-O bond; and, alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered saturated, partially saturated and unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S (O) p, and 0-3 double bonds, and substituted with 0-2 RC1.

In another preferred embodiment, the present invention provides a novel compound, wherein; Rc, at each occurrence, is independently selected from: C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl,-ORa, Cl, F, Br, =O, -NRaRa1, CF3, -(CRaRa1)r1C(O)Ra1, - (CRaRal) r1C(O)ORa, -(CRaRa1)r1C(O0NRaRa1, -(CRaRa1)r1S(O)pRa3, and -(CRaRa1)r1SO2NRaRa1.

In another preferred embodiment, the present invention provides a novel compound, wherein; Rd, at each occurrence, is independently selected from: C1-6 alkyl,-ORa, Cl, F, Br, =0,-CN,-NRaRal,-C (0) Ra, -C (O) ORa,-C (O) NRaRal,-S (0) 2NRaRal,-S (O) pRa3, CF3, C3-6 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.

In another preferred embodiment, the present invention provides a novel compound, wherein ; Rd, at each occurrence, is independently selected from: C1-6 alkyl, ORa, Cl, F, Br, =0,-NRaRal,-C (O) Ra, -C (O) NRaRa1,-S (O) 2NRaRa1,-S (o) pRa3, CF3 and phenyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; R3 is H or C1 4 alkyl ; and, R4 is H or C1 4 alkyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; R3 is H, methyl, or ethyl; and, R4 is H, methyl, or ethyl.

In another preferred embodiment, the present invention provides a novel compound, wherein; R6, at each occurrence, is selected from: phenyl, naphthyl, C1-6 alkyl-phenyl-C1_6 alkyl-, 3-3 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-6 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1_6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-4 alkyl)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, [5-(Ra)-1, 3-dioxa-cyclopenten-2-one-yl] methyl, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyl, -C1-6 alkyl-NR7R7a, -CH(R8) OC (=O) R9, and - CH (R8) OC (=O) OR9; R7 is selected from: H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ; R7a is selected from: H and CI-6 alkyl, 2-6 alkenyl, C3-6 cycloalkyl-C1_3 alkyl-, and phenyl-C1_6 alkyl- ; R8 is selected from: H and 1-4 linear alkyl ;

R9 is selected from: H, C1_6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb ; and, Rf, at each occurrence, is selected from: C1_4 alkyl, C3-6 cycloalkyl, Cl-5 alkoxy, and phenyl substituted with 0-2 Rb.

In another preferred embodiment, the present invention provides a novel compound, wherein; R10, at each occurrence, is independently selected from: H, C1-6 alkyl substituted with 0-1 Rcl, 2-6 alkenyl substituted with 0-1 Rd, C2_6 alkynyl substituted with 0-1 RC1,- (CRaRal) sNRaRal,- (CRaRal) rlC (0) Ral, - (CRaRal) riC (O)ORa1, -(CRaRa1)r1C(O)NRaRa1, - (CRaRa1)r1S(O)pRa3, -(CRaRa1)r1SO2NRaRa1, -(CRaRa1) rl-C3-6 carbocycle substituted with 0-1 RC1, and-(CRaRa1) rl-5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S (O) p, and substituted with 0-1 Rd ; In another preferred embodiment, the present invention provides a novel compound, wherein; R10 at each occurrence, is independently selected from: H, C1-6 alkyl, C2_6 alkenyl, 2-6 alkynyl, - (CRaRal) sNRaRa1, -(CRaRa1)r1C(O)Ra1, - (CRaRa1)r1C(O)ORa1, -(CRaRa1)r1C(O)NRaRa1,

-(CRaRal) rlS (o) pRa3 ~ (CRaRal) rlSO2NRaRalZ phenyl, and benzyl; In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel 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 of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.

In another embodiment, the present invention provides a novel method of treating a disease or condition selected from 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, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener's granulomatosis.

In another embodiment, the present invention provides novel compounds of the present invention for use in therapy.

In another embodiment, the present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.

In another embodiment, the present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, 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-a inhibitors, TNF-a sequestration agents, and methotrexate.

In another embodiment, the present invention provides a novel article of manufacture, comprising : (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of an inflammatory disorder.

In another embodiment, the present invention provides a novel article of manufacture, comprising: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat an inflammatory disorder.

In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.

This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. It is also understood that each and every element of any embodiment is intended to be a separate specific embodiment.

Furthermore, any elements of an embodiment are meant to be

combined with any and all other elements from any of the embodiments to describe additional embodiments.

DEFINITIONS The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and C=N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention..

Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

Preferably, the molecular weight of compounds of the present invention is less than about 500,550, 600,650, 700,750, 800, 850, or 900 grams per mole. More preferably, the molecular weight is less than about 850 grams per mole. Even more preferably, the molecular weight is less than about 750 grams per mole. Still more preferably, the molecular weight is less than about 700 grams per mole.

The term"substituted,"as used herein, means that any one or more hydrogens on the designated atom is replaced

with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i. e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e. g. , carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i. e. , within) of the ring.

The term"acylation"as used herein describes the functionalization of a primary or secondary amine by reacting it with an"acylator"to form a stable compound.

Examples of acylators include (but are not limited to) an acid chloride, a carboxylic acid anhydride, a sulfonyl chloride, a chloroformate, an isocyanate, an isothiocyanate, etc. the product of which is an amide, a sulfonamide, a carbamate, a urea, and a thiourea respectively.

The present invention is intended to include all isotopes of atoms occurring in the present compounds.

Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

The present invention is also intended to include all stable oxides of thiol and amino groups, even when not specifically written. When an amino group is listed as a substituent, the N-oxide derivative of the amino group is also included as a substituent. When a thiol group is present, the S-oxide and S, S-dioxide derivatives are also included.

The term"independently selected from", "independently, at each occurrence"or similar language, means that the labeled R substitution group. may appear more

than once and that each appearance may be a different atom or molecule found in the definition of that labeled R substitution group. Thus if the labeled Ra substitution group appear four times in a given permutation of Formula I, then each of those labeled Ra substitution groups may be a different group falling in the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When any variable (e. g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein,"alkyl"or"alkylene is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1_10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, Cg, and C1o alkyl

groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl."Haloalkyl"is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example-CvFw where v = 1 to 3 and w = 1 to (2v+1)).

Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl."Alkoxy"represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1_lo alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, Cg, and C1O alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.

"Cycloalkyl"is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups."Alkenyl"or"alkenylene"is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, Cg, and C1o alkenyl groups."Alkynyl"or "alkynylene"is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-1, 0 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, Cg, and C1o alkynyl groups.

"Halo"or"halogen"as used herein refers to fluoro, chloro, bromo, and iodo; and"counterion"is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein,"carbocycle"or"carbocyclic residue" is intended to mean any stable 3,4, 5,6, or 7-membered monocyclic or bicyclic or 7,8, 9,10, 11,12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3. 0] bicyclooctane, [4.3. 0] bicyclononane, [4.4. 0] bicyclodecane, [2.2. 2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

As used herein, the term"heterocycle"or "heterocyclic group"is intended to mean a stable 3,4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, or 10- membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1,2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i. e. , N or NR wherein R is H or another substituent if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized.

It is preferred that when the total number of S and O atoms

in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. As used herein, the term"aromatic heterocyclic group"or"heteroaryl"is intended to mean a stable 5,6, or 7-membered monocyclic or bicyclic or 7,8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1,2, 3, or 4 heterotams independently selected from the group consisting of N, O, and S. It is to be noted that total number of S and 0 atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5,2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, 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, thiophenyl, 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. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The phrase"pharmaceutically acceptable"is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.

The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from

inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e. g. , solubility, bioavailability, manufacturing, etc...) the compounds of the present invention may be delivered in prodrug form.

Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same."Prodrugs" are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved,

either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

"Stable compound"and"stable structure"are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

As used herein,"treating"or"treatment"cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i. e. , arresting it development; and/or (c) relieving the disease-state, i. e., causing regression of the disease state.

"Therapeutically effective amount"is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22: 27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when

administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anti-inflammatory effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.

All references cited herein are hereby incorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are

compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

Compounds of formula I wherein B is a 5-7 membered heterocycle, R1 and R2 are H, X is a bond, and A is a hydroxamic acid can be prepared using the methods described in Scheme 1. The hetereocycle 1 wherein R is a methyl or tert-butyl and R'is a methyl or ethyl group is subjected to a treatment with BBr3 in methylene chloride or TFA to provide the phenol derivative 2. Alkylation of 2 with 4- chloromethyl-2-methylquinoline using a base such as potassium carbonate gives rise to the intermediate 3 which is converted to a hydroxamic acid 4 by treatment with a solution of hydroxylamine in methanol.

Scheme 1 R-O H i 4-chloromethyl-2- C02R'BBr3/CH2CI2 I CO2R'methylquinoline or TFA K2C03/DMF 0= 0. ou zu 1 2 HONH2 HCI Fo i i XCO2R'NaOMe/MeOH XCONHOH 0-B 0 B ,, 5 In the above and following schemes, O-R is intended to be Ua-Xa-Ya-Za or a precursor thereto. For example, in Scheme 1 O-R can be OH or 0-protecting group.

The B ring in formula I can be constructed using the methods depicted in Schemes 2-6. The-sulfonylcarboxylate 11 can be prepared starting from a phenol derivative 5.

Reaction of 5 with 5-chlorovaleroyl chloride or 4- chlorobutyryl chloride using aluminum chloride provides the ketone derivative 6. The ketone in 6 is reduced using a reducing agent such as sodium borohydride and the resulting alcohol is converted to a chloride. Treatment of the dichloro compound 8 with sodium sulfide produces the tetrahydrothiophene or tetrahydrothiopyran derivative 9.

OXONE oxidation of 9 provides the corresponding sulfone derivative 10. LDA-promoted alkylation of 10 with a bromoacetate affords the ß-sulfonylcarboxylate 11.

Scheme 2

5-chlorovaleryl R-O /-\ htriHQ ! n Nabn/i/tnr R-043 chloride up) 01 or 4-chlorobutyri wCI 5 chloride 6 0 AlCI3/C H2CI2 R-O SOC12/CH2CI2 7 OH 8 7 oh OH 8 R 0 'I Oxane° _ Na2S/DMF MeOH/H20 In su O=so 9 10 R-O LDA/THF C02R' ) 0- la5) 1-2 bromoacetate O-, S) 1-2 d 11

Alternatively, compound 11 can be prepared using the sequence outlined in Scheme 3. The intermediate 6 is reacted with triethyl phosphonoacetate using sodium hydride to provide the olefin derivative 12. Displacement of the chloro with potassium thioacetate produces the thioacetate 13 which is hydrolyzed with potassium carbonate in ethanol to give the thiol 14. Cyclization using sodium hydride gives rise to the tetrahydrothiophene or tetrahydrothiopyran derivative 15. Oxidation using OXONE affords the-sulfonylcarboxylate 11.

Scheme 3 triethyl R-0 I phosphonoacetate KSAc/DMF CI ('j-ZCI 6 o NaH/THF tCO2Et Bu4NI 6 cet 6 covet R-0 R-0 1-2SAC K2Co3IEtOH SH NaH/DMF CCEt"COoEt 13 14 One" C02Et C02Et 1) 1-2 OH/H. T),., 15 11 d 15 The ring B of structure 24 can be prepared using the protocol shown in Scheme 4. The vinylbenzene derivative 16 is subjected to a treatment with an oxidizing agent such as hydrogen peroxide or MCPBA to give an epoxide 17. Ring opening with 2-chloroethanol in the presence of boron

trifluoride gives rise to the ether 18. The alcohol in 18 is oxidized using an oxidant such as pyridinium dichromate to give the ketone 19 which is then converted to the 1,4- thioxane dioxide derivative 24 in a manner analogous to that described in Scheme 3.

Scheme 4 OH H202-chloroethanol R °\+ R-0i917 BF3 R-OU 18 triethyl CO2Et PDC/CH2CI2 phosphonoacetate CI NaH/'FHF J) J NaH/THF jj J-' R-O 19 R-Ow 20 KSAc/DMF SCO2Et K2CO3/EtOH lí C02Et No I-I R-0 21 R-0 22 NaH/DMF t1 rCO2Et Oxanee CO2Et w -9 MeOH/H20 °ó sJ 23 24 23 24

The B ring of structure 34 can be prepared according to Scheme 5. The intermediate 17 is subjected to a ring opening with benzylamine. Reductive amination of'the resulting secondary amine with chloroacetalhyde using sodium triacetoxyborohydride furnishes the tertiary amine 26. The alcohol in 26 is oxidized using an oxidant such as pyridinium dichromate to give the ketone 27. Reaction of

the ketone with triethyl phosphonoacetate, displacement of the chlorine with potassium thioacetate and hydrolysis of the thioacetate with potassium carbonate followed by ring closure using sodium hydride afford the thiomorpholine derivative 31. Oxane oxidation followed by hydrogenolysis provides the thiomorpholine-1, 1-dioxide 33. Reductive amination with an aldehyde or ketone, acylation or sulfonylation of 33 gives the B ring structure 34.

Scheme 5 0 OH H benzyiamine N chloroacetaidehyde I, I DMF Na (OAc) 3BH 17 R'o 25 R=Me, tert-butyl CI OH PDC/CH2CI2 0 N-I N Iw Iw R-OX 26 R-0 27 Ci triethyl Et02C KSAc/DMF phosphonoacetate N NaH/THF N R-Ow 28 SAc SH EtO2C) 0 < K2CO3/EtOH EtO2C) 0 < NaH/DMF N N R-0 29 R-0 30 R-O CO2Et Oxanee R-On CO2Et H2/Pd-C MeOH/H N N 31 32 R-O CO Et R-0 C02Et reductive amination XON2RE1to """NH-------------- ""NF° acylation or sulfonylation p S J Oz 33 34

Alternatively, the B ring of structure 40-can be prepared using the method outlined in Scheme 6. The intermediate 35 wherein X is a methylene, an oxygen or a benzylamino is treated with sodium iodide in acetone at reflux to give the iodo derivative 36. The iodo in 36 is

then displaced with thiourea to yield the amidinothio derivative 37 which is subjected to a cyclization by refluxing in an aqueous potassium hydroxide solution. The resulting carboxylic acid in 38 is converted to a methyl ester and the sulfide in 39 is oxidized using Oxane to afford the sulfone intermediate 40.

Scheme 6 Ci Et02C J EtOC Nallacetone ( thiourea/EtOH w X I reflux 11 reflux 36 35 X=CH2, O, benzylamino 36 SC (NH) NH2 R-O C H KOH/H20 Mel/K2CO3 /~ reflux SJX DMF 37 38 R-0 C02Me Oxanee R-0 I C02Me X XX MeOH/H20 XX sJ °õsJ 39 40

One diastereomer of a compound of formula (I) may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.

When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972,308 pp or using enantiomerically pure acids and bases. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e. g. , Jacobsen, E. Acc. Chem. Res. 2000,33, 421-431 or using other enantio-and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES Abbreviations used in the Examples are defined as <BR> <BR> <BR> <BR> follows :"1 x"for once,"2 x"for twice, "3 x"for thrice, "°C"for degrees Celsius, "eq"for equivalent or equivalents, "g"for gram or grams, "mg"for milligram or milligrams,"mL"for milliliter or milliliters,"ZL"for microliter or microliters,"1H"for proton,"h"for hour or hours, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "NMR" for

nuclear magnetic resonance spectroscopy, "rt"for room temperature,"tlc"for thin layer chromatography,"v/v"for volume to volume ratio."a"," (3","R"and"S"are stereochemical designations familiar to those skilled in the art.

Example 1 N-hydroxy-2- (4-isopropyl-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-l, l-dioxido-2- thiomorpholinyl) acetamide (la) To a solution of 4-tert-butoxystyrene (17.6 g, 100 mmol) in methylene chloride (200 mL) cooled in an ice bath is added a solution of 32% peracetic acid in acetic acid (31.5 mL, 150 mmol). The mixture is stirred at rt overnight and quenched by addition of saturated sodium bicarbonate solution. The organic phase is separated, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo.

Chromatography on silica gel provides 2-(4-tert- butoxyphenyl) oxirane.

(lb) A mixture of la (15.4 g, 80 mmol) and benzylamine (12.9 g, 120 mmol) in DMF (100 mL) is stirred at 50 °C overnight. After cooling to rt, ethyl acetate (500 mL) is added. The solution is washed with brine three times, dried over magnesium sulfate, and concentrated in vacuo.

Purification on silica gel provides 2- (benzylamino)-1- (4- tert-butoxyphenyl) ethanol.

(1c) To a solution of 1b (15 g, 50 mmol) and chloroacetaldehyde (10.2 mL, 50% solution in water, 80 mmol) in THF (100 mL) is added sodium triacetoxyborohydride

(14.8 g, 70 mmol). The mixture is stirred at rt overnight and concentrated in vacuo. The residue is taken up in ethyl acetate. The resulting solution is washed with sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel provides 2- [benzyl (2-chloroethyl) amino]-1- (4-tert- butoxyphenyl) ethanol.

(1d) To a solution of lc (14.5 g, 40 mmol) in methylene chloride (300 mL) is added pyridinium dichromate (30 g, 80 mmol). The mixture is stirred at rt overnight and filtered through a pad of Celte The Celite is thoroughly rinsed with methylene chloride. The combined solution is concentrated in vacuo. The residue is purified on silica gel to provide 2- [benzyl (2-chloroethyl) amino]-1- (4-tert- butoxyphenyl) ethanone.

(le) To a suspension of sodium hydride (2.4 g, 60% oil dispersion, 60 mmol) in THF (100 mL) in an ice bath is added a solution of triethyl phosphonoacetate (5.9 mL, 30 mmol) in THF (20 mL). After stirring at the same temperature for 30 min, a solution of 1d (10. 8 g) in THF (20 mL) is added. The mixture is refluxed overnight.

After cooling to rt, the mixture is poured into ice water.

The organic phase is separated and the water phase is extracted with ethyl acetate. The combined organic phase is dried over magnesium sulfate and concentrated.

Purification on silica gel provides ethyl 4- [benzyl (2- chloroethyl) amino]-3- (4-tert-butoxyphenyl)-2-butenoate.

(If) A mixture of le (8.6 g, 20 mmol), potassium thioacetate (2.7 g, 24 mmol) and tetrabutyl ammonium iodide (200 mg) in DMF (40 mL) is stirred overnight at rt. The mixture is poured into saturated aqueous ammonium chloride

and extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, and evaporated in vacuo. Purification on silica gel provides ethyl 4- [ [2- (acetylthio) ethyl] (benzyl) amino]-3- (4-t : ert- butoxyphenyl)-2-butenoate.

(1g) A mixture of If (4.8 g, 10 mmol) and potassium carbonate (2.1 g, 15 mmol) in ethanol (30 mL) is stirred for 6 h at rt and concentrated in vacuo. The residue is partitioned between ethyl acetate and aqueous citric acid.

The separated organic phase is washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give ethyl 4- [benzyl (2-mercaptoethyl) amino]-3- (4-tert- butoxyphenyl)-2-butenoate.

(1h) To a solution of lg (4.27 g, 10 mmol) in DMF (30 mL) cooled in an ice bath is added sodium hydride (0.6 g, 60% oil dispersion, 15 mmol). The mixture is stirred at rt overnight and poured into ice water. Ethyl acetate is added. The separated organic phase is washed with brine, dried over magnesium sulfate, and concentrated.

Purification on silica gel provides ethyl [4-benzyl-2- (4- tert-butoxyphenyl) -2-thiomorpholinyl] acetate.

(li) To a mixture of 1h (4.27 g, 10 mmol) in methanol (50 mL) is added a solution of Oxane (9.2 g, 15 mmol) in water (50 mL). The mixture is stirred at rt for 5 h. Methanol is removed under reduced pressure. After being neutralized with sodium bicarbonate, ethyl acetate is added. The separated organic phase is washed with brine, dried over magnesium sulfate and concentrated to provide ethyl [4- benzyl-2- (4-tert-butoxyphenyl)-1, 1-dioxido-2- thiomorpholinyl] acetate.

(1j) To a solution of li (4.6 g, 10 mmol) in ethanol (50 mL) is added palladium hydroxide on carbon (0.9 g). The mixture is stirred under hydrogen at 50 psi overnight. The catalyst is filtered off and the filtrate is concentrated to provide ethyl [2- (4-tert-butoxyphenyl)-1, 1-dioxido-2- thiomorpholinyl] acetate.

(1k) To a solution of lj (1.85 g, 5 mmol) in THF (20 mL) is added acetone (1.2 g, 20 mmol) followed by sodium triacetoxyborohydride (1.3 g, 6 mmol). The mixture is stirred at rt overnight. Ethyl acetate is added. The resulting solution is washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated.

Chromatography on silica gel provides ethyl {2- (4-tert- butoxyphenyl)-4-isopropyl-1, 1-dioxido-2- thiomorpholinyl] acetate.

(11) A solution of lk (2.06 g, 5 mmol) in TFA (10 mL) and water (0.1 mL) is stirred at rt for 5 h. Evaporation under reduced pressure removes volatiles to provide ethyl [2- (4- hydroxyphenyl)-4-isopropyl-1, 1-dioxido-2- thiomorpholinyl] acetate.

(1m) A mixture of 11 (1. 78 g, 5 mmol), 4-chloromethyl-2- methylquinoline hydrochloride (1.15 g, 5 mmol) and potassium carbonate (1. 38 g, 10 mmol) in DMF (15 mL) is stirred at 80 °C for 5 h. After cooling to rt, ethyl acetate is added. The solution is washed with brine three times, dried over magnesium sulfate, and concentrated.

Purification on silica gel provides ethyl (4-isopropyl-2- {4-[(2-methyl-4-quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetate.

(In) Hydroxylamine hydrochloride (2.34 g) is dissolved in hot methanol (12 mL). To it is added a solution of potassium hydroxide (2.81 g) in methanol (7 mL). After cooling to rt, filtering removes insoluble materials. To this solution (3 mL) is added lm (200 mg). After being stirred at rt for 30 min, the reaction is quenched by addition of a solution of TFA (0.3 mL) in methylene chloride (3 mL). The solution is evaporated in vacuo. The residue is purified by reversed phase HPLC to provide N- hydroxy-2- (4-isopropyl-2- {4- [ (2-methyl-4- quinolinyl) methoxy] phenyl}-1, 1-dioxido-2- thiomorpholinyl) acetamide.

The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formula at the start of the table. For example, example 1 in Table 1 is intended to be paired with each of formulae A-L.

Table 1 Ex # R (= -Ua-Xa-Ya-Za) 1 (2-methyl-4-quinolinyl) methoxy 2 (2-ethyl-4-quinolinyl) methoxy 3 (2-isopropyl-4-quinolinyl) methoxy 4 (2-trifluoromethyl-4-quinolinyl) methoxy 5 (2-methyl-4-quinolinyl) methyl 6 (2-ethyl-4-quinolinyl) methyl 7 (2-isopropyl-4-quinolinyl) methyl 8 (2-trifluoromethyl-4-quinolinyl) methyl 9 (2,3-dimethyl-4-quinolinyl) methyl 10 (2-methyl-1-benzimidazolyl) methyl 11 (2-ethyl-1-benzimidazolyl) methyl 12 (2-isopropyl-l-benzimidazolyl) methyl 13 (2-trifluoromethyl-1-benzimidazolyl) methyl 14 (2-cyclopropyl-1-benzimidazolyl) methyl 15 (1, 1-dioxodo-4-benzothiazinyl) methyl 16 (2, 2-dimethyl-1, 1-dioxodo-4- benzothiazinyl) methyl Table 2 Ex # RIO 1 H 2 methyl 3 ethyl 4 propyl 5 isopropyl 6 isobutyl 7 allyl 8 propargyl

9 3-tertrahydrofuranyl 10 4-tetrahydropyranyl 11 acetyl 12 propionyl 13 butyryl 14 isopropylcarbonyl 15 methanesulfonyl 16 butanesulfonyl 17 isopropanesulfonyl 18 methoxycarbonyl 19 ethoxycarbonyl 20 propyloxycarbonyl 21 isopropyloxycarbonyl UTILITY The compounds of formula I are expected to possess matrix metalloprotease and/or aggrecanase and/or TNF-a inhibitory activity. The MMP inhibitory activity of the compounds of the present invention is demonstrated using assays of MMP activity, for example, using the assay described below for assaying inhibitors of MMP activity.

The compounds of the present invention are expected to be bioavailable in vivo as demonstrated, for example, using the ex vivo assay described below. The compounds of formula I are expected to have the ability to suppress/inhibit cartilage degradation in vivo, for example, as demonstrated using the animal model of acute cartilage degradation described below.

The compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit MPs.

These would be provided in commercial kits comprising a compound of this invention.

Metalloproteinases have also been implicated in the degradation of basement membranes to allow infiltration of cancer cells into the circulation and subsequent penetration into other tissues leading to tumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews, 1990, 9, 289-303). The compounds of the present invention should be useful for the prevention and treatment of invasive tumors by inhibition of this aspect of metastasis.

The compounds of the present invention should also have utility for the prevention and treatment of osteopenia associated with matrix metalloprotease-mediated breakdown of cartilage and bone that occurs in osteoporosis patients.

Compounds that inhibit the production or action of TACE, aggrecanase and/or MMP's are potentially useful for the treatment or prophylaxis of various inflammatory, infectious, immunological or malignant diseases or conditions. Thus, the present invention relates to a method of treating various inflammatory, infectious, immunological or malignant diseases. These include 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 (including cachexia resulting from cancer or HIV), 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 (including inflammatory bowl disease), 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 (including juvenile rheumatoid arthritis and adult 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.

Some compounds of the present invention have been shown to inhibit TNF production in lipopolysacharride stimulated mice, for example, using the assay for TNF induction in mice and in human whole blood as described below.

Some compounds of the present invention have been shown to inhibit aggrecanase, a key enzyme in cartilage breakdown, as determined by the aggrecanase assay described below.

The compounds of the present invention can be administered alone or in combination with one or more additional anti-inflammatory agents. These agents include, but are not limited to, selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-a inhibitors, and TNF-a sequestration agents.

By"administered in combination"or"combination therapy"it is meant that a compound of the present

invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated.

When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

The term selective COX-2 inhibitors, as used herein, denotes agents that selectively inhibit COX-2 function.

Such agents include, but are not limited to, celecoxib (Celebrex@), rofecoxib (Vioxx meloxicam (Movicox etoricoxib, and valdecoxib.

TNF-a sequestration agents that may be used in combination with the compounds of this invention, are TNF-a binding proteins or anti-TNF-a antibodies. These agents include, but are not limited to, etanercept (Enbrel infliximab (Remicade), adalimumab (D2E7), CDP-571 (Humicade), and CDP-870.

Other anti-inflammatory agents that may be used in combination with the compounds of this invention, include, but are not limited to, methotrexate, interleukin-1 antagonists (e. g. , anakinra (Kineret@)), dihydroorotate synthase inhibitors (e. g. , leflunomide (Arava and p38 MAP kinase inhibitors.

Administration of the compounds of the present invention (i. e. , a first therapeutic agent) in combination with at least one additional therapeutic agent (i. e. , a second therapeutic agent), preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each (i. e. , a synergistic combination). A lower dosage minimizes the

potential of side effects, thereby providing an increased margin of safety. It is preferred that at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses. Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.

As used herein "µg" denotes microgram, "mg"denotes milligram"tg denotes gram,"pL"denotes microliter, "mL" denotes milliliter,"L"denotes liter,"nM"denotes nanomolar,"uM"denotes micromolar, "mM"denotes millimolar, "M"denotes molar and"nm"denotes nanometer.

"Sigma stands for the Sigma-Aldrich Corp. of St. Louis, MO.

A compound is considered to be active if it has an IC50 or Ki value of less than about 10 uM for the inhibition of a desired MP. Preferred compounds of the present invention have Ki's or Iso's of # 1 µM. More preferred compounds of the present invention have Ki's or IC50's of : 0. 1 uM. Even more preferred compounds of the present invention have Ki's or Iso's of < 0. 01, uM. Still more preferred compounds of the present invention have Ki's or IC5o's of < 0. 001 uM.

Aggrecanase Enzymatic Assay A novel enzymatic assay was developed to detect potential inhibitors of aggrecanase. The assay uses active aggrecanase accumulated in media from stimulated bovine nasal cartilage (BNC) or related cartilage sources and

purified cartilage aggrecan monomer or a fragment thereof as a substrate.

The substrate concentration, amount of aggrecanases time of incubation and amount of product loaded for Western analysis were optimized for use of this assay in screening putative aggrecanase inhibitors. Aggrecanase is generated by stimulation of cartilage slices with interleukin-1 (IL- 1), tumor necrosis factor alpha (TNF-a) or other stimuli.

Matrix metalloproteinases (MMPs) are secreted from cartilage in an inactive, zymogen form following stimulation, although active enzymes are present within the matrix. We have shown that following depletion of the extracellular aggrecan matrix, active MMPs are released into the culture media (Tortorella, M. D. et al. Trans.

Ortho. Res. Soc. 1995,20, 341). Therefore, in order to accumulate BNC aggrecanase in culture media, cartilage is first depleted of endogenous aggrecan by stimulation with 500 mg/ml human recombinant IL-6 for 6 days with media changes every 2 days. Cartilage is then stimulated for an additional 8 days without media change to allow accumulation of soluble, active aggrecanase in the culture media. In order to decrease the amount of other matrix metalloproteinases released into the media during aggrecanase accumulation, agents which inhibit. MMP-1, -2, - 3, and-9 biosynthesis are included during stimulation.

This BNC conditioned media, containing aggrecanase activity is then used as the source of aggrecanase for the assay.

Aggrecanase enzymatic activity is detected by monitoring production of aggrecan fragments produced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody, BC-3 (Hughes, CE, et al. , Biochem J 306: 799-804,1995).

This antibody recognizes aggrecan fragments with the N- terminus, 374ARGSVIL, generated upon cleavage by

aggrecanase. The BC-3 antibody recognizes this neoepitope only when it is at the N-terminus and not when it is present internally within aggrecan fragments or within the aggrecan protein core. Other proteases produced by cartilage in response to IL-1 do not cleave aggrecan at the Glu373-Ala374 aggrecanase site; therefore, only products produced upon cleavage by aggrecanase are detected.

Kinetic studies using this assay yield a Km of 1.5 +/-0.35 WM for aggrecanase.

To evaluate inhibition of aggrecanase, compounds are prepared as 10 mM stocks in DMSO, water or other solvents and diluted to appropriate concentrations in water. Drug (50 JLL) is added to 50 gL of aggrecanase-containing media and 50 RL of 2 mg/ml aggrecan substrate and brought to a final volume of 200 AL in 0.2 M Tris, pH 7.6, containing 0.4 M NaCl and 40 mM CaCl2. The assay is run for 4 h at 37 °C, quenched with 20 mM EDTA and analyzed for aggrecanase- generated products. A sample containing enzyme and substrate without drug is included as a positive control and enzyme incubated in the absence of substrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core protein. Therefore, for analysis of aggrecan fragments generated by cleavage at the Glu373-Ala374 site, proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 units/10 jig GAG) for 2 h at 37. °C and then with keratanase (0.1 units/10 jig GAG) and keratanase II (0.002 units/10 Rg GAG) for 2 h at 37 °C in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5. After digestion, aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in

30 AL of Tris glycine SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loaded and then separated by SDS-PAGE under reducing conditions with 4-12% gradient gels, transferred to nitrocellulose and immunolocated with 1: 500 dilution of antibody BC3.

Subsequently, membranes are incubated with a 1: 5000 dilution of goat anti-mouse IgG alkaline phosphatase second antibody and aggrecan catabolites visualized by incubation with appropriate substrate for 10-30 minutes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount of product produced in the presence versus absence of compound.

TNF PBMC ASSAY Human peripheral blood mononuclear cells (PBMC) were obtained from normal donor blood by leukophoresis and isolated by Ficoll-Paque density separation. PBMCs were suspended in. 5ml RPMI 1640 with no serum at 2 x 106 cells/ml in 96 well polystyrene plates. Cells were preincubated 10 minutes with compound, then stimulated with 1 ug/ml LPS (Lipopolysaccharide, Salmonella typhimurium) to induce TNF production. After an incubation of 5 h at 37 °C in 95% air, 5% C02 environment, culture supernatants were removed and tested by standard sandwich ELISA for TNF production.

TNF Human Whole Blood Assay Blood is drawn from normal donors into tubes containing 143 USP units of heparin/10 mL. 225 RL of blood is plated directly into sterile polypropylene tubes.

Compounds are diluted in DMSO/serum free media and added to the blood samples so the final concentration of compounds

are 50,10, 5,1,. 5,,. 1, and. 01 uM. The final concentration of DMSO does not exceed 0. 5%. Compounds are preincubated for 15 min before the addition of 100 mg/mL LPS. Plates are incubated for 5 h in an atmosphere of 5% C02 in air. At the end of 5 h, 750 iL of serum free media is added to each tube and the samples are spun at 1200 RPM for 10 min. The supernatant is collected off the top and assayed for TNF-a production by a standard sandwich ELISA.

The ability of compounds to inhibit TNF-a production by 50% compared to DMSO treated cultures is given by the IC5o value.

TNF Induction In Mice Test compounds are administered to mice either I. P. or P. O. at time zero. Immediately following compound administration, mice receive an I. P. injection of 20 mg of D-galactosamine plus 10 ug of lipopolysaccharide. One hour later, animals are anesthetized and bled by cardiac puncture. Blood plasma is evaluated for TNF levels by an ELISA specific for mouse TNF. Administration of representative compounds of the present invention to mice results in a dose-dependent suppression of plasma TNF levels at one hour in the above assay.

MMP ASSAYS The enzymatic activities of recombinant MMP-1,2, 3, 7,8, 9,10, 12,13, 14,15, and 16 were measured at 25 °C with a fluorometric assay (Copeland, R. A. et al. Bioorganic Med. Chem. Lett. 1995, 5,1947-1952). Final enzyme concentrations in the assay were between 0.05 and 10 nM depending on the enzyme and the potency of the inhibitor tested. The permissive peptide substrate, MCA-Pro-Leu-Gly- Leu-DPA-Ala-Arg-NH2, was present at a final concentration

of 10 MM in all assays. Initial velocities, in the presence or absence of inhibitor, were measured as slopes of the linear portion of the product progress curves. ICso values were determined by plotting the inhibitor concentration dependence of the fractional velocity for each enzyme, and fitting the data by non-linear least squares methods to the standard isotherm equation (Copeland, R. A. Enzymes: A practical Introduction to Structure, Mechanism and Data Analysis, Wiley-VHC, New York, 1996, pp 187-223). All of the compounds studied here were assumed to act as competitive inhibitors of the enzyme, binding to the active site Zn atom as previously demonstrated by crystallographic studies of MMP-3 complexed with related hydroxamic acids (Rockwell, A. et al. J. Am.

Chem. Soc. 1996, 118, 10337-10338). Based on the assumption of competitive inhibition, the ICso values were converted to Ki values as previously described.

Compounds tested in the above assay are considered to be active if they exhibit a Ki of 10 uM. Preferred compounds of the present invention have Ki's of < 1 uM.

More preferred compounds of the present invention have Ki's of zu 0.1 uM. Even more preferred compounds of the present invention have Ki's of < 0. 01 uM. Still more preferred compounds of the present invention have Ki's of < 0. 001 uM.

Using the methodology described above, a number of compounds of the present invention were found to exhibit Ki's of < 10 uM, thereby confirming the utility of the compounds of the present invention.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present

invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of an inflammatory disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat an inflammatory disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e. g. , for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e. g. , cardboard or plastic), crates, cartons, bags (e. g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first

container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e. g. , the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e. g. , paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc. ) on which the desired information has been formed (e. g. , printed or applied).

Dosage and Formulation The compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions.

The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage

forms is Remington's Pharmaceutical Sciences, Mack Publishing.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiinflammatory and antiarthritic agent.

The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug

required to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 70 to 1400 mg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.

Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 100 mg of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release, products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and

glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The compounds of the present invention may be administered in combination with a second therapeutic agent, especially non-steroidal anti-inflammatory drugs (NSAID's). The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.

The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc. ). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent. When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic agent

occurs less than about one hour apart, more preferably less than about 5 to 30 min apart.

Preferably the route of administration of the compound of Formula I is oral. Although it is preferable that the compound of Formula I and the second therapeutic agent are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in

the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.

Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of osteoarthritis or rheumatoid arthritis, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. , as will be readily apparent to those skilled in the art. Instructions, either as inserts or as

labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.