WO2009075790A1 - Metalloprotease inhibitors for intra-articular application - Google Patents

Abstract

The present invention relates to the prolonged durability of metalloprotease inhibiting compounds, particularly amide containing heterobicyclic matrix metalloproteinase-13 (MMP-13) inhibiting compounds upon intra-articular (IA) administration for the treatment of diseases including traumatic, painful, infectious, inflammatory, immunologic, metabolic, malignant and degenerative disease involving metalloprotease-mediated destruction of structural components of a joint, particularly cartilage.

Description

METALLOPROTEASE INHIBITORS FOR INTRA ARTICULAR

APPLICATION

This application claims the benefit of two U.S. Provisional Application No.'s 61/005,766, filed December 7, 2007 and 61/008,636 filed December 21, 2007, which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the prolonged durability metalloprotease inhibiting compounds, particularly amide containing heterobicyclic matrix metalloproteinase-13 (MMP- 13) inhibiting compounds upon intra-articular (IA) administration for the treatment of diseases including traumatic, painful, infectious, inflammatory, immunologic, metabolic, malignant and degenerative disease involving metalloprotease-mediated destruction of structural components of a joint, particularly cartilage. BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS = a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally-related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors of traumatic, infectious, inflammatory, immunologic, metabolic, malignant and degenerative disease processes. MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in sports injuries, inflammatory diseases such as rheumatoid arthritis and juvenile rheumatoid arthritis, degenerative joint diseases such as osteoarthritis and intervertebral disc disorders, systemic lupus erythematosus (SLE), osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis. The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti- Inflammatory Anti-Allergy Agents 2005, 4, 251-264).

The mammalian MMP family has been reported to include at least 20 enzymes {Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP- 13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).

The activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexed with the catalytic zinc (II) ion. X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-I and MMP- 14 catalytic domain and TIMP-2 also reveal ligation of the catalytic zinc (II) ion by the thiol of a cysteine residue. The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.

MMP-3 (stromelysin-1; transin-1) is another member of the MMP family (FASEB J. 1991, 5, 2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Am. J. Pathol. 1989, 135, 1055- 64). MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers.

MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing (J. Clin. Invest. 1994, 94, 79-88).

MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis (Arthritis Rheum. 2000, 43, 852-8) and in osteoarthritis patients (Clin. Orthop. Relat. Res. 2004, 428, 272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Rheumatology 2006, 45, 414-20).

MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatin, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, IX, X (Clin. Orthop. Relat. Res. 2004, 428, 272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Arthritis Res. 2001, 5, 107-13; Clin. Orthop. Relat. Res. 2004, 427, S 118-22). MMP-3 can activate other MMP family members such as MMP-I, MMP-7, MMP-8, MMP-9 and MMP- 13 (Ann. Rheum. Dis. 2001, 60 Suppl 3:iii62-7).

MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβl from the ECM, activating TNFα, inactivating IL- lβ and releasing IGF (Nat. Rev. Immunol. 2004, 4, 617-29). A potential role for MMP-3 in the regulation of macrophage infiltration is based on the ability of the enzyme to convert active MCP species into antagonistic peptides (Blood 2002, 100, 1160-

7).

The metalloprotease inhibitors with prolonged durability for intra-articular administration may be synthesized for example according WO06/083454, WO06/128184, WO07/079199, US2007/155738, US2007/155737, WO06/061715, WO06/061706, WO05/105760, WO05/061926, WO04/064842, WO04/014923, WO04/014921, WO04/014916, WO04/014909, WO04/014908, WO04/014892, WO04/014880, WO04/014869, WO04/014868, WO04/014866, WO04/014389, WO04/014388, WO04/014384, WO04/014379, WO04/014378, WO04/014377, WO04/014375, WO04/014366, WO04/014365, WO04/014354, WO04/007469, WO04/000322, WO04/000321, WO03/076416, WO03/033478, WO03/033477, WO03/032999, WO02/064599, WO02/064598, WO02/064595, WO02/064578, WO02/064572, WO02/064571, WO02/064568, WO02/064547, EP 1394159, and EP 1291345. More preferred the metalloprotease inhibitors with prolonged durability for intra-articular administration have the structure as described in WO06/128184 and US2007/155738.

Osteoarthritis is characterized by a loss of articular cartilage resulting in chronic pain and disability. The disease is non-systemic by nature and is commonly restricted to a few joints. In addition to the loss of cartilage there is an observed reduction in the viscous properties of the synovial fluid. A variety of intra-articular (IA) agents including corticosteroids and several hyaluronate products are currently available for symptomatic relief of osteoarthritis (OA). Intra-articular corticosteroids are widely used in an attempt to provide pain relief and suppress synovitis in OA patients, especially in those with joint effusion or inflammation (Arthritis Rheum. 1995, 38, 1541-6; Neustadt, In: Osteoarthritis Diagnosis and Medical/Surgical Management, Moskowitz et al, ed WB Saunders Company: Philadelphia, 2001, 3^rd ed, 393-411). They are used usually as an adjunctive therapy when one or two joints are resistant to systemic therapy, including acetaminophen, NSAIDs, and other analgesics (Neustadt, ^.Osteoarthritis Diagnosis and Medical/Surgical Management, Moskowitz et al, ed WB Saunders Company: Philadelphia, 2001, 3^rd ed, pp. 393-411).

Clinical trials data suggest that for most patients the corticosteroid treatment results in a slightly better improvement in symptoms than placebo and that the effects do not last more than 4 weeks (Curr. Opin. Rheumatol. 1999, 11, 417-21 ; Arthritis Rheum. 1999, 42, 475-82; J Rheumatol. 2003, 42, 1477). However, higher doses (equivalent to 50 mg prednisone) of intra-articular corticosteroids are effective in improving symptoms of knee OA up to 16 to 24 weeks (J. Rheumatol. 2003, 42, UIl; Arthritis Rheum. 1999, 42, 475-82). Triamcinolone diacetate, triamcinolone hexacetonide, methylprednisolone acetate, betamethasone acetate and betamethasone sodium phosphate and hydrocrotisone tebutate are some of the commercially available corticosteroid preparations for intra-articular use. There is no major difference in efficacy of these agents. However, more soluble compounds more rapidly are absorbed and as a result, demonstrate short duration of action. Tiamcinolone hexacetonide is the most insoluble preparation and has a longer duration of action {Med. Clin. N. Am. 2007, 91 , 241 ; Neustadt, ^.Osteoarthritis Diagnosis and Medical/Surgical

Management, Moskowitz et al, ed WB Saunders Company: Philadelphia, 2001, 3^rd ed, pp. 393-411). The observed pain relief for all of these agents is however short lived (1-4 weeks from administration). The precise mechanism by which corticosteroids exert their beneficial effects in an OA joint is not known. They are believed to act as broad-spectrum anti-inflammatory agents.

A variety of nonsteroidal agents also have been tested intra-articularly for symptomatic relief of OA, including lactic acid, phenylbutazone, cytotoxic compounds, sodium salicylate, osmic acid and aspirin. However, these agents have not gained popularity because of their limited efficacy and / or associated toxicities (Neustadt, ^.Osteoarthritis Diagnosis and Medical/Surgical

Management, Moskowitz et al, ed WB Saunders Company: Philadelphia, 2001, 3^rd ed, pp. 393-41 1).

The US Food and Drug Administration (FDA) has designated four preparations of intra-articular viscosupplements based on hyaluronate (Hyalgan , Synvisc^®, Supartz^®, and Orthovisc^®) as new devices for the treatment of pain in OA of the knee for individuals who have failed to respond adequately to other therapy, such as non pharmacological therapy and simple analgesics (e.g. acetaminophen). Synvisc^® (8 mg/injection) is injected intra-articularly into the knee joint once per week for a total of 3 injections over a 2- week period. In contrast, 5 weekly injections are recommended for the Hyalgan^® (20 mg/injection) and Supartz^® (25 mg/injection) products, and 3-4 weekly injections are recommended for OrthoVisc^® (15 mg/injection). It is reported that pain relief is usually obtained by 8 to 12 weeks after the first injection and can last up to six months. The intra-articular hyaluronate products are believed to work through viscosupplementation of the compromised synovial fluid in the OA diseased joint. The synovial fluid in the OA is less viscous and has lower rheologic properties than that of normal synovial fluid. The viscosupplementation is aimed to relieve pain and improve function in OA patients. While the hyaluronate products have a half-life of 2-8 days, the clinical effects are reported to far exceed the synovial half-life of these agents. Some studies have reported reduction in pain and improvement in function lasting up to a year (Int. J. Clin. Pr act. 2002, 56, 804-13; American College of Rheumatology Subcommittee on Osteoarthritis Guidelines, 2000).

The intra-articular hyaluronate may be modified by cross-linking in a suitable manner as described in http://www.glycoforum.gr.jp/science/hyaluronan/HA18/HA18.pdf or others

(Biomaterials 2007, 28, 1778-86). Hylan G-F 20 (J. Manag. Care Pharm. 2007, 13, 113-121) is one preferred example of such a cross-linked hyaluronate. Although corticosteroids as well as non-steroidal agents including hyaluronate products are being widely used to treat signs and symptoms of OA, to date, there is no agent, oral or intra-articular, on the market that has proven to be disease/structure modifying. MMP- 13 is a key MMP that is responsible for degradation of collagen in cartilage and has been shown to be up-regulated in OA. Moreover, both in vitro and in animal models of OA, MMP- 13 inhibitors have been shown to be chondroprotective (e.g demonstrate cartilage protection). Thus, there is compelling data demonstrating the potential of MMP- 13 inhibitors as disease-modifying osteoarthritis drugs (DMOAD). While there have been efforts to evaluate potential DMOADs including MMP- 13 inhibitors via an oral route of administration, very little information is available on potential intra-articular DMOADs (IA DMOADs). The IA route of administration has a distinct advantage over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to target cartilage and minimizing systemic exposure. The IA route of administration can be used to assess potential DMOADs such as MMP- 13 inhibitors.

In the majority of cases where either intra-articular administration of coritcosteroids or viscosupplements were applied no effort had been made to analytically measure the presence of such agents in the joint as a function of time. Without this type of direct measurement correlation between the level of pain and/or disease modification and the amount of agent still present within the joint cannot be made. This makes it very difficult to rule out the placebo effect as the main mechanism of action. In the few cases where the joint synovial fluid was analyzed for the presence of for example the corticosteroid, remexolone, it was found that the agent was present on average for about 25 days. No attempt was made to assay the activity of the agent via its affects on cartilage. As for the presence of the viscosupplement, hyaluronate, very little was found to be still present within the joint after two weeks (half life = 2-8 days). After extensive review of the various studies on the use of viscosupplements it was determined that a primary mechanism action was in fact the placebo effect (Curr. Med Chem. Immun. Endoc & Metab. Agents 2005, 5, 229-240).

When tackling osteoarthritis of the joint one would like to have disease modifying agents which can remain both biologically active and localized within the joint cavity (cartilage and surrounding synovial fluid) for long periods of time. This phenomenon which we have termed "durability" would be made up of two parts:

1) having a measured presence in the joint as a function of time.

2) exhibiting a measurable biological activity as a function of time. To target diseases such as osteoarthrits of the joint one would like to have compounds whose durability ultimately results in disease modification and/or cartaliage protection for periods longer than four weeks without having systemic exposure. Ideally, one would like to administer intra-articularly the durable agent no more than once every 2-4 months. For this reason developing compounds that are durable is critical to the successful treatment of inflammatory diseases such as osteoarthritis.

This invention discloses a series of metalloprotease inhibitors with surprising and unexpected properties. The unexpected advantages observed for compounds of this invention include prolonged durability within the joint cavity, as is evident by measuring the level of compound concentration and MMP- 13 inhibition as a function of time. Additionally, this durability was shown to directly result in cartilage protection in animal models. It is believed that these new findings will lead to inhibitors of metalloproteases that are tailored for intraarticular administration for the treatment of various MMP mediated diseases.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical agents and their intraarticular uses which inhibit metalloproteases, in particular, MMP- 13, and exhibit durability in the joint cavity when administered intra-articularly. More particular, the present invention provides a new class of potent metalloprotease inhibiting compounds that exhibit durability in the joint cavity when administered intra- articularly, resulting in cartilage protection and their uses.

The present invention provides several classes of amide containing heterobicyclic metalloprotease compounds, of which some are represented by the following general formulas:

Formula (I) Formula (II) Formula (III)

Formula (IV) Formula (V) Formula (VI) wherein all variables in the preceding Formulas (I) to (VI) are as defined hereinbelow.

The metalloprotease inhibiting compounds of the present invention can be used for intra-articular treatment of all or any joint disease, including those of the temporomandibular, atlanto-axial, shoulder, clavicular, thoracic and lumbosacral spine, rib cage, hips, knees, feet, thumb, back, ankles, toe, elbow, hands and fingers. The joint diseases may be genetic, traumatic, infectious, inflammatory, immunologic, metabolic, malignant, or degenerative in nature, or of unknown etiology, and involve metalloprotease-mediated damage to various structural components of a joint, particularly cartilage, including articular, fϊbro- and elastic cartilage. The compounds in the present invention may be used to prevent or treat diseases in human as well as in other animals (for example, cow, horse, pig, sheep, dog, cat and the like). Some specific examples of diseases that can be treated with the heterobicyclic metalloprotease inhibitors include, but are not limited to, achondroplasia, acute inflammation, acute suppurative arthritis, allograft rejections, angiogenesis, arthritis mutilans, articular sports injuries, bone pain, chemical exposure or oxidative damage to tissues, chondrocalinosis, chondrodystrophy, chondroma, chondromalacia patella, chondromalacia, chondrosarcoma, chronic inflammation, chronic periodontitis, costochondritis, crystal induced arthritis, early transplantation rejection, ectopic cartilage, failure in restoration and cure of fractures, fibrosis, fracture callus, gingivitis, gout, graft vs. host reaction, gram negative sepsis, hereditary dysplasias, herniated disk, hyperoxia-induced inflammation, inflammatory pain, intervertebral disc disorders, intra-articular localized nodular synovitis, joint pain, lupus, multiple chondritis, osteoarthritis, osteochondroma, osteochondrosis dissecans, osteochondrosis, osteogensis imperfecta, osteoporosis, periodontitis, post surgical trauma, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, spondylitis deformans, spondylitis deformans, sprains, strains, synovial chondrosarcoma, synovial sarcoma, syphilitic arthritis, tuberculosis arthritis, systemic lupus erythematosus, sports injuries, intervertebral disc disorders, multiple chondritis, and wear and tear associated with aging process. Because the metalloprotease inhibiting compounds of the present invention exhibit prolonged durability, they can be used more preferred for intra-articular (IA) treatment of osteoarthritis, rheumatoid arthritis, sports injuries, intervertebral disc disorders, and multiple chondritis.

In particular, the metalloprotease inhibiting compounds of the present invention may be used intraraticularly for prevention, slowing or reversing MMP- 13-mediated tissue destruction and disease progression of osteoarthritis, and may also be used for treating MMP- 13 mediated symptoms, including inflammation, pain and malignancy resulting from excessive extracellular matrix degradation and/or remodelling.

The present invention also provides metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease - especially MMP- 13 - mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for IA or other parenteral administration, comprising one or more of the metalloprotease inhibiting compounds disclosed herein. The present invention further provides methods of inhibiting metalloproteases, by administering formulations via an intra-articular route for prophylactic or therapeutic treatment of diseases. Although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compounds from this invention may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

The metalloprotease inhibiting compounds, especially the metalloprotease inhibiting compounds of the invention can be tested intra-articularly in a rat model of medial meniscal tear that has been accepted as a model of human osteoarthritis (J Musculoskel. Neuron. Interact. 2001, 1, 363-376; Osteoarthritis Cartilage 2002, 10, 785-491). The model is performed by transection of the medial collateral ligament and cutting of the medial meniscus at its narrowest point. The model is of relatively short duration and animals are very consistent in their response to the surgery. This model has been routinely used to evaluate MMP inhibitors (Osteoarthritis Cartilage 2002, 10, 785-491). Intra-articular evaluation of the metalloprotease inhibiting compounds can be done as follows: Male Lewis rats (20/group) with medial meniscal tear induced cartilage degeneration in the right knee joint are treated on day -1 or day 3 post surgery with vehicle or compound (0.5 mg) by a single intra-articular injection (50 μL). Three weeks after post-injection of the compound, the animals are sacrificed and the right operated knees from animals are collected for histopathology evaluation of chondroprotective effects.

The metalloprotease inhibiting compounds, especially the metalloprotease inhibiting compounds of the present invention may also be used in combination with a disease modifying antirheumatic drug (such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like), a nonsteroidal anti-inflammatory drug (such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like), a COX-2 selective inhibitor (such as, for example, rofecoxib, celecoxib, valdecoxib and the like), a COX-I inhibitor (such as, for example, piroxicam, tenoxicam and the like), an immunosuppressive (such as, for example, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin, sulfasalazine, azathioprine and the like), a steroid (such as, for example, betamethasone, cortisone, prednisone, dexamethasone, fluticasone, mometasone, prednisolone, methylprednisolone, triamcinolone, budesonide, beclomethasone and the like), a biological response modifier (such as, for example, inflixmab, adalimumab, entanercept, ankinra and the like), a viscosupplement (such as, for example, hyaluronates and the like), a pain reducing drug (such as, for example, acetaminophen, aspirin, salicylic acid, codeine, oxymorphone, fentanyl, oxycodone, lidocaine and the like) or other anti-inflammatory agents or therapeutics useful for the treatment of chemokines mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a method of treating a metalloprotease mediated disease in a subject in need thereof, comprising the step of intra-articular joint administration of an effective amount of at least one metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability.

Another aspect of the invention relates to a metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability for use in a method for intra-articular joint treatment of a metalloprotease mediated disease in a subject in need thereof.

Another aspect of the invention relates to a pharmaceutical composition comprising at least one metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability; and a pharmaceutically acceptable carrier.

In one embodiment in conjunction with any above or below embodiments, the pharmaceutical composition additionally comprises a co-therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal antiinflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; (h) a small molecule inhibitor of pro-inflammatory cytokine production; (i) a viscosupplement; and (j) a pain reducing drug.

In another embodiment in conjunction with any above or below embodiments, the co-therapeutic is selected from: (a) a steroid; and (b) a viscosupplement.

In another embodiment in conjunction with any above or below embodiments, the metalloprotease modulating compound has the structure:

wherein:

R¹ in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl, wherein R¹ is optionally substituted one or more times, or wherein R¹ is optionally substituted by one R¹⁶ group and optionally substituted by one or more R⁹ groups; or wherein optionally two hydrogen atoms on the same atom of one or more R¹ groups are replaced with =0;

R² in each occurrence is independently selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times;

R³ Is NR²⁰R²¹;

R⁴ in each occurrence is independently selected from R¹ , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF₃, (C₀-C₆)-alkyl- COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (Co-QO-alkyl-NR'V ', (C₀-C₆)-alkyl-NO₂, (C₀-C₆)- alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (Co-C₆)-alkyl-S(0)_yNR¹⁰R^π, (C₀-C₆)-alkyl- NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- 3^yI-OC(O)NR¹⁰R¹ \ (C₀-C₆)-alkyl-C(=NR¹⁰)NR¹⁰R¹ ', (C₀-C₆)-alkyl- NR¹⁰C(=NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(0)OR¹⁰, (Co-C₆)-alkyl-C(0)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹ *, (C₀-C₆)-alkyl-C(O)-NR¹ '-CN, O-(C₀-C₆)-alkyl- C(O)NR¹⁰R¹ \ S(0)_x-(Co-C₆)-alkyl-C(0)OR¹⁰, S(O)_x-(C₀-C₆)-alkyl-C(O)NR¹⁰R¹ ', (Co-C₆)-alkyl-C(0)NR¹⁰-(Co-C₆)-alkyl-NR¹⁰R", (Co-C₆)-alkyl-NR¹⁰-C(0)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)-NR¹⁰R¹ ', (C₀-C₆)-alkyl- NR¹⁰-S(O)_yNR¹⁰R", (C₀-C₆)-alkyl-NR¹⁰-S(O)_yR¹⁰, O-(C₀-C₆)-alkyl-aryl and O- (C₀-C₆)-alkyl-heteroaryl, wherein each R group is optionally substituted one or more times, or wherein each R⁴ group is optionally substituted by one or more R¹⁴ groups; R⁵ in each occurrence is independently selected from hydrogen, alkyl, C(O)NR¹⁰R¹¹, aryl, arylalkyl, SO₂NR¹⁰R¹¹ and C(O)OR¹⁰, wherein alkyl, aryl and arylalkyl are optionally substituted one or more times; R⁹ in each occurrence is independently selected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF₂, CF₃, OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)- alkyl-NR¹⁰R^π, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-P(0)₂OH, (Co-C₆)-alkyl-S(0)_yNR¹⁰R¹¹, (Co-C₆)-alkyl- NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- alkyl-OC^NR'V ', (C₀-C₆)-alkyl-C(=NR¹⁰)NR¹⁰R¹ ', (C₀-C₆)-alkyl- NR¹⁰C(=NR¹ ^NR¹⁰R¹ ', (C₀-C₆)-alkyl-NR^I0C(=N-CN)NR¹⁰R^I ', (C₀-C₆)-alkyl- C(=N-CN)NR¹⁰R^π, (Co-C₆)-alkyl-NR¹⁰C(=N-N0₂)NR¹⁰R¹¹, (Co-C₆)-alkyl-C(=N- NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (Co-C₆)-alkyl-C(0)NR^IOR^π, (C₀-C₆)- alkyl-C(O)NR¹⁰SO₂R^π, C(O)NR¹⁰-(C₀-C₆)-alkyl-heteroaryl, C(O)NR¹ °-(C₀-C₆)- alkyl-aryl, S(O)₂NR¹ °-(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰-(C₀-C₆)-alkyl-heteroaryl, S(O)₂NR¹⁰-alkyl, S(O)₂-(C₀-C₆)-alkyl-aryl, S(O)₂-(C₀-C₆)-alkyl-heteroaryl, (C₀- C₆)-alkyl-C(O)-NR¹ '-CN, O-(C₀-C₆)-alkyl-C(O)NR¹⁰R¹ ', S(O)_x-(C₀-C₆)-alkyl- C(O)OR¹⁰, S(0)_x-(Co-C₆)-alkyl-C(0)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(0)NR¹⁰-(Co-C₆)- alkyl-NR¹⁰R^π, (C₀-C₆)-alkyl-NR¹⁰-C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (C₀- C₆)-alkyl-NR¹⁰-C(O)-NR¹⁰R¹ \ (C₀-C₆)-alkyl-NR¹⁰-S(O)_yNR¹⁰R¹ \ (C₀-C₆)-alkyl- NR^l0-S(O)_yR^π, O-(C₀-C₆)-alkyl-aryl and O-(C₀-C₆)-alkyl-heteroaryl, wherein each R⁹ group is optionally substituted, or wherein each R⁹ group is optionally substituted by one or more R¹⁴ groups; R¹⁰ and R¹¹ in each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R¹⁰ and R¹ ' when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times;

R¹⁴ is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times; R¹⁶ is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ϋ):

(i) (ϋ) wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times; R²⁰ is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times;

R²¹ is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and wherein R²¹ is optionally substituted one or more times, or wherein R²¹ is optionally substituted by one or more R⁹ groups;

R²² is selected from hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO₂, NR¹⁰R¹¹, CN, SR¹⁰, SSR¹⁰, PO₃R¹⁰, NR¹⁰NR¹⁰R¹¹,

NR¹⁰N=CR¹⁰R¹¹, NR¹⁰SO₂R¹¹, C(O)OR¹⁰, C(O)NR¹⁰R¹¹, SO₂R¹⁰ , SO₂NR¹⁰R¹¹ and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times;

R³⁰ is selected from alkyl and (C₀-C₆)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;

R⁵⁰ in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰ and SO₂NR⁸⁰R⁸¹ , wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;

R⁸⁰ and R⁸¹ in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R⁸⁰ and R⁸¹ when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)_x, -NH, and -N(alkyl) and which is optionally substituted one or more times;

E is selected from a bond, CR¹⁰R¹¹, O, NR⁵, S, S=O, SC=O)₂, CC=O),

N(R¹⁰XC=O), (C=O)N(R¹⁰), N(R¹⁰)S(=O)₂, S(=O)₂N(R¹⁰), C=N-OR¹¹,

-C(R¹⁰R¹^C(R¹⁰R^{1 1})-, -CH₂-W¹- and

Q is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴;

D is a member selected from CR²² and N; U is selected from C(R⁵R¹⁰), NR⁵, O, S, S=O and S(=O)₂;

W is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴;

W¹ is selected from O, NR⁵, S, S=O, S(=O)₂, N(R¹⁰)(C=O), N(R¹⁰)S(=O)₂ and

S(=O)₂N(R¹⁰); X is selected from a bond and (CR¹⁰R¹¹^E(CR¹⁰R¹ ')_w; g and h are independently selected from 0-2; w is independently selected from 0-4; x is selected from 0 to 2; y is selected from 1 and 2; wherein optionally two hydrogen atoms on the same carbon atom are replaced with =O, =S or =NR¹⁰; and

N-oxides and pharmaceutically acceptable salts thereof.

In another embodiment in conjunction with any above or below embodiments, the metalloprotease modulating compound is selected from:

L² is CH or CF; M² is CH or CF; T² is CH or CF; and R²⁵ and R¹⁹ are both H; and N-oxides and pharmaceutically acceptable salts thereof.

In another embodiment in conjunction with any above or below embodiments, the metalloprotease modulating compound is selected from:

N-oxides and pharmaceutically acceptable salts thereof.

In another embodiment in conjunction with any above or below embodiments, R³ is selected from:

and wherein

N- NH

R⁹ is selected from hydrogen, fluoro, halo, CN, alkyl, CO₂H, ^X K V^

In another embodiment in conjunction with any above or below embodiments, the metalloprotease modulating compound is selected from:

acceptable salts thereof.

In another embodiment in conjunction with any above or below embodiments, the joint is selected from the temporomandibular, atlanto-axial, shoulder, clavicular, thoracic spine, lumbosacral spine, rib cage, hip, knee, feet, thumb, back, ankle, toe, elbow, hand and finger joints. In another embodiment in conjunction with any above or below embodiments, the disease is selected from rheumatoid arthritis, osteoarthritis, sports injuries, intervertebral disc disorders, and multiple chondritis.

In another embodiment in conjunction with any above or below embodiments, the joint is selected from the temporomandibular, atlanto-axial, shoulder, clavicular, thoracic spine, lumbosacral spine, rib cage, hip, knee, feet, thumb, back, ankle, toe, elbow, hand and finger joints.

In another embodiment in conjunction with any above or below embodiments, the disease is selected from rheumatoid arthritis, osteoarthritis, sports injuries, intervertebral disc disorders, and multiple chondritis. The term "durable" as used herein alone or as part of another group refers to a substance or substances having a measured presence and biological activity as a function of time. For example when refereeing to the disease osteoarthritis, the measure of a compound's presence can be obtained directly via mass spectrometry of synovial fluid within the joint cavity using an internal standard as reference. Conversely the measure may be obtained indirectly via an enzymatic inhibition assay of one or more proteins within the joint. The biological activity of the durable substance may be obtained via the inhibition or activation of one or more biomarkers associated with the joint. Although not required to satisfy the definition of the term "durable", it would be most preferred if the durable substance produced a disease modifying effect. The term "intra-articular administration" or "IA administration" as used herein refers to the deposit of a the metalloprotease inhibiting compounds alone or in combination with a pharmaceutically acceptable carrier and/or a co-therapeutic into the joint by injection, surgery or other routes, including, but not limited to, topical, parenteral, intramuscular, or periarticular routes. The terms "alkyl" or "alk", as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (— COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂-CO-), substituted carbamoyl (R¹⁰XR¹ ')N-CO- wherein R¹⁰ or R¹¹ are as defined below, except that at least one of R¹⁰ or R¹¹ is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (-SH).

The terms "lower alk" or "lower alkyl" as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain. The term "alkoxy" denotes an alkyl group as described above bonded through an oxygen linkage (~O— ).

The term "alkenyl", as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (— COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂ -CO-), substituted carbamoyl (R¹⁰)(R^π)N-CO~ wherein R¹⁰ or R¹¹ are as defined below, except that at least one of R¹⁰ or R¹¹ is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (--SH). The term "alkynyl", as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂-CO-), substituted carbamoyl ((R¹⁰)(R^U)N~CO- wherein R¹⁰ or R¹ ' are as defined below, except that at least one of R¹⁰ or R¹ ' is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (--SH).

The term "cycloalkyl", as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, containing one ring with 3 to 9 carbons. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The term "bicycloalkyl", as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic bridged hydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents. The term "spiroalkyl", as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom. Exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The term "spiroheteroalkyl", as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. Exemplary unsubstituted such groups include, but are not limited to, 1,3-diaza- spiro[4.5]decane-2,4-dione. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The terms "ar" or "aryl", as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents. The term "heterocycle" or "heterocyclic system" denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. 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. Examples of heterocycles include, but are not limited to, lH-indazole, 2- pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2-dithiazinyl, dihydrofuro[2,3-&]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, moφholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,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.

Further examples of heterocycles include, but not are not limited to, "heterobicycloalkyl" groups such as 7-oxa-bicyclo[2.2.1]heptane, 7-aza- bicyclo[2.2.1]heptane, and l-aza-bicyclo[2.2.2]octane.

"Heterocyclenyl" denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. "Heterocyclenyl" as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, 82, 5566, the contents all of which are incorporated by reference herein. Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1 ,2,3,4- tetrahydrohydropyridine,

1 ,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6- tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. "Heterocyclyl," or "heterocycloalkyl," denotes a non-aromatic saturated monocyclic or multi cyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

"Heterocyclyl" as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in , particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, 82, 5566. Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

"Heteroaryl" denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The "heteroaryl" may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J Am. Chem. Soc. 1960, 82, 5566. Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, , oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4- thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-l,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.

The phrase "fused" means that the group, mentioned before "fused" is connected via two adjacent atoms to the ring system mentioned after "fused" to form a bicyclic system. For example, "heterocycloalkyl fused aryl" includes, but is not limited to, 2,3-dihydro-benzo[l,4]dioxine, 4H-benzo[l,4]oxazin-3-one, 3H- Benzooxazol-2-one and 3,4-dihydro-2H-benzo[/)[l,4]oxazepin-5-one.

The term "amino" denotes the radical -NH₂ wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert- butylamino, methylpropylamino and ethyldimethylamino.

The term "cycloalkylalkyl" denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.

The term "arylalkyl" denotes an aryl group as described above bonded through an alkyl, as defined above. The term "heteroarylalkyl" denotes a heteroaryl group as described above bonded through an alkyl, as defined above.

The term "heterocyclylalkyl," or "heterocycloalkylalkyl," denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.

The terms "halogen", "halo", or "hal", as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.

The term "haloalkyl" denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.

The term "aminoalkyl" denotes an amino group as defined above bonded through an alkyl, as defined above. The phrase "bicyclic fused ring system wherein at least one ring is partially saturated" denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.

The phrase "tricyclic fused ring system wherein at least one ring is partially saturated" denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,1 l-dihydro-5H- dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-lH-cyclobuta[a]indene.

The term "pharmaceutically acceptable salts" refers 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; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, piperazine, choline, lysine, arginine or N-methyl-glucamine salts, and the like.

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, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, 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, isethionic, and the like.

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. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" denotes 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.

The phrase "pharmaceutically acceptable carrier" denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Non-limiting examples of a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, lipid emulsions, liposomes (see e.g. Am. J. Drug Deliv. 2004, 2, 213-227; Drugs Pharmaceut. ScL 2006, 158, 317; Adv. Drug Deliv. Rev. 2006, 58, 226; the contents of which are incorporated herein by reference), and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)). Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.

Some of these "pharmaceutically acceptable carrier" can be used as extended-release formulation that releases the intra-articular administered drug slowly over time. The advantages of extended-release formulations are that they can often be taken less frequently and that they keep steadier levels of the drug e.g. in the cartilage or joint. Non-limiting example for extended-release formulation are above mentioned microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)).

Pharmaceutically acceptable carriers particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

The compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients. Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g. , lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or «-propyl/»-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.

The term "formulation" denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.

The term "N-oxide" denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3- chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about -10 to 80°C, desirably about 0°C.

The term "polymorph" denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations. The term "tautomer" denotes to an organic compound that is interconvertible by a chmical reaction called tautomerization (Smith, M. B.; March, J. Advanced Organic Chemistry, 5^th ed., Wiley Interscience, New York, 2001). As most commonly encountered, this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond (e.g. enol-ketone tautomerism). In solution where tautomerization is possible, a chemical equilibrium of the tautomers will be reached, wherein the ratio depends of several factors, e.g. temperature, pH and solvent.

The term "hydrate" denotes to a compound, wherein the hydrate is formed by the addition of water to a host molecule for example in the crystalline arrangement. The term "solvate" denotes to a compound, wherein a solvent (e.g. ethanol) is added to the host molecule.

Tautomers are organic compounds that are interconvertible by a chemical reaction called tautomerization. As most commonly encountered, this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. Tautomerism is a special case of structural isomerism and can play an important role in non-canonical base pairing in DNA and especially RNA molecules.

The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.

The term "racemic mixture" denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically- pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) through (VI).

Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods. Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography "HPLC" and the formation and crystallization of chiral salts. See, e.g., Jacques, J., et al.,

Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 1977, 33, 2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972); Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N. Y.). Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. "Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0) group, then 2 hydrogens on the atom are replaced. Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from: C₁-C₄ alkyl;

C₂-C₄ alkenyl;

C₂-C₄ alkynyl;

CF₃; halo; OH;

0-(Ci-C₄ alkyl);

OCH₂F;

OCHF₂;

OCF₃; ONO₂;

OC(O)-(Ci-C₄ alkyl); OC(O)-(C₁-C₄ alkyl);

OC(O)NH-(C₁-C₄ alkyl);

OC(O)N(C₁-C₄ alkyl)₂;

OC(S)NH-(C₁-C₄ alkyl); OC(S)N(C₁-C₄ alkyl)₂;

SH;

S-(C₁-C₄ alkyl);

S(O)-(C-C₄ alkyl);

S(O)₂-(C₁-C₄ alkyl); SC(O)-(Ci-C₄ alkyl);

SC(O)O-(Ci-C₄ alkyl);

NH₂;

N(H)-(Ci-C₄ alkyl);

N(C₁-C₄ alkyl)₂; N(H)C(O)-(C-C₄ alkyl);

N(CH₃)C(O)-(Ci-C₄ alkyl);

N(H)C(O)-CF₃;

N(CH₃)C(O)-CF₃;

N(H)C(S)-(Ci-C₄ alkyl); N(CH₃)C(S)-(C-C₄ alkyl);

N(H)S(O)₂-(C₁-C₄ alkyl);

N(H)C(O)NH₂;

N(H)C(O)NH-(C-C₄ alkyl);

N(CH₃)C(O)NH-(C-C₄ alkyl); N(H)C(O)N(C-C₄ alkyl)₂;

N(CH₃)C(O)N(C₁-C₄ alkyl)₂;

N(H)S(O)₂NH₂);

N(H)S(O)₂NH-(C-C₄ alkyl);

N(CH₃)S(O)₂NH-(C-C₄ alkyl); N(H)S(O)₂N(C-C₄ alkyl)₂;

N(CH₃)S(O)₂N(C₁-C₄ alkyl)₂; N(H)C(O)O-(C₁-C₄ alkyl);

N(CH₃)C(O)O-(C-C₄ alkyl);

N(H)S(O)₂O-(C₁-C₄ alkyl);

N(CH₃)S(O)₂O-(Ci-C₄ alkyl); N(CH₃)C(S)NH-(C₁-C₄ alkyl);

N(CH₃)C(S)N(C₁-C₄ alkyl)₂;

N(CH₃)C(S)O-(C₁-C₄ alkyl);

N(H)C(S)NH₂;

NO₂; CO₂H;

CO₂-(C₁-C₄ alkyl);

C(O)N(H)OH;

C(O)N(CH₃)OH:

C(O)N(CH₃)OH; C(O)N(CH₃)O-(C₁-C₄ alkyl);

C(O)N(H)-(C₁-C₄ alkyl);

C(O)N(C₁-C₄ alkyl)₂;

C(S)N(H)-(C₁-C₄ alkyl);

C(S)N(C₁-C₄ alkyl)₂; C(NH)N(H)-(C₁-C₄ alkyl);

C(NH)N(C₁-C₄ alkyl)₂;

C(NCH₃)N(H)-(C₁-C₄ alkyl);

C(NCH₃)N(C₁-C₄ alkyl)₂;

C(O)-(C₁-C₄ alkyl); C(NH)-(C₁-C₄ alkyl);

C(NCH₃HC₁-C₄ alkyl);

C(NOH)-(C₁-C₄ alkyl);

C(NOCHs)-(C₁-C₄ alkyl);

CN; CHO;

CH₂OH; CH₂O-(C₁-C₄ alkyl);

CH₂NH₂;

CH₂N(H)-(C₁-C₄ alkyl);

CH₂N(C₁-C₄ alkyl)₂; aryl; heteroaryl; cycloalkyl; and heterocyclyl.

In some cases, a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring. The number of such substituents present on a ring is indicated in subscript by a number. Moreover, the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace. For illustrative purposes, if variable R were defined as being:

this would indicate a cyclohexyl ring bearing five R^x substituents. The R^x substituents may be bonded to any available ring atom. For example, among the configurations encompassed by this are configurations such as:

, and

These configurations are illustrative and are not meant to limit the scope of the invention in any way.

Biological Activity The metalloprotease inhibiting compounds of the invention are tested in an

"Acute Model of Cartilage Degradation" that is assayed 24 hours or 7 days after a single intra-articular (IA) injection containing 0.25 or 0.5 mg of the compound. Table 1 lists typical examples of metalloprotease inhibiting compounds of the invention after IA injection of 0.25 or 0.5 mg compound and the inhibition activity of MMP- 13 as measured ex vivo.

TABLE 1 Summary of MMP-13 Inhibition 24 Hours after IA injection

Table 2 lists typical examples of metalloprotease inhibiting compounds of the invention with the % inhibition of MMP- 13 activity 7 days after IA injection of 0.5 mg compound. TABLE 2 Summary of MMP-13 Inhibition 7 Days after IA injection

Example 1 Assay for Determining Inhibition of Collagen Degradation in Bovine

Cartilage Explants

The loss of aggrecan and type II collagen due to enhanced activity of aggrecanases and collagenases are the principle features of articular cartilage degradation in osteoarthritis and rheumatoid arthritis. Pro-inflammatory cytokines up-regulate expression and activation of many matrix metalloproteases (MMPs) and aggrecanases. IL- lα in combination with oncostatin M (OSM) induce aggrecan and collagen degradation. Inhibitors of cartilage degradation process were tested for efficacy to reduce the release of collagen fragments from the cartilage. Bovine articular cartilage was freshly isolated from the first phalanges of adult cows direct after slaughter. The cartilage was cut into ~3 mm pieces and transferred into a 48 well plate (30 mg/well). The cartilage was pre-cultured in DMEM medium (Invitrogen; Cat. No 42430) supplemented with insulin, transferring, sodium selenite (ITS, Roche Diagnostics; No 10745447) and ascorbic acid (Sigma Aldrich Chemie, No A4403) for 2 days at 37°C and 5% CO₂. The explants were cultured without (control) and in presence of 5 ng/ml IL- lα (Tebu-bio; No 200-0 IA) and 50 ng/ml OSM (Tebu-bio; No 300- 10B) and varying inhibitor concentrations for 11 days. The conditioned medium was collected every 3-4 days and replaced with fresh medium supplemented with IL- lα/OSM and inhibitors. The conditioned medium was stored at -20°C until assayed. Collagen degradation products were measured in the supernatant of the 11 days cultured explants using specific ELISA-kit (C1,2C; Ibex) according to the protocol of the supplier. Control broad spectrum MMP inhibitors Ilomastat (GM6001) and Trocade showed inhibition of collagen degradation with an IC₅₀ value <50 nM and <500 nM respectively.

Example 2 Acute Model of Cartilage Degradation The "Acute Model of Cartilage Degradation" is carried out by an intraarticular injection of the compound into the right knee joint of a rat and after an appropriate time the animal is sacrificed and the cartilage is harvested and assayed ex vivo for C1,2C epitope release in response to an MMP- 13 challenge.

A suspension of the inhibitor (5 mg/mL or 10 mg/mL) is obtained by mixing the compound in phosphate buffered saline and placed in a sonicating water bath for 30-60 minutes and then vortexing immediately before intraarticular injection.

Sprague-Dawley (Harlan, Indianapolis, Indiana) rats weighing 175 g to 200 g are anesthetized in an inhalation chamber using isoflurane. The rats are then removed from the chamber and the hair surrounding the injection site are clipped and cleaned with 70% ethanol. The skin over the injection site are disinfected again with 70% ethanol and then with Betadine solution. Rats in two vehicle groups receive a single intra-articular injection of 50 μL phosphate buffered saline into their right knee joint. Rats in the inhibitor groups receive a single intra-articular injection of 0.25 mg or 0.5 mg compound suspended in

50 μL phosphate buffered saline into their right knee joint. Each group contains 3 animals. 24 hours or 7 days after the intra-articular injection the animals are sacrificed via CO₂ asphyxiation and then the cartilage from the tibia of the right joints is collected by shaving it from the bone with a scalpel.

A solution of recombinant human Matrix Metalloprotease 13 (MMP-13) (Invitek, Germany) is made from a stock of 200 μg/mL MMP- 13 in 50 mM Tris- HCl, pH 7.5, 150 mM NaCl, 5 mM CaCl₂, 0.05% Brij-35 with 1 mM 4- aminophenylmercuric acetate (1 mM APMA) (Sigma) to activate the MMP-13. A 10 μg/mL solution of MMP- 13 is made by adding 25 μL of MMP- 13 stock to 475 μL of 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM CaCl₂. 25 μL of the 10 μg/mL MMP- 13 solution is added to each tube with the shaved cartilage and incubated for 24 hours at 37°C. Samples from one vehicle group (Veh 100%) are an exception as they are incubated for 24 hours at 37°C in 25 μL 50 mM Tris- HCl, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ without MMP-13. 75 μL of 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ is added to each tube after the incubation. The supernatant is then transferred to a new tube with 2 μL of

500 mM ethylenediaminetetraacetic acid to a final concentration of 10 mM. The supernatant is then stored at -40° C for further analysis.

Cartilage degradation during the MMP- 13 ex vivo challenge is assessed by C1,2C release into the supernatant. The supernatant is assayed for C1,2C by ELISA (Ibex, Canada) in 50 μL duplicates that have been diluted 1 :2 with 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ (100 μL supernatant and 100 μL buffer). The ELISA is analyzed with the use of a BioTek Synergy HT microplate reader and KC4 software.

One vehicle group (Veh 100%) contains no MMP- 13 in the incubation step and the Cl ,2C average for the group is used as the value for 100% inhibition of MMP-13. The other vehicle group (Veh 0%) contains no inhibitors and the C1,2C average for the group is used as the value for 0% inhibition. The % inhibition value for each sample is calculated with the following formula:

[1 - (C 1 ,2Csample ^~ C 1 ,2Cγeh 100%, Ave) / (C 1 ,2Cγeh 0%, Ave ~ C 1 ,2Cveh 100%, Ave)] * 100% Example 3 Coinjection of a Heterobicyclic Metalloprotease Inhibitor with

SYNVISC^®

The study consisted of eight groups, each with three male Sprague-Dawley rats weighing 175 to 200 g. The right knee joint of rats in Groups 1, 3, 5, and 7 was injected intra-articularly with 0.5 mg compound suspended in 50 μL of phosphate buffered saline (PBS). The right knee joint of rats in Groups 2, 4, 6, and 8 was injected intra-articularly with 0.5 mg compound suspended in 50 μL of Synvisc^®. Animals were sacrificed 1 day (Groups 1 and 2), 7 days (Groups 3 and 4), 14 days (Groups 5 and 6), and 21 days (Groups 7 and 8) after the intra-articular injections. The cartilage, synovial fluid lavage, and plasma were collected at each time-point to determine compound concentration.

Tibia from both knee joints was collected from each animal at sacrifice. The cartilage from tibial articular surface was shaved using a scalpel and placed into a pre- weighed tube. The cartilage and tube were weighed and then stored at - 70 ± 10°C until analyzed.

Synovial fluid from both the injected knee joints and the contralateral knee joints was collected from all animals at sacrifice. Collection of fluid was done by injecting 50 μL of saline into the knee joint space. After waiting for 10 seconds, the fluid was then drawn out using the same syringe and needle used to inject saline. The sample was then centrifuged and the supernatant is collected into a new tube. The supernatant was stored at —70 ± 10°C until analyzed.

Terminal blood (400 to 500 μL) was collected from all study animals by cardiac puncture. The terminal blood collection was at the time of sacrifice for each group. All blood samples were collected into tubes containing dipotassium ethylenediaminetetraacetic acid (K₂ EDTA) as the anticoagulant. For each sample, the tubes were inverted approximately 5 times immediately after blood was collected. Samples were placed on wet ice until processed into plasma. Once processed into plasma, samples were stored at -70 ± 10°C until analyzed. Cartilage samples were digested in a buffer before compound concentration was determined. Cartilage was placed in 100 μL of a papain digestion buffer and incubated for 3 hours in a water bath at 65 °C. This digestion buffer contained 6.9 mg/mL NaH₂PO₄, 74.4 mg/mL EDTA, 0.35 mg/ml cystein, and 3 LVmL papain (Roche Diagnostics) in water, pH 6.5.

A protein precipitation step was conducted with acetonitrile. Prepared 100 μL acetonitrile including the internal standard inhibitor (example 2450 of

WO2006/083454; 1 μM) in a 96-deepwell plate. Added 50 μL of papain digestion solution into 100 μL acetonitrile, shaken for 10 min at room temperature (450 rpm). Centrifuged samples at 3000g for 30 min at 10°C and carefully pipette the supernatant into a new plate for MS analysis. Calibration for MS analysis was done by preparing a standard solution of the title compound from example 419 in WO2006/128184 (5 concentrations starting from 1 μM, 1 :2 dilutions) in 50 μL cartilage digestion solution and precipitated the proteins with 100 μL CAN.

For HPLC-MS/MS analysis a Quattro Ultima mass spectrometer (Waters) coupled online to a 1100 binary pump with micro degasser (Agilent) and HTC

PAL auto sampler (PAL) with cool stack System was used.

Analysis was performed in the MRM mode after separation by HPLC using Atlantis dC18 2x 50 mm column (Waters). Eluents were H₂O + 0.01%

HCOOH and acetonirile + 0.1 5 HCOOH, Gradient elution was used. Injection volumn was 20 μL.

Iontransitions used: example 419 of WO2006/128184: m/z 574.3 Da -> 400.0 Da, 56 V, 11 eV example 2450 of WO2006/083454: m/z 554.8 Da -

Matrix for calibration of plasma and synovial fluid was done using plasma as matrix. For calibration of example 419 of WO2006/128184 was diluted to 2000 ng in 1 mL acetonitrile and diluted 10 times 1/2 using acetonitrile. To 50 μL of blank plasma 50 μL of the standards were added. After vortexing 10 μL internal standard and 90 μL acetonitrile were added and samples were shaken at room temperature for 15 min. Samples were centrifuged for 30 min at 3000g, 10°C. 50 μL of the supernatant were diluted 1/1 by H₂O and analysed by HPLC- MS/MS.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a metalloprotease mediated disease in a subject in need thereof, comprising the step of intra-articular joint administration of an effective amount of at least one metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability.

2. The method according to Claim 1, wherein the metalloprotease modulating compound has the structure:

Formula (I) Formula (II) Formula (III)

Formula (IV) Formula (V) Formula (VI) wherein:

R¹ in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl, wherein R¹ is optionally substituted one or more times, or wherein R¹ is optionally substituted by one R¹⁶ group and optionally substituted by one or more R⁹ groups; or wherein optionally two hydrogen atoms on the same atom of one or more R¹ groups are replaced with =0;

R² in each occurrence is independently selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times; R³ Js NR²⁰R²¹; R⁴ in each occurrence is independently selected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF₃, (C₀-C₆)-alkyl- COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)- alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R^π, (C₀-C₆)-alkyl- NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- alkyl-OC(O)NR¹⁰R^π, (C₀-C₆)-alkyl-C(=NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl-

NR¹⁰C(=NR¹¹)NR¹⁰R¹¹, (Co-C₆)-alkyl-C(0)OR¹⁰, (Co-C₆)-alkyl-C(0)NR¹⁰R^π, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹ \ (Co-C₆)-alkyl-C(0)-NR' '-CN, O-(C₀-C₆)-alkyl- C(O)NR¹⁰R¹¹, S(O)_x-(C₀-C₆)-alkyl-C(O)OR¹⁰, S(0)_x-(Co-C₆)-alkyl-C(0)NR¹⁰R^u, (Co-C^-alkyl-C^NR^-^o-C^-alkyl-NR^R¹¹, (C₀-C₆)-alkyl-NR¹⁰-C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (Co-C^-alkyl-NR¹ ^C(O)-NR¹⁰R¹ ', (C₀-C₆)-alkyl- NR¹^S(O)_xNR¹⁰R¹ ', (C₀-C₆)-alkyl-NR^I0-S(O)_yR¹⁰, O-(C₀-C₆)-alkyl-aryl and O- (Co-C₆)-alkyl-heteroaryl, wherein each R⁴ group is optionally substituted one or more times, or wherein each R⁴ group is optionally substituted by one or more R¹⁴ groups; R⁵ in each occurrence is independently selected from hydrogen, alkyl,

C(O)NR¹⁰R^{1 1}, aryl, arylalkyl, SO₂NR¹⁰R¹¹ and C(O)OR¹⁰, wherein alkyl, aryl and arylalkyl are optionally substituted one or more times; R⁹ in each occurrence is independently selected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF₂, CF₃, OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)- alkyl-NR¹⁰R^π, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-P(O)₂OH,

NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- ^yI-OC(O)NR¹⁰R¹ ', (C₀-C₆)-alkyl-C(=NR¹⁰)NR¹⁰R¹ ', (C₀-C₆)-alkyl- NR¹⁰C(=NR' ^NR¹⁰R¹ ', (Co-C^-alkyl-NR^C^N-C^NR^R¹ ', (C₀-C₆)-alkyl- Q=N-CN)NR¹⁰R¹ ', (Co-C₆)-alkyl-NR¹⁰C(=N-Nθ₂)NR¹⁰R¹ \ (C₀-C₆)-alkyl-C(=N- NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)- alkyl-C(O)NR¹⁰SO₂R¹¹, C(O)NR¹⁰-(C₀-C₆)-alkyl-heteroaryl, C(0)NR^IO-(Co-C₆)- alkyl-aryl, S(O)₂NR¹⁰-(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰-(C₀-C₆)-alkyl-heteroaryl, S(O)₂NR¹⁰-alkyl, S(O)₂-(C₀-C₆)-alkyl-aryl, S(O)₂-(C₀-C₆)-alkyl-heteroaryl, (C₀- C₆)-alkyl-C(O)-NR' '-CN, O-(C₀-C₆)-alkyl-C(O)NR¹⁰R¹ \ S(O)_x-(C₀-C₆)-alkyl- C(O)OR¹⁰, S(0)_x-(Co-C₆)-alkyl-C(0)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰-(C₀-C₆)- alkyl-NR¹⁰R^π, (Co-C^-alkyl-NR¹ ^C(O)R¹ °, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (C₀- C₆)-alkyl-NR¹⁰-C(O)-NR¹⁰R^u, (Co-C₆)-alkyl-NR¹⁰-S(0)_yNR¹⁰R¹¹, (Co-C₆)-alkyl- NR¹⁰-S(O)yR^π, O-(C₀-C₆)-alkyl-aryl and O-(C₀-C₆)-alkyl-heteroaryl, wherein each R⁹ group is optionally substituted, or wherein each R⁹ group is optionally substituted by one or more R¹⁴ groups; R¹⁰ and R¹¹ in each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R¹⁰ and R¹ ' when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times; R¹⁴ is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R¹⁶ is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):

(i) (ϋ) wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;

R²⁰ is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times;

R²¹ is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and wherein R²¹ is optionally substituted one or more times, or wherein R²¹ is optionally substituted by one or more R⁹ groups;

R²² is selected from hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO₂, NR¹⁰R^{1 1}, CN, SR¹⁰, SSR¹⁰, PO₃R¹⁰, NR¹⁰NR¹⁰R¹¹, NR¹⁰N=CR¹⁰R¹¹, NR¹⁰SO₂R¹¹, C(O)OR¹⁰, C(O)NR¹⁰R¹¹, SO₂R¹⁰ , SO₂NR¹⁰R¹¹ and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times; R³⁰ is selected from alkyl and (Co-C₆)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;

R⁵⁰ in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰ and SO₂NR⁸⁰R⁸¹, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times; R and R in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R⁸⁰ and R⁸¹ when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)_x, -NH, and -N(alkyl) and which is optionally substituted one or more times;

E is selected from a bond, CR¹⁰R¹¹, O, NR⁵, S, S=O, SC=O)₂, C(=0), N(R¹⁰XC=O), (C=O)N(R¹⁰), N(R¹⁰)S(=O)₂, S(^O)₂N(R¹⁰), C=N-OR¹ ', -C(R¹⁰R¹^C(R¹⁰R¹¹)-, -CH₂-W¹- and

Q is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴; D is a member selected from CR²² and N;

U is selected from C(R⁵R¹⁰), NR⁵, O, S, S=O and S(=0)₂;

W is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴; W¹ is selected from O, NR⁵, S, S=O, SC=O)₂, N(R¹⁰)(C=O), N(R¹⁰)S(=O)₂ and S(=O)₂N(R¹⁰);

X is selected from a bond and (CR¹⁰R¹¹^E(CR¹⁰R¹¹V; g and h are independently selected from 0-2; w is independently selected from 0-4; x is selected from O to 2; y is selected from 1 and 2; wherein optionally two hydrogen atoms on the same carbon atom are replaced with =0, =S or =NR¹⁰; and N-oxides and pharmaceutically acceptable salts thereof.

3. The method according to Claim 2, wherein the metalloprotease modulating compound is selected from:

L² is CH or CF;

M² is CH or CF; T² is CH or CF; and R²⁵ and R¹⁹ are both H; and N-oxides and pharmaceutically acceptable salts thereof.

4. The method according to Claim 3, wherein the metalloprotease modulating compound is selected from:

N-oxides and pharmaceutically acceptable salts thereof.

5. The method according to Claim 3, wherein R³ is selected from:

and wherein

N- NH

R⁹ is selected from hydrogen, fluoro, halo, CN, alkyl, CO₂H, * N'^N ,

6. The method according to Claim 1 , wherein the metalloprotease modulating compound is selected from:

, and pharmaceutically acceptable salts thereof.

7. The method according to Claim 1, wherein the joint is selected from the temporomandibular, atlanto-axial, shoulder, clavicular, thoracic spine, lumbosacral spine, rib cage, hip, knee, feet, thumb, back, ankle, toe, elbow, hand and finger joints.

8. The method according to Claim 1, wherein the disease is selected from rheumatoid arthritis, osteoarthritis, sports injuries, intervertebral disc disorders, and multiple chondritis.

9. The method according to Claim 5, wherein the joint is selected from the temporomandibular, atlanto-axial, shoulder, clavicular, thoracic spine, lumbosacral spine, rib cage, hip, knee, feet, thumb, back, ankle, toe, elbow, hand and finger joints.

10. The method according to Claim 5, wherein the disease is selected from rheumatoid arthritis, osteoarthritis, sports injuries, intervertebral disc disorders, and multiple chondritis.

11 A method according to Claim 1 , additionally comprising an effective amount of a co-therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; (h) a small molecule inhibitor of pro-inflammatory cytokine production; (i) a viscosupplement; and (j) a pain reducing drug.

12. The method according to Claim 11, wherein the co-therapeutic is selected from: (a) a steroid; and (b) a viscosupplement.

13. A metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability for use in a method for intraarticular joint treatment of a metalloprotease mediated disease in a subject in need thereof.

14. The compound according to Claim 13, wherein the metalloprotease modulating compound has the structure:

Formula (I) Formula (II) Formula

(III)

and

Formula (IV) Formula (V)

Formula (VI) wherein:

R¹ in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl, wherein R¹ is optionally substituted one or more times, or wherein R¹ is optionally substituted by one R¹⁶ group and optionally substituted by one or more R⁹ groups; or wherein optionally two hydrogen atoms on the same atom of one or more R¹ groups are replaced with =0;

R² in each occurrence is independently selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times;

R³ Js NR²⁰R²¹; R⁴ in each occurrence is independently selected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF₃, (C₀-C₆)-alkyl- COR¹⁰, (Co-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)- alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R", (C₀-C₆)-alkyl- NR¹⁰CONR^{1 1}SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- alkyl-OC(0)NR¹⁰R¹¹, (Co-C₆)-alkyl-C(=NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl- NR¹⁰C(=NR' ^NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (Co-C^-alkyl-C^NR^R¹¹, (Co-C₆)-alkyl-C(0)NR¹⁰S0₂R¹ ', (C₀-C₆)-alkyl-C(O)-NR¹ '-CN, O-(C₀-C₆)-alkyl- C(O)NR¹⁰R¹¹, S(0)_x-(Co-C₆)-alkyl-C(0)OR¹⁰, S(O)_x-(C₀-C₆)-alkyl-C(O)NR^I0R^π, (Co-C₆)-alkyl-C(0)NR¹⁰-(C₀-C₆)-alkyl-NR¹⁰R¹¹, (Co-C₆)-alkyl-NR¹⁰-C(0)R¹⁰, (Co-C₆)-alkyl-NR¹⁰-C(0)OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)-NR¹⁰R¹ \ (C₀-C₆)-alkyl- NR¹⁰-S(O)_yNR¹⁰Rⁿ, (Co-C₆)-alkyl-NR¹⁰-S(0)_yR¹⁰, O-(C₀-C₆)-alkyl-aryl and O- (Co-C₆)-alkyl-heteroaryl, wherein each R⁴ group is optionally substituted one or more times, or wherein each R⁴ group is optionally substituted by one or more R¹⁴ groups; R⁵ in each occurrence is independently selected from hydrogen, alkyl, C(O)NR¹⁰R", aryl, arylalkyl, SO₂NR¹⁰R¹¹ and C(O)OR¹⁰, wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;

R⁹ in each occurrence is independently selected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF₂, CF₃, OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)- alkyl-NR¹⁰R^π, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-P(O)₂OH, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R^u, (C₀-C₆)-alkyl-

NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)- alkyl-OC^NR'V ', (C₀-C₆)-alkyl-C(-NR^I0)NR¹⁰R", (C₀-C₆)-alkyl- NR¹⁰C(^NR¹ ^NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(=N-CN)NR¹⁰R¹ ', (C₀-C₆)-alkyl- C(=N-CN)NR¹⁰R¹ \ (C₀-C₆)-alkyl-NR¹⁰C(=N-NO₂)NR¹⁰R¹ ', (C₀-C₆)-alkyl-C(=N- NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰Rⁿ, (C₀-C₆)- alkyl-C(0)NR¹⁰S0₂R¹¹, C(0)NR^IO-(Co-C₆)-alkyl-heteroaryl, C(0)NR^IO-(Co-C₆)- alkyl-aryl, S(O)₂NR¹ °-(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰-(C₀-C₆)-alkyl-heteroaryl, S(O)₂NR¹⁰-alkyl, S(O)₂-(C₀-C₆)-alkyl-aryl, S(O)₂-(C₀-C₆)-alkyl-heteroaryl, (C₀- C₆)-alkyl-C(O)-NR' '-CN, 0-(Co-C₆)-alkyl-C(0)NR¹⁰R' ', S(O)_x-(C₀-C₆)-alkyl- C(O)OR¹⁰, S(0)_x-(Co-C₆)-alkyl-C(0)NR¹⁰R¹ ', (C₀-C₆)-alkyl-C(O)NR¹⁰-(C₀-C₆)- alkyl-NR¹⁰R^π, (C₀-C₆)-alkyl-NR¹⁰-C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (C₀-

(C₀-C₆)-alkyl- NR¹⁰-S(O)_yR", O-(C₀-C₆)-alkyl-aryl and O-(C₀-C₆)-alkyl-heteroaryl, wherein each R group is optionally substituted, or wherein each R⁹ group is optionally substituted by one or more R¹⁴ groups; R¹⁰ and R¹¹ in each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R¹⁰ and R¹ ' when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰ and which is optionally substituted one or more times;

R¹⁴ is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R¹⁶ is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):

(i) (ii) wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;

R²⁰ is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times; R²¹ is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and wherein R²¹ is optionally substituted one or more times, or wherein R²¹ is optionally substituted by one or more R⁹ groups;

R²² is selected from hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO₂, NR¹⁰R^{1 1}, CN, SR¹⁰, SSR¹⁰, PO₃R¹⁰, NR¹⁰NR¹⁰R¹¹, NR¹⁰N=CR¹⁰R¹¹, NR¹⁰SO₂R¹¹, C(O)OR¹⁰, C(O)NR¹⁰R¹¹, SO₂R¹⁰ , SO₂NR¹⁰R¹¹ and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times; R³⁰ is selected from alkyl and (Co-C₆)-alkyl-aryl, wherein alkyl and aryl are optionally substituted; R⁵⁰ in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰ and SO₂NR⁸⁰R⁸¹, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times; R⁸⁰ and R⁸¹ in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R⁸⁰ and R⁸¹ when taken together with the nitrogen to which they are attached complete a 3- to 8- membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)_x, -NH, and -N(alkyl) and which is optionally substituted one or more times;

E is selected from a bond, CR¹⁰R¹¹, O, NR⁵, S, S=O, S(=O)₂, C(=O), N(R¹⁰XC=O), (C=O)N(R¹⁰), N(R^I0)S(=O)₂, S(=O)₂N(R¹⁰), C=N-OR^{1 1}, -C(R¹⁰R¹^C(R¹⁰R¹¹)-, -CH₂-W¹- and

Q is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴;

D is a member selected from CR and N; U is selected from C(R⁵R¹⁰), NR⁵, O, S, S=O and SC=O)₂;

W is a 5- or 6-membered ring selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴;

W¹ is selected from O, NR⁵, S, S=O, SC=O)₂, N(R¹⁰)(C=O), N(R¹⁰)S(=O)₂ and

S(=O)₂N(R¹⁰); X is selected from a bond and (CR¹⁰R¹¹VE(CR¹⁰R¹¹^; g and h are independently selected from 0-2; w is independently selected from 0-4; x is selected from O to 2; y is selected from 1 and 2; wherein optionally two hydrogen atoms on the same carbon atom are replaced with =0, =S or =NR¹⁰; and

N-oxides and pharmaceutically acceptable salts thereof.

15. The compound according to Claim 14, wherein the metalloprotease modulating compound is selected from:

acceptable salts thereof.

16. A pharmaceutical composition comprising at least one metalloprotease modulating compound, or a pharmaceutically acceptable salt thereof, that demonstrates durability; and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to Claim 16, additionally comprising a co-therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; (h) a small molecule inhibitor of pro-inflammatory cytokine production; (i) a viscosupplement; and (j) a pain reducing drug.

18. The pharmaceutical composition according to Claim 17, wherein the co- therapeutic is selected from: (a) a steroid; and (b) a viscosupplement.

19. A pharmaceutical composition comprising a compound according to Claim 14; and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to Claim 19, additionally comprising a co-therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; (h) a small molecule inhibitor of pro-inflammatory cytokine production; (i) a viscosupplement; and (j) a pain reducing drug.

21. The pharmaceutical composition according to Claim 20, wherein the co- therapeutic is selected from: (a) a steroid; and (b) a viscosupplement.